US 2013 0096.050A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2013/0096050 A1 Shandler (43) Pub. Date: Apr. 18, 2013

(54) HIGHILY ACTIVE POLYPEPTDES AND Publication Classification METHODS OF MAKING AND USING THE SAME (51) Int. Cl. A638/22 (2006.01) (75) Inventor: Scott J Shandler, Philadelphia, PA (US) (52) U.S. Cl. CPC ...... A61 K38/2278 (2013.01) (73) Assignee: Longevity Biotech, Inc., Philadelphia, USPC ...... 514/1.7:435/7.21: 435/6.13: 530/309; PA (US) 436/501: 514/13.1; 530/303: 514/6.9; 514/7.3; 51475.3 (21) Appl. No.: 13/642,757 (22) PCT Fled: Apr. 22, 2011 (57) ABSTRACT (86) PCT NO.: PCT/US11A33684 This invention relates to novel compositions comprising ana logs of naturally occurring polypeptides, wherein the analog S371 (c)(1), comprises an a-amino acid and at least one B-amino acid. (2), (4) Date: Jan. 2, 2013 Administration of the compositions may be used for effecting treatment or prevention of a plurality of disease states caused Related U.S. Application Data by dysfunctional biochemical or biological pathways. The (60) Provisional application No. 61/327,098, filed on Apr. compositions and methods of this invention are particularly 22, 2010, provisional application No. 61/364,359, useful to identify novel therapeutic modulators of in-vivo filed on Jul. 14, 2010, provisional application No. receptor activity with extended half-lives and relevant bioac 61/405,560, filed on Oct. 21, 2010, provisional appli tivity as compared to the naturally translated polypeptides cation No. 61/445,468, filed on Feb. 22, 2011. upon which the analogs are derived. Patent Application Publication Apr. 18, 2013 Sheet 1 of 4 US 2013/0096.050 A1

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HIGHILY ACTIVE POLYPEPTDES AND 0005 HDL cholesterol level is inversely related to the METHODS OF MAKING AND USING THE incidence of coronary heart disease and recently received SAME increasing attention as a novel target in lipid management of treating atherosclerotic vascular disease. Direct vascular pro CROSS-REFERENCE TO RELATED tective effects of HDL have been attributed to apolipoprotein APPLICATIONS (apo) A-I or apoA-I-associated molecules in HDL using direct intravenous injections of homologous HDL.3 recom 0001. This application claims priority to U.S. Provisional binant mutantapoA-Imilano or apoA-I gene therapy, or use of Ser. No. 61/327,098, filed on Apr. 22, 2010; U.S. Provisional transgenic animals overexpressing apoA-I or apoA1-related Ser. No. 61/364,359, filed on Jul. 14, 2010; U.S. Provisional molecules Such as paraoXonase. A recent phase II randomized Ser. No. 61/405,560, filed on Oct. 21, 2010; and U.S. Provi trial showed that 5 weekly intravenous injections of recom sional Ser. No. 61/445,468, filed on Feb. 22, 2011, all of binant apoA-Imilano induced rapid regression of coronary which are herein incorporated by reference in their entirety. atherosclerotic lesions in humans. It is desirable to identify polypeptides that mimic the function of apoA-I Such as FIELD OF THE INVENTION paraoxonase, but have increased half-life and equivalent or more bioactivity than the naturally occurring paraoXonase 0002 The invention relates generally to compositions amino acid sequence. It is also desirable to identify another comprising modified polypeptide sequences with greater peptidomimetic of apoA-I to have association to a natural resistance to degradation and equivalent and/or increased ligand for apoA-I as compared to wild-type sequences. bioactivity as compared to naturally encoded, unmodified polypeptide sequences, and to methods of making the com 0006 Cytokines mediate cellular activities in a number of positions and methods of using the compositions as pharma ways. Cytokines Support the proliferation, growth, and dif ferentiation of pluripotential hematopoietic stem cells into ceutically active agents to treat disease in animals, including vast numbers of progenitors comprising diverse cellular lin humans. eages making up a complex immune system. Proper and balanced interactions between the cellular components are BACKGROUND OF THE INVENTION necessary for a healthy immune response. The different cel 0003. The secretin family is a family of well-conserved lular lineages often respond in a different manner when animal proteins with a variety of biological functions. Bio cytokines are administered in conjunction with other agents. logically active members of the secretin family are generally 0007 Cytokines mediate communication between cells of from about 26 to about 65 amino acids in length and are the immune system, e.g., antigen presenting cells (APCs) and thought to have relatively simple alpha-helical secondary T lymphocytes. Dendritic cells (DCs) are the most potent of structures. Many members are originally produced in vivo as antigen presenting cells. See, e.g., Paul (ed.) (1993) Funda larger pro-peptides, which are eventually converted in the mental Immunology 3d ed., Raven Press, NY. Antigen pre active forms. Members of the secretin family include the sentation refers to the cellular events in which a proteinaceous following proteins: GHRF, GIP, GLP-1, Glucagon, PACAP antigen is taken up, processed by antigen presenting cells 27, PACAP-38, PHM, PrP, and secretin. The q25 region of (APC), and then recognized to initiate an immune response. chromosome 6 on the human genome encodes another secre The most active antigen presenting cells have been character tin family member that is 170 amino acids long which ized as the macrophages (which are direct developmental becomes post-translationally cleaved to form vasoactive products from monocytes), dendritic cells, and certain B intestinal peptide (VIP). The active form of the VIP polypep cells. DCs are highly responsive to inflammatory stimuli Such tide is a 28 amino acid protein that functions, among other as bacterial lipopolysaccharides (LPS), and cytokines such as ways, to reduce arterial blood pressure, to increase vasodila tumor necrosis factor alpha (TNFalpha). Cytokines or tion of blood vessel walls, to relax smooth muscle in the stimuli. Such as LPS, can induce a series of phenotypic and respiratory system and gastrointestinal tissues, reduce functional changes in DC that are collectively referred to as inflammatory responses through both promotion of Th2 dif maturation. See, e.g., Banchereau and Schmitt (eds.) (1995) ferentiation as well as the reduction of Th1 responses, modu Dendritic Cells in Fundamental and Clinical Immunoloy, Ple late both the innate and adaptive immune response, and to num Press, NY. It is desirable to identify polypeptides that stimulate secretion of electrolytes in the gut. VIP has also mimic the function of cytokine families such as IL-10, IL-2, been shown to be active in the central nervous system as a IL-4, IL-12, and IL-17, but have increased half-life and neurotransmitter and in communication with lymphocytes. equivalent or more bioactivity than the naturally occurring Bioactivity of VIP is transmuted through three known recep IL-10, IL-2, IL-4, IL-12, and IL-17 representative amino acid tor subtypes: VIP, R, VIPR, and PACR. These receptors are sequences. It is also desirable to identify another peptidomi known to induce cAMP concentration as well as stimulate the metic of a cytokine Such as IL-17 to have association to a production of intracellular calcium. Their affinities for secre natural receptor for IL-17 as compared to wild-type tins such as VIP vary depending upon the subtype and the Sequences. amino acid sequence of the ligand. 0008 Chemists have long sought to extrapolate the power 0004 Secretin family members have short half-lives. For of biological catalysis and recognition to synthetic systems. instance, VIP has a half-life of about two minutes in the blood These efforts have focused largely on low-molecular weight stream. It is desirable to identify polypeptides that mimic the catalysts and receptors. Most biological systems, however, function of secretins such as VIP, but have increased half-life rely almost exclusively on large polymers such as proteins and equivalent or more bioactivity than the naturally occur and RNA to perform complex biochemical and/or biological ring VIP amino acid sequence. It is also desirable to identify functions. There is a long-felt need to identify synthetic poly another peptidomimetic of VIP to have association to one mers of amino acids which display discrete and predictable receptor Subtype over another secretin receptor. folding propensities to mimic natural biological systems. US 2013/0096050 A1 Apr. 18, 2013

Such polypeptides are designed to provide a molecular B-amino acids in the analog is from about 14 percent to about equivalent or improved functionality as compared to natu 50 percent of the total number of amino acids of the analog. In rally occurring protein-protein interactions specifically Some embodiments, the composition comprises a secretin because of their ability to mimic natural interactions in addi analog wherein the total number of B-amino acids in the tion to their resistance to natural degradative enzymes in a analog is from about 16 percent to about 50 percent of the Subject. Whereas a naturally occurring probe, comprised total number of amino acids of the analog. In some embodi entirely of C.-amino acid residues, will be readily degraded by ments, the composition comprises a secretin analog wherein any number of proteases and peptidases, the secretin analogs the total number off-amino acids in the analog is from about of the present invention comprising a mixture of C- and 18 percent to about 50 percent of the total number of amino B.-amino acid residues are not degraded in the same manner. acids of the analog. In some embodiments, the composition 0009. There is a need for secretin analogs that exhibit comprises a secretin analog wherein the total number of increased conformational constraints or increased conforma B-amino acids in the analog is from about 20 percent to about tional flexibility and greater half-lives. Increased conforma 50 percent of the total number of amino acids of the analog. In tional constraints may lock the active domain of the polypep Some embodiments, the composition comprises a secretin tides into their active state. Increased conformational analog wherein the total number of B-amino acids in the flexibility of the polpeptide may yield a high affinity selec analog is from about 30 percent to about 50 percent of the tivity for the naturally occurring polypeptide's natural bio total number of amino acids of the analog. logical target. There is a need for use of Such analogs, com In some embodiments, the composition comprises a secretin positions comprising Such analogs, and methods of using the analog wherein the total number of B-amino acids in the compositions as pharmaceutically active agents to treat dis analog is from about 40 percent to about 50 percent of the ease in animals. New polypeptide analogs are disclosed that total number of amino acids of the analog. In some embodi may provide one of more increased half-life, reduced degra ments, the composition comprises a secretin analog wherein dation upon administration, reduced degradation upon solu the total number off-amino acids in the analog is from about bilization, increased conformational constraints and that pro 45 percent to about 50 percent of the total number of amino duce the same or greater biological effect as compared to acids of the analog. In some embodiments, the composition naturally occurring secretin family members. The present comprises a secretin analog wherein the total number of invention addresses these and other needs associated with B-amino acids in the analog is from about 40 percent to about treatment and prevention of disease that implicate dysfunc 45 percent of the total number of amino acids of the analog. tion of biological systems involving naturally occurring In some embodiments, the composition comprises a secretin polypeptides. analog wherein the total number of B-amino acids in the analog is from about 30 percent to about 40 percent of the SUMMARY OF THE INVENTION total number of amino acids of the analog. In some embodi 0010. In some embodiments, the invention relates to com ments, the composition comprises a secretin analog wherein positions comprising a helical polypeptide synthesized with a the total number off-amino acids in the analog is from about repeated pattern off-amino acids at positions along the entire 35 percent to about 40 percent of the total number of amino length of a polypeptide chain. For any of the peptides acids of the analog. In some embodiments, the composition described herein, there may embodiments in which there are comprises a secretin analog wherein the total number of no B-amino acids within the peptide. The selected pattern of B-amino acids in the analog is from about 20 percent to about synthetic amino acids along the helical polypeptide decreases 30 percent of the total number of amino acids of the analog. the rate at which the polypeptide may degrade when admin 0012. In some embodiments, the composition comprises a istered to a subject or when reconstituted or placed in solu secretin analog wherein the total number of B-amino acids in tion. Selected side chains of the amino acids increase the the analog is from about 10 percent to about 20 percent of the conformational rigidity of the polypeptide in order to con total number of amino acids of the analog. In some embodi strain the polypeptide in its active state. The selected pattern ments, the composition comprises a secretin analog wherein of synthetic amino acids along the helical polypeptide the total number off-amino acids in the analog is from about increases the half-life of the polypeptide as compared to 15 percent to about 20 percent of the total number of amino naturally encoded polypeptides with the same O-amino acid acids of the analog. In some embodiments, the composition sequence. In some embodiments, the polypeptide comprises comprises a secretin analog wherein the total number of B-amino acids that spatially aligned along a longitudinal axis B-amino acids in the analog is from about 20 percent to about of the analog in order to confer degradation resistance to the 25 percent of the total number of amino acids of the analog. In composition while preserving the native binding interface. In Some embodiments, the composition comprises a secretin Some embodiments, the composition comprises a secretin analog wherein the total number of B-amino acids in the analog. In some embodiments, the composition comprises a analog is from about 25 percent to about 30 percent of the vasoactive intestinal peptide (VIP) analog, wherein said ana total number of amino acids of the analog. In some embodi log comprises an O-amino acid and at least one B-amino acid. ments, the composition comprises a secretin analog wherein 0011. In some embodiments, the composition comprises a the total number off-amino acids in the analog is from about secretin analog wherein the total number of B-amino acids in 30 percent to about 35 percent of the total number of amino the analog is from about 10 percent to about 60 percent of the acids of the analog. total number of amino acids of the analog. In some embodi 0013. In some embodiments, the invention relates to ana ments, the composition comprises a secretin analog wherein logs of various protein targets. In some embodiments, the the total number off-amino acids in the analog is from about amino acid sequences upon which the analogs are based or 12 percent to about 50 percent of the total number of amino derived include biologically active polypeptides chosen from acids of the analog. In some embodiments, the composition the group of transcription factors, ligands for cellular recep comprises a secretin analog wherein the total number of tors, hormones and extracellular binding peptides. In some US 2013/0096050 A1 Apr. 18, 2013 embodiments, the invention comprises analogs of derived 0016. The term “GLP-1 polypeptide' encompasses from amino acid sequences chosen from human and non GLP-1 polypeptides comprising one or more amino acid Sub human enkephlin, LHRH, neuropeptides, glycoincretins, stitutions, additions ordeletions. Exemplary Substitutions in a integrin, glucagons and glucagon-like peptides, antithrom wide variety of amino acid positions in naturally-occurring botic peptides, cytokines and interleukins, transferrins, inter GLP-1 have been described, including but not limited to, ferons, endothelins, natriuretic hormones, extracellular substitutions that modulate one or more of the biological kinase ligands, angiotensin enzyme inhibitors, peptide anti activities of GLP-1. Such as but not limited to, increase ago viral compounds, thrombin, Substance P. Substance G. Soma nist activity, increase solubility of the polypeptide, convert totropin, Somatostatin, GnRH, bradykinin, vasopressin, insu the polypeptide into an antagonist, decrease peptidase or pro lin, and growth factors. The amino acid sequences of these tease Susceptibility, etc. and are encompassed by the term proteins or peptides are known to the skilled artisan and can “GLP-1 polypeptide.” be obtained by numerous means. The amino acid sequences 0017 Human GLP-1 antagonists include, but are not lim are incorporated herein by reference from databases such as, ited to, those with a substitutions at: 7, 8, 9, 22, 18, 29, 25, 32, for example, GenBank. 21, 28, 17, 24, 31, and 20 (other GLP-1 sequence of U.S. 0014. As used herein, “glucagon-like peptide-1 or "GLP Patent Application Publication 2010-0048871). In some 1 shall include those polypeptides and proteins that have at embodiments, the GLP-1 antagonist comprises a non-natu least one biological activity of human GLP-1, including but rally encoded amino acid linked to a water soluble polymer not limited to those described in U.S. Patent Publication No. that is present in a receptor binding region of the GLP-1 2004O127412, EP 06996.86-A2 and EP0733,644, U.S. Pat. molecule. In some embodiments the water soluble polymer is Nos. 5,545,618; 5,118,666; 5,512,549; WO 91/11457; WO coupled to the GLP-1 polypeptide at one or more of the amino 90/11296; WO87/06941 which are incorporated by reference acid positions: 7,8,9, 22, 18, 29, 25, 32, 21, 28, 17, 24, 31, and herein, as well as GLP-1 analogs, GLP-1 isoforms, GLP-1 20 (U.S. Patent Application Publication 2010-0048871). mimetics, GLP-1 fragments, hybrid GLP-1 proteins, fusion 0018 For the GLP-1 amino acid sequence as well as the proteins, oligomers and multimers, homologues, glycosyla exendin-4 and exendin-3 amino acid sequence. His Ala Glu tion pattern variants, and muteins, thereof, regardless of the GlyThr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly GIn Ala biological activity of same, and further regardless of the Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Arg (GLP-1 method of synthesis or manufacture thereof including Syn (7-36)); His Ala Glu GlyThr Phe Thr Ser Asp Val Ser Ser Tyr thetic, transgenic, and gene activated methods. Numerous Leu Glu Gly Glin Ala Ala Lys Glu Phe Ile Ala Trp LeuVal Lys GLP-1 analogs and derivatives are known and are referred to Gly Arg Gly (GLP-1 (7-37)); {His Gly Glu GlyThr Phe Thr herein as “GLP-1 compounds.” These GLP-1 analogs include Ser Asp Leu Ser Lys GIn Met Glu Glu Glu Ala Val Arg Leu the Exendins which are peptides found in the venom of the Phelle Glu Trp Leu Lys Asn Gly Gly Pro Ser Ser Gly Ala Pro GILA-monster. Specific examples of GLP-1 include, but are Pro Pro Ser (exendin-4); and His Ser Asp Gly Thr Phe Thr not limited to, GLP-1 (3-36), GLP-1 (3-37), GLP-1(1-45), and Ser Asp Leu Ser Lys Gln Met Glu Glu Glu Ala Val Arg Leu Exendins 1 through 4. Further, it is possible to obtain GLP-1 Phe He Glu Trp Leu Lys Asn Gly Gly Pro Ser Ser Gly Ala Pro through the use of recombinant DNA technology, as dis Pro Pro Ser (exendin-3). In some embodiments, GLP-1 closed by Maniatis, T., et al., Molecular Biology: A Labora polypeptides of the invention are substantially identical to the tory Manual, Cold Spring Harbor, N.Y. (1982), and produce sequences above, or any other sequence of a GLP-1 polypep GLP-1 in host cells by methods known to one of ordinary skill tide (see, U.S. Patent Application Publication 2010 in the art. 0048871). Nucleic acid molecules encoding GLP-1 mutants 0.015 The term “human GLP-1 (GLP-1) or “GLP-1 and mutant GLP-1 polypeptides are well known. Examples of polypeptide' refers to GLP-1 as described herein, as well as a GLP-1 mutants include those disclosed in U.S. Patent Publi polypeptide that retains at least one biological activity of a cation No. 20040127412A1; which is incorporated by refer naturally-occurring GLP-1. GLP-1 polypeptides also include ence herein. the pharmaceutically acceptable salts and prodrugs, and pro 0019. A number of GLP-1 products are in preclinical and drugs of the salts, polymorphs, hydrates, Solvates, biologi clinical development, including GLP-1 peptide analogs, con cally-active fragments, biologically active variants and stere jugates, fusion proteins, and drug delivery or combination oisomers of the naturally-occurring human GLP-1 as well as therapies. Some of the products in development are Exenatide agonist, mimetic, and antagonist variants of the naturally (AC2993, Amylin/Eli Lilly), AVE-0010 (ZP10, Zealand occurring human GLP-1, the family of exendins including Pharm/Aventis), BIM-51077 (Ipsen/Roche), Liraglutide exendins 1 through 4, and polypeptide fusions thereof. (NN2211, Novo Nordisk), CIC-1131 (Conjuchem), Albugon Examples of GLP-1 polypeptides include, but are not limited (Human Genome Sciences/GlaxoSmithKline), GLP-1 trans to, those described in U.S. Pat. No. 5,118,666; which is incor ferrin (Biorexis), AC2993 LAR (Amylin/Alkermes), GLP-1 porated by reference herein. Fusions comprising additional nasal (Suntory) and GLP-1-INT (Transition Therapeutics). amino acids at the amino terminus, carboxyl terminus, or 0020. The biological activities of GLP-1 have been dis both, are encompassed by the term “GLP-1 polypeptide.” closed and are known in the art, and can be found, for Exemplary fusions include, but are not limited to, e.g., example, in U.S. Patent Publication No. 20040082507A1 and fusions for the purpose of purification (including, but not 20040232754A1 which are incorporated by reference herein. limited to, to poly-histidine or affinity epitopes), fusions with 0021 Variants of OLP-1 (7-37) and analogs thereof, also serum albumin binding peptides; fusions with serum proteins have been disclosed. These variants and analogs include, for Such as serum albumin; fusions with constant regions of example, Gln-GLP-1 (7-37), D-Gln-GLP-1 (7-37), acetyl immunoglobulin molecules Such as Fc.; and fusions with fatty Lys-GLP-1 (7-37), Thr-Lys-GLP-1 (7-37), Lys-GLP-1 acids. The naturally-occurring GLP-1 nucleic acid and amino (7-37) and the like, and derivatives thereof including, for acid sequences for various forms are known, as are variants example, acid addition salts, carboxylate salts, lower alkyl Such as single amino acid variants or splice variants. esters, and amides (see, e.g., WO 91/11457; EP0733,644 US 2013/0096050 A1 Apr. 18, 2013

(1996); and U.S. Pat. No. 5,512,549 (1996), which are incor protease Susceptibility, etc. and are encompassed by the term porated by reference). Generally, the various disclosed forms “DP-178 polypeptide, the DP-178 amino acid sequence, of GLP-1 are known to stimulate insulin secretion (insulino (Tyr Thr Ser Leu He His Ser Leu Ile Glu Glu Ser GIn Asn Gln tropic action) and cAMP formation (see, e.g., Mojsov, S., Int. Gln Glu Lys Asn Glu Gln Glu Leu Leu Glu Leu Asp Lys Trp J. Peptide Protein Research, 40:333-343 (1992)). Ala Ser Leu Trp Asn Trp Phe). In some embodiments, DP-178 0022. As used herein, “T-20” or “DP-178 shall include polypeptides of the invention are substantially identical to the those polypeptides and proteins that have at least one biologi following sequences or functional fragments thereof: (Tyr cal activity of human DP-178, as well as DP-178 analogs, Thr Ser Leu. He His Ser Leu Ile Glu Glu Ser GIn ASn Glin Glin DP-178 isoforms, DP-178 mimetics, DP-178 fragments, Glu Lys Asn Glu GIn Glu Leu Leu Glu Leu Asp Lys Trp Ala hybrid DP-178 proteins, fusion proteins, oligomers and mul Ser Leu Trp Asn Trp Phe); Glu Trp Asp Arg Glu Ile ASn Asn timers, homologues, glycosylation pattern variants, and Tyr Thr Ser Leu Ile His Ser Leu Ile Glu Glu Ser Gln Asn Gln muteins, thereof, regardless of the biological activity of same, Gln Glu Lys Asn Glu GIn Glu Leu Leu Glu Leu Asp Lys Trp and further regardless of the method of synthesis or manufac Ala Ser Leu Trp Asn Trp Phe; or any other sequence of a ture thereof including, but not limited to, recombinant DP-178 polypeptide. Nucleic acid molecules encoding (whether produced from cDNA, genomic DNA, synthetic DP-178 mutants and mutant DP-178 polypeptides are well DNA or otherform of nucleic acid), synthetic, transgenic, and known. gene activated methods. Hyphenated and non-hyphenated (0026. A commercially available form of DP-178 is forms (T20, DP178) of the terms are equivalent. FuZeon R. (enfuvirtide. Roche Laboratories Inc. and Trim 0023 The term “human DP-178” or “DP-178 polypep eris, Inc.). FuZeon R has an acetylated N terminus and a car tide' refers to DP-178 or T-20 as described herein, as well as boxamide as the C-terminus. It is used in combination with a polypeptide that retains at least one biological activity of a other antivirals in HIV-1 patients that show HIV-1 replication naturally-occurring DP-178. “DP-178 includes portions, despite ongoing antiretroviral therapy. analogs, and homologs of DP-178, all of which exhibit anti (0027. As used herein, “PYY and “peptide YY shall viral activity. Antiviral activity includes, but is not limited to, include those polypeptides and proteins that have at least one the inhibition of HIV transmission to uninfected CD-4+ cells. biological activity of human PYY, as well as PYY analogs, Further, the invention relates to the use of DP-178 and PYY isoforms, PYY mimetics, PYY fragments, hybrid PYY DP-178 fragments and/or analogs or homologs as inhibitors proteins, fusion proteins, oligomers and multimers, homo of retroviral transmission, in particular HIV, to uninfected logues, glycosylation pattern variants, and muteins, thereof, cells, in both humans and non-humans. Non retroviral viruses regardless of the biological activity of same, and further whose transmission may be inhibited by the peptides of the regardless of the method of synthesis or manufacture thereof invention include, but are not limited to enveloped viruses, including, but not limited to, recombinant (whether produced human respiratory syncytial virus, canine distemper virus, from cDNA, genomic DNA, synthetic DNA or other form of Newcastle disease virus, human parainfluenza virus, and nucleic acid), synthetic, transgenic, and gene activated meth influenza viruses. ods. 002.4 DP-178 polypeptides also include the pharmaceuti 0028. The term “PYY or “PYY polypeptide” refers to cally acceptable salts and prodrugs, and prodrugs of the salts, PYY as described herein, as well as a polypeptide that retains polymorphs, hydrates, Solvates, biologically-active frag at least one biological activity of a naturally-occurring PYY. ments, biologically active variants and stereoisomers of the 0029. “PYY” includes portions, analogs, and homologs of naturally-occurring human DP-178 as well as agonist, PYY including, but not limited to, PYY(3-36), full-length mimetic, and antagonist variants of the naturally-occurring PYY, PYY(22-36), and DPPIV resistant variants of PYY. The human DP-178, and polypeptide fusions thereof. Fusions term “PYY” includes the human full length: Tyr Pro Ile Lys comprising additional amino acids at the amino terminus, Pro Glu Ala Pro Gly Glu ASpAla Ser Pro Glu Glu Leu Asn carboxyl terminus, or both, are encompassed by the term Arg Tyr Tyr Ala Ser Leu Arg His Tyr Leu Asn LeuVal Thr Arg “DP-178 polypeptide.” Exemplary fusions include, but are Gln Arg Tyr, which is disclosed in International Publication not limited to, e.g., methionyl DP-178 in which a methionine No. WO 02/47712 (which is the PCT counterpart to U.S. is linked to the N-terminus of DP-178 resulting from the patent Publication No. 2002/014-1985, which is hereby incor recombinant expression of DP-178, fusions for the purpose of porated by reference) and the following amino acid sequences purification (including, but not limited to, to poly-histidine or from Tatemoto, Proc Natl AcadSci U.S.A. 79:2514-8, 1982, affinity epitopes), T-20 extended at the N-terminus, fusions which are incorporated by reference herein: with serum albumin binding peptides; fusions with serum proteins such as serumalbumin; fusions with constant regions of immunoglobulin molecules Such as Fc.; and fusions with 1. Tyr-Pro-Ala-Lys-Pro-Glu-Ala-Pro-Gly fatty acids. The naturally-occurring DP-178 nucleic acid and amino acid sequences are known, as are variants such as 2. Tyr-Pro-Ala-Lys-Pro-Glu-Ala-Pro-Gly-Glu-Asp single amino acid variants or splice variants. Ala-Ser-Pro-Glu-Glu-Leu-Ser-Arg 0025. The term “DP-178 polypeptide encompasses DP-178 polypeptides comprising one or more amino acid 3. Tyr-Tyr-Ala-Ser-Leu-Arg Substitutions, additions or deletions. Exemplary Substitutions 4. His-Tyr-Leu-Asn-Leu-Val-Thr-Arg in a wide variety of amino acid positions in naturally-occur ring DP-178 have been described, including but not limited 5. Tyr-Pro-Ala-Lys-Pro-Glu-Ala-Pro-Gly to, substitutions that modulate one or more of the biological 6. Tyr-Pro-Ala-Lys-Pro-Glu-Ala-Pro-Gly-Glu-Asp activities of DP-178, such as but not limited to, increase agonist activity, increase solubility of the polypeptide, con Ala-Ser-Pro-Glu-Glu-Leu-Ser-Arg-Tyr-Tyr-Ala Vert the polypeptide into an antagonist, decrease peptidase or US 2013/0096050 A1 Apr. 18, 2013

- Continued regions of immunoglobulin molecules Such as Fc.; and fusions with fatty acids. The naturally-occurring PYY nucleic acid Ser-Leu-Arg-His-Tyr-Leu-Asn-Leu-Val-Thr-Arg and amino acid sequences are known, as are variants such as single amino acid variants or splice variants. 0034. The term “PYY polypeptide' encompasses PYY 0030 PYYagonists are also included in the term “PYY”. polypeptides comprising one or more amino acid substitu PYYagonists include any compound which elicits an effect tions, additions or deletions. Exemplary Substitutions in a of PYY to reduce nutrient availability, for example a com wide variety of amino acid positions in naturally-occurring pound (1) having activity in the food intake, gastric emptying, PYY have been described, including but not limited to, sub pancreatic secretion, or weight loss assays described in stitutions that modulate one or more of the biological activi Examples 1, 2, 5, or 6 of WO 02/47712 and U.S. patent ties of PYY, such as but not limited to, increase agonist Publication No. 2002/014 1985, and (2) which binds specifi activity, increase solubility of the polypeptide, convert the cally in a Y receptor assay (Example 10 of WO 02/47712 and polypeptide into an antagonist, decrease peptidase or pro U.S. patent Publication No. 2002/014 1985) or in a competi tease Susceptibility, etc. and are encompassed by the term tive binding assay with labeled PYY or PYY (3-361 from “PYY polypeptide.” certain tissues having an abundance ofY receptors, including 0035. In some embodiments, PYY polypeptides of the e.g., area postrema (Example 9 of WO 02/47712 and U.S. invention are substantially identical to Ile Lys Pro Glu Ala Pro patent Publication No. 2002/014-1985), wherein the PYY Gly Glu Asp Ala SerPro Glu Glu Leu Asn Arg Tyr Tyr Ala Ser agonist is not pancreatic polypeptide. In some embodiments, Leu Arg His Tyr Leu Asn LeuVal Thr Arg Glin Arg Tyr or any PYYagonists would bind in such assays with an affinity of other sequence of a PYY polypeptide (see, U.S. Patent Appli greater than about 1 uM, or with an affinity of greater than cation Publication 2010-0048871). Nucleic acid molecules about 1 nM to about 5 nM. encoding PYY mutants and mutant PYY polypeptides are 0031. Such agonists can comprise a polypeptide having a well known. functional PYY domain, an active fragment of PYY, or a 0036 Various references disclose modification of chemical or small molecule. PYYagonists may be peptide or polypeptides by polymer conjugation or glycosylation. The peptide-nonpeptide hybrid molecules, and include “PYY term analog includes polypeptides conjugated to a polymer agonist analogs, which refer to any compound structurally such as PEG and may be comprised of one or more additional similar to a PYY that have PYYactivity typically by virtue of derivatizations of cysteine, lysine, or other residues. In addi binding to or otherwise directly or indirectly interacting with tion, analogs of the instant invention may comprise a linker or a PYY receptor or other receptor or receptors with which polymer, wherein the amino acid to which the linker or poly PYY itself may interact to elicit a biological response. Such meris conjugated may be a non-natural amino acid, or may be compounds include derivatives of PYY. fragments of PYY. conjugated to a naturally encoded amino acid utilizing tech extended PYY molecules having more than 36 amino acids, niques known in the art such as coupling to lysine or cysteine. truncated PYY molecules having less than 36 amino acids, 0037 Polymer modification of polypeptides has been and substituted PYY molecules having one or more different reported. U.S. Pat. No. 4,904,584 discloses PEGylated lysine amino acids as compared to the wild-type or consensus depleted polypeptides, wherein at least one lysine residue has sequence, or any combination of the above. Such compounds been deleted or replaced with any other amino acid residue. may also be modified by processes such as pegylation, ami WO 99/67291 discloses a process for conjugating a protein dation, glycosylation, acylation, Sulfation, phosphorylation, with PEG, wherein at least one amino acid residue on the acetylation and cyclization. protein is deleted and the protein is contacted with PEG under 0032. One such PYYagonist analog is PYY (3-36), iden conditions Sufficient to achieve conjugation to the protein. tified as Ile Lys Pro Glu Ala Pro Gly Glu Asp Ala Ser Pro Glu WO99/03887 discloses PEGylated variants of polypeptides Glu Leu Asn Arg Tyr Tyr Ala Ser Leu Arg His Tyr Leu Asn belonging to the growth hormone Superfamily, wherein a Leu Ile Lys pro Glu Ala Pro Gly Glu ASpAla SerPro Glu Glu cysteine residue has been Substituted with a non-essential Leu Asn Arg Tyr Tyr Ala Ser Leu Arg His Tyr Leu Asn LeuVal amino acid residue located in a specified region of the Thr Arg Glin Arg Tyr Val Thr Arg Glin Arg Tyr; Eberlein, polypeptide. WO 00/26354 discloses a method of producing Eysselein et al., Peptides 10:797-803 (1989); and Grandy, a glycosylated polypeptide variant with reduced allergenicity, Schimiczek et al., Regul Pept 51:151-9 (1994). Additional which as compared to a corresponding parent polypeptide PYY fragments and derivatives are described in U.S. Patent comprises at least one additional glycosylation site. U.S. Pat. Publication 2005.0002927 whose sequences follow. All of the No. 5,218,092 discloses modification of granulocyte colony above referenced patent publications are incorporated by ref stimulating factor (G-CSF) and other polypeptides so as to erence herein. introduce at least one additional carbohydrate chain as com 0033 PYY polypeptides also include the pharmaceuti pared to the native polypeptide. Examples of PEGylated pep cally acceptable salts and prodrugs, and prodrugs of the salts, tides include GW395058, a PEGylated peptide thrombopoi polymorphs, hydrates, Solvates, biologically-active frag etin receptor (TPOr) agonist (de Serres M., et al., StemCells. ments, biologically active variants and stereoisomers of the 1999; 17(4):203-9), and a PEGylated analogue of growth naturally-occurring human PYY as well as agonist, mimetic, hormone releasing factor (PEG-GRP: D’Antonio M. et al. and antagonist variants of the naturally-occurring human Growth Horm IGF Res. 2004 June; 14(3):226-34). PYY, and polypeptide fusions thereof. Fusions comprising 0038. The term analog also includes glycosylated analogs, additional amino acids at the amino terminus, carboxyl ter Such as but not limited to, analogs glycosylated at any amino minus, or both, are encompassed by the term “PYY polypep acid position, N-linked or O-linked glycosylated forms of the tide.” Exemplary fusions include, but are not limited to, e.g., polypeptide. In addition, splice variants are also included. fusions with serum albumin binding peptides; fusions with The term analog also includes heterodimers, homodimers, serum proteins such as serum albumin; fusions with constant heteromultimers, or homomultimers of any one or more US 2013/0096050 A1 Apr. 18, 2013 polypeptide, protein, carbohydrate, polymer, Small molecule, facilitate purification, or improve or alter a particular route of linker, ligand, or other biologically active molecule of any administration. Similarly, analogs of the present invention type, linked by chemical means or expressed as a fusion may comprise protease cleavage sequences, reactive groups, protein, as well as polypeptide analogs containing, for antibody-binding domains (including but not limited to, example, specific deletions or other modifications yet main FLAG or poly-His) or other affinity based sequences (includ tain biological activity. ing but not limited to, FLAG, poly-His, GST, etc.) or linked 0.039 Various references disclose additional variants of molecules (including but not limited to, biotin) that improve GLP-1 and acylation of GLP-1, including, but not limited to, detection (including but not limited to, GFP), purification or the GLP-1 parent analogs and acylation sites described in J. of other traits of the polypeptide. Med. Chem. (2000) 43:1664-1669, which is incorporated 0044. A “non-naturally encoded amino acid refers to an herein by reference. amino acid that is not one of the 20 common amino acids or 0040 Those of skill in the art will appreciate that amino pyrolysine or seienocysteine. Other terms that may be used acid positions corresponding to positions in analogs can be synonymously with the term “non-naturally encoded amino readily identified in any other molecule Such as analog acid are “non-natural amino acid, “unnatural amino acid.” fusions, variants, fragments, etc. For example, sequence “non-naturally-occurring amino acid, and variously hyphen alignment by visual means or computer programs such as ated and non-hyphenated versions thereof. The term “non BLAST can be used to align and identify a particular position naturally encoded amino acid also includes, but is not lim in a protein that corresponds with a position in the analog of ited to, amino acids that occur by modification (e.g. post polypeptide sequences identified in this application or other translational modifications) of a naturally encoded amino GLP-1, VIP, PYY, IL-10, PACAP, Ghrelin, ANP/BNP/CNP, acid (including but not limited to, the 20 common amino acids Maxadilan/M65, Apollipoprotein mimetic polypeptides and or pyrolysine and selenocysteine) but are not themselves any other analog sequences are intended to also refer to Sub naturally incorporated into a growing polypeptide chain by stitutions, deletions or additions incorresponding positions in the translation complex. Examples of Such non-naturally GLP-1, VIP, PYY, IL-10, PACAP, Ghrelin, ANP/BNP/CNP, occurring amino acids include, but are not limited to, Maxadilan/M65, Apollipoprotein mimetic polypeptides N-acetylglucosaminyl-L-serine, N-acetylglucosaminyl-L- fusions, variants, fragments, etc. described herein or known threonine, and O-phosphotyrosine. in the art and are expressly encompassed by the present inven 0045 An "amino terminus modification group’ refers to tion. any molecule that can be attached to the amino terminus of a 0041. The term analog encompasses polypeptides com polypeptide. Similarly, a “carboxy terminus modification prising one or more amino acid Substitutions, additions or group' refers to any molecule that can be attached to the deletions. Analogs of the present invention may be comprised carboxy terminus of a polypeptide. Terminus modification of modifications with one or more natural amino acids in groups include, but are not limited to, various water soluble conjunction with one or more non-natural amino acid modi polymers, peptides or proteins such as serum albumin, immu fication. Exemplary Substitutions in a wide variety of amino noglobulin constant region portions such as Fc., or other moi acid positions in naturally-occurring analogs have been eties that increase serum half-life of peptides. described, including but not limited to substitutions that 0046. The terms “functional group”, “active moiety'. modulate one or more of the biological activities of the ana “activating group”, “leaving group”, “reactive site', 'chemi logs, such as but not limited to, increase agonist activity, cally reactive group' and “chemically reactive moiety' are increase solubility of the polypeptide, convert the polypep used in the art and herein to refer to distinct, definable por tide into an antagonist, decrease peptidase or protease Sus tions or units of a molecule. The terms are somewhat synony ceptibility, etc. and are encompassed by the term analog. mous in the chemical arts and are used herein to indicate the 0042 Human GLP-1 antagonists include, but are not lim portions of molecules that perform some function or activity ited to, those with a substitutions at: 19, 23, 26, 27, 28, 29, 30, and are reactive with other molecules. and 33 of the consensus sequence identified in Table 4. In 0047. The term “linkage” or “linker” is used hereinto refer Some embodiments, the GLP-1 antagonist comprises a non to groups or bonds that normally are formed as the result of a naturally encoded amino acid linked to a water Soluble poly chemical reaction and typically are covalent linkages. Hydro mer that is present in a receptor binding region of the GLP-1 lytically stable linkages means that the linkages are Substan molecule. In some embodiments, the water soluble polymer tially stable in water and do not react with water at useful pH is coupled to the GLP-1 polypeptide at one or more of the values, including but not limited to, under physiological con amino acid positions: 19, 23, 26, 27, 30, and 33 of the con ditions for an extended period of time, perhaps even indefi sensus sequence identified in Table 4. nitely. Hydrolytically unstable or degradable linkages mean 0043. In some embodiments, the analogs further comprise that the linkages are degradable in water or in aqueous solu an addition, Substitution or deletion that modulates biological tions, including for example, blood. Enzymatically unstable activity of the analogs. For example, the additions, Substitu or degradable linkages mean that the linkage can be degraded tion or deletions may modulate one or more properties or by one or more enzymes. As understood in the art, PEG and activities of the analog. For example, the additions, Substitu related polymers may include degradable linkages in the tions or deletions may modulate affinity for the analog recep polymer backbone or in the linker group between the polymer tor orbinding partner, modulate (including but not limited to, backbone and one or more of the terminal functional groups increases or decreases) receptor dimerization, stabilize recep of the polymer molecule. For example, ester linkages formed tor dimers, modulate the conformation or one or more bio by the reaction of PEG carboxylic acids or activated PEG logical activities of a binding partner, modulate circulating carboxylic acids with alcohol groups on a biologically active half-life, modulate therapeutic half-life, modulate stability of agent generally hydrolyze under physiological conditions to the polypeptide, modulate cleavage by peptidases or pro release the agent. Other hydrolytically degradable linkages teases, modulate dose, modulate release or bio-availability, include, but are not limited to, carbonate linkages; imine US 2013/0096050 A1 Apr. 18, 2013 linkages resulted from reaction of an amine and an aldehyde; mone peptides, adrenomedullin peptides, allatostatin pep phosphate ester linkages formed by reacting an alcohol with tides, amylin peptides, amyloid beta-protein fragment pep a phosphate group; hydrazone linkages which are reaction tides, angiotensin peptides, antibiotic peptides, antigenic product of a hydrazide and an aldehyde; acetal linkages that polypeptides, anti-microbial peptides, apoptosis related pep are the reaction product of an aldehyde and an alcohol; tides, atrial natriuretic peptides, bag cell peptides, bombesin orthoester linkages that are the reaction product of a formate peptides, bone GLA peptides, bradykinin peptides, brain and an alcohol; peptide linkages formed by an amine group, natriuretic peptides, C-peptides, C-type natriuretic peptides, including but not limited to, at an end of a polymer Such as calcitonin peptides, calcitonin gene related peptides, CART PEG, and a carboxyl group of a peptide; and oligonucleotide peptides, casomorphin peptides, chemotactic peptides, chole linkages formed by a phosphoramidite group, including but cystokinin peptides, colony-stimulating factor peptides, cor not limited to, at the end of a polymer, and a 5’ hydroxyl group ticortropin releasing factor peptides, cortistatin peptides, of an oligonucleotide. cytokine peptides, dermorphin peptides, dynorphin peptides, 0048. The term “biologically active molecule”, “biologi endorphin peptides, endothelin peptides, ETa receptor cally active moiety' or “biologically active agent' when used antagonist peptides, ETh receptor antagonist peptides, herein means any Substance which can affect any physical or enkephalin peptides, fibronectin peptides, galanin peptides, biochemical properties of a biological system, pathway, mol gastrin peptides, glucagon peptides, Gn-RH associated pep ecule, or interaction relating to an organism, including but not tides, growth factor peptides, growth hormone peptides, limited to, viruses, bacteria, bacteriophage, transposon, GTP-binding protein fragment peptides, guanylin peptides, prion, insects, fungi, plants, animals, and humans. In particu inhibin peptides, insulin peptides, interleukin peptides, lami lar, as used herein, biologically active molecules include, but nin peptides, leptin peptides, leucokinin peptides, luteinizing are not limited to, any Substance intended for diagnosis, cure, hormone-releasing hormone peptides, mastoparan peptides, mitigation, treatment, or prevention of disease in humans or mast cell degranulating peptides, melanocyte stimulating other animals, or to otherwise enhance physical or mental hormone peptides, morphiceptin peptides, motilin peptides, well-being of humans or animals. Examples of biologically neuro-peptides, neuropeptide Y peptides, neurotropic factor active molecules include, but are not limited to, peptides, peptides, orexin peptides, opioid peptides, oxytocin peptides, proteins, enzymes, Small molecule drugs, hard drugs, soft PACAP peptides, pancreastatin peptides, pancreatic polypep drugs, carbohydrates, inorganic atoms or molecules, dyes, tides, parathyroid hormone peptides, parathyroid hormone lipids, nucleosides, radionuclides, oligonucleotides, toxins, related peptides, peptide T. peptides, prolactin-releasing pep cells, viruses, liposomes, microparticles and micelles. tides, peptide YY peptides, renin substrate peptides, secretin Classes of biologically active agents that are suitable for use peptides. Somatostatin peptides, Substance P peptides, tachy with the invention include, but are not limited to, drugs, kinin peptides, thyrotropin-releasing hormone peptides, prodrugs, radionuclides, imaging agents, polymers, antibiot toxin peptides, vasoactive intestinal peptides, vasopressin ics, fungicides, anti-viral agents, anti-inflammatory agents, peptides, and virus related peptides. (see U.S. Pat. No. 6,858, anti-tumor agents, cardiovascular agents, anti-anxiety agents, 580). hormones, growth factors, steroidal agents, microbially 0051 Examples of polypeptides include, but are not lim derived toxins, and the like. ited to, pituitary hormones Such as Vasopressin, oxytocin, 0049. A “bifunctional polymer refers to a polymer com melanocyte stimulating hormones, adrenocorticotropic hor prising two discrete functional groups that are capable of mones, growth hormones; hypothalamic hormones Such as reacting specifically with other moieties (including but not growth hormone releasing factor, corticotropin releasing fac limited to, amino acid side groups) to form covalent or non tor, prolactin releasing peptides, gonadotropin releasing hor covalent linkages. Abifunctional linker having one functional mone and its associated peptides, luteinizing hormone release group reactive with a group on a particular biologically active hormones, thyrotropin releasing hormone, orexins, and component, and another group reactive with a group on a Somatostatin; thyroid hormones Such as calcitonins, calcito second biological component, may be used to form a conju nin precursors, and calcitonin gene related peptides; parathy gate that includes the first biologically active component, the roid hormones and their related proteins; pancreatic hor bifunctional linker and the second biologically active com mones such as insulin and insulin-like peptides, glucagon, ponent. Many procedures and linker molecules for attach Somatostatin, pancreatic polypeptides, amylin, peptide YY. ment of various compounds to peptides are known. See, e.g., and neuropeptide Y, digestive hormones such as gastrin, gas European Patent Application No 188.256; U.S. Pat. Nos. trin releasing peptides, gastrin inhibitory peptides, cholecys 4,671,958, 4,659,839, 4,414,148, 4,699,784; 4,680,338: tokinin, Secretin, motilin, and vasoactive intestinal peptide; 4,569,789; and 4,589,071 which are incorporated by refer natriuretic peptides Such as atrial natriuretic peptides, brain ence herein. A "multi-functional polymer refers to a polymer natriuretic peptides, and C-type natriuretic peptides; neuro comprising two or more discrete functional groups that are kinins such as neurokinin A, neurokinin B, and Substance P. capable of reacting specifically with other moieties (includ renin related peptides such as renin Substrates and inhibitors ing but not limited to, amino acid side groups) to form cova and angiotensins; endothelins, including big endothelin, lent or non-covalent linkages. A bi-functional polymer or endothelin A receptor antagonists, and Sarafotoxin peptides; multi-functional polymer may be any desired molecular and other peptides Such as adrenomedullin peptides, alla length or molecular weight, and may be selected to provide a to statin peptides, amyloid beta protein fragments, antibiotic particular desired spacing or conformation between one or and antimicrobial peptides, apoptosis related peptides, bag more molecules linked to the analog and its binding partner or cell peptides, bombesin, bone Gla protein peptides, CART the analog. peptides, chemotactic peptides, cortistatin peptides, fibronec 0050 Representative non-limiting classes of polypeptides tin fragments and fibrin related peptides. FMRF and analog useful in the present invention include those falling into the peptides, galanin and related peptides, growth factors and following therapeutic categories: adrenocorticotropic hor related peptides, G therapeutic peptide-binding protein frag US 2013/0096050 A1 Apr. 18, 2013 ments, guanylin and uroguanylin, inhibin peptides, interleu secretin (cholecystokinin is not insulinotropic in man), are kin and interleukin receptor proteins, laminin fragments, lep insulinotropic, but the only physiologically important ones, tin fragment peptides, leucokinins, mast cell degranulating those that are responsible for the incretin effect, are the glu peptides, pituitary adenylate cyclase activating polypeptides, cose-dependent insulinotropic polypeptide, GIP, and gluca pancreastatin, peptide T. polypeptides, virus related peptides, gon-like peptide-1 (GLP-1). signal transduction reagents, toxins, and miscellaneous pep 0053 GIP is composed of 42 amino acids, processed from tides Such as adjuvant peptide analogs, alpha mating factor, a 153 amino acid precursor (Takeda et al., PNAS USA (1987) antiarrhythmic peptide, antifreeze polypeptide, anorexigenic 84:7005-7008). GIP is secreted by K cells present in the peptide, bovine pineal antireproductive peptide, bursin, C3 duodenum and in the Small intestinal mucosa in response to peptide P16, tumor necrosis factor, cadherin peptide, chro carbohydrate and lipid containing meals (Mortensen et al. mogranin Afragment, contraceptive tetrapeptide, conantokin Ann. NY Acad. Sci. (2000) 921:469-472). Expression of the G, conantokin T. crustacean cardioactive peptide, C-telopep GIP receptor has been shown in pancreatic islets, the adrenal tide, cytochrome b588 peptide, decorsin, delicious peptide, cortex, gut, heart, adipose tissue, several regions of the brain, delta-sleep-inducing peptide, diazempam-binding inhibitor and the pituitary gland (Usdin et al. (1993) Endocrinology fragment, nitric oxide synthase blocking peptide, OVA pep 133:2861-2870). tide, platelet calpain inhibitor (PI), plasminogen activator 0054 Because of its insulinotropic effect, GIP, isolated in inhibitor 1, rigin, Schizophrenia related peptide, serum thy 1973 (Pederson RA. Gastric Inhibitory Polypeptide. In Walsh mic factor, sodium potassium A therapeutic peptidease J. H. Dockray G. J. (eds.) Gut peptides: Biochemistry and inhibitor-1, speract, sperm activating peptide, systemin, Physiology. Raven Press, New York 1994, pp. 217-259) thrombin receptor agonists, thymic humoral gamma2 factor, immediately attracted considerable interest among diabetolo thymopentin, thymosin alpha 1, thymus factor, tuftsin, adi gists. However, numerous investigations carried out during pokinetic hormone, uremic pentapeptide, glucose-dependent the following years clearly indicated that a defective secretion insulinotropic polypeptide (GIP), glucagon-like peptide-1 of GIP was not involved in the pathogenesis of insulin depen (GLP-1), glucagon-like peptide-2 (GLP-1), exendin-3, exen dent diabetes mellitus (IDDM) or non insulin-dependent dia din-4, and other therapeutic peptides or fragments thereof. betes mellitus (NIDDM) (Krarup T. Endocr Rev 1988: 9: Additional examples of peptides include ghrelin, opioid pep 122-134). Furthermore, as an insulinotropic hormone, GIP tides (casomorphin peptides, demorphins, endorphins, was found to be almost ineffective in NIDDM (Krarup T., enkephalins, deltorphins, dynorphins, and analogs and Endocr Rev 1988: 9: 122-134). The other incretin hormone, derivatives of these), thymic peptides (thymopoietin, thymu GLP-1 is the most potent insulinotropic substance known lin, thymopentin, thymosin, Thymic Humoral Factor (THF)), (Orskov C., Diabetologia 1992:35:701-711). Unlike GIP, it cell adhesion peptides, complement inhibitors, thrombin is Surprisingly effective in stimulating insulin secretion in inhibitors, trypsin inhibitors, alpha-1 antitrypsin, Sea Urchin NIDDM patients. In addition, and in contrast to the other Sperm Activating Peptide, Asterosap, SHU-9119 MC3-R & insulinotropic hormones (perhaps with the exception of MC4-R Antagonist, glaspimod (immunostimulant, useful secretin), it also potently inhibits glucagon Secretion. against bacterial infections, fungal infections, immune defi Because of these actions, it has pronounced blood glucose ciency immune disorder, leukopenia), HP-228 (melanocor lowering effects particularly in patients with NIDDM. tin, useful against chemotherapy induced emesis, toxicity, pain, diabetes mellitus, inflammation, rheumatoid arthritis, 0055 GLP-1, a product of the proglucagon gene (Bell G.I. obesity), alpha 2-plasmin inhibitor (plasmin inhibitor), APC et al., Nature 1983: 304:368-371), is one of the members of tumor Suppressor (tumor Suppressor, useful against neo the secretin-VIP family of peptides, and is established as an plasm), early pregnancy factor (immunosuppressor), important gut hormone with regulatory function in glucose endozepine diazepam binding inhibitor (receptor peptide), metabolism and gastrointestinal Secretion and metabolism gamma interferon (useful against leukemia), glandular kal (Hoist J.J., 1994; Gastroenterology. 1994 December: 107(6): likrein-1 (immunostimulant), placental ribonuclease inhibi 1848-55). The glucagon gene is processed differently in the tor, sarcolecin binding protein, surfactant protein D. Wilms pancreas and in the intestine. In the pancreas (Hoist JJ, et al., tumor suppressor, GABAB 1b receptor peptide, prion related J Biol Chem, 1994; 269: 18827-18833), the processing leads peptide (iPrP13), choline binding protein fragment (bacterial to the formation and parallel secretion of 1) glucagon itself. related peptide), telomerase inhibitor, cardiostatin peptide, occupying positions 33-61 of proglucagon (PG); 2) an N-ter endostatin derived peptide (angiogenesis inhibitor), prion minal peptide of 30 amino acids (PG (1-30)) often called inhibiting peptide, N-methyl D-aspartate receptor antagonist, glicentin-related pancreatic peptide, GRPP (Moody AJ, et al., Nature 1981; 289: 514-516; Thim L., et al., Biochim C-peptide analog (useful against diabetic complications), Biophys Acta 1982; 703: 134-141); 3) a hexapeptide corre RANTES, NTY receptors, NPY2-R (neuropeptide Y type sponding to PG (64-69); 4) and, finally, the so-called major 2-receptor) ligands, NC4R peptides, or fragments thereof. proglucagon fragment (PG (72-158)), in which the two glu Other analogs and polypeptides upon which the analogs of cagon-like sequences are buried (Hoist JJ, et al., J Biol Chem, the instant invention are derived are found in U.S. Pat. No. 1994; 269: 18827-18833). Glucagon seems to be the only 6,849,714 which is incorporated by reference herein. biologically active product. In contrast, in the intestinal 0052. The hormones regulating insulin secretion belong to mucosa, it is glucagon that is buried in a larger molecule, the so-called enteroinsular axis, designating a group of hor while the two glucagon-like peptides are formed separately mones released from the gastrointestinal mucosa in response (Orskov C, et al., Endocrinology 1986; 119:1467-1475). The to the presence and absorption of nutrients in the gut, which following products are formed and secreted in parallel: 1) promote an early and potentiated release of insulin. The glicentin, corresponding to PG (1-69), with the glucagon enhancing effect on insulin secretion, the so-called incretin sequence occupying residues Nos. 33-61 (Thim L., et al., effect, is probably essential for a normal glucose tolerance. Regul Pept 1981;2:139-151); 2) GLP-1 (7-36)amide (PG (78 Many of the gastrointestinal hormones, including gastrin and 107))amide (Orskov C, et al., J. Biol. Chem. 1989: 264: US 2013/0096050 A1 Apr. 18, 2013

12826-12829), not as originally believed PG (72-107)amide known. It may involve a calcium-induced calcium release or 108, which is inactive). Small amounts of C-terminally (Gromada J, et al., Diabetes 1995; 44; 767-774; Holz G. G. et glycine-extended but equally bioactive GLP-1 (7-37), (PG al., J Biol Chem, 1996; 270: 17749-17759). As already men (78-108)) are also formed (Orskov C, et al., Diabetes 1991; tioned, the insulinotropic action of GLP-1 is preserved in 43: 535-539); 3) intervening peptide-2 (PG (111-122)amide) diabetic P-cells. The relation of the latter to its ability to (Buhl T, et al., J. Biol. Chem. 1988; 263:8621-8624); and 4) convey "glucose competence' to isolated insulin-secreting GLP-2 (PG (126-158)) (Buhl T, et al., J. Biol. Chem. 1988: cells (Gromada J, et al., Diabetes 1995, 44; 767-774; Holz G 263:8621-8624: Orskov C, et al., FEBS letters, 1989: 247: G, et al., Nature 1993,361:362-365), which respond poorly to 193-106). A fraction of glicentin is cleaved further into GRPP glucose or GLP-1 alone, but fully to a combination of the two, (PG (1-30)) and oxyntomodulin (PG (33-69)) (Hoist J. J. is also not known. Equally importantly, however, the hor Biochem J. 1980; 187:337-343; Bataille D, et al., FEBS Lett mone also potently inhibits glucagon Secretion (Orskov C, et 1982: 146:79-86). al., Endocrinology 1988: 123:2009-2013). The mechanism is 0056 Being secreted in parallel with glicentin/enteroglu not known, but seems to be paracrine, via neighbouring insu cagon, it follows that the many studies of enteroglucagon lin or somatostatin cells (Fehmann H C, et al., Endocrine secretion (Hoist J.J., Gastroenterology 1983; 84:1602-1613; Reviews, 1995; 16:390-410). Also the glucagonostatic action Hoist J J, et al., Glucagon and other proglucagon-derived is glucose-dependent, so that the inhibitory effect decreases peptides. In Walsh J H. Dockray G. J, eds. Gut peptides: as blood glucose decreases. Because of this dual effect, if the Biochemistry and Physiology. Raven Press, New York, pp. plasma GLP-1 concentrations increase either by increased 305-340, 1993) to some extent also apply to GLP-1 secretion, secretion or by exogenous infusion, the molar ratio of insulin but GLP-1 is metabolized more quickly with a plasma half to glucagon in the blood that reaches the liver via the portal life in humans of 2 minutes (Orskov C, et al., Diabetes 1993; circulation is greatly increased, whereby hepatic glucose pro 42:658-661). Carbohydrate or fat-rich meals stimulate secre duction decreases (Hvidberg A, et al., Metabolism 1994: tion (Elliott R M, et al., J. Endocrinol 1993: 138: 159-166), 43: 104-108). As a result blood glucose concentrations presumably as a result of direct interaction of yet unabsorbed decrease. Because of the glucose dependency of the insuli nutrients with the microvilli of the open-type L-cells of the notropic and glucagonostatic actions, the glucose lowering gut mucosa. effect is self-limiting, and the hormone, therefore, does not 0057 The incretin function of GLP-1 (29-31) has been cause hypoglycaemia regardless of dose (Qualmann C, et al., clearly illustrated in experiments with the GLP-1 receptor Acta Diabetologica, 1995; 32: 13-16). The effects are pre antagonist, exendin 9-39, which dramatically reduces the served in patients with diabetes mellitus (Nauck MA, et al., J incretin effect elicited by oral glucose in rats (Kolligs F, et al., Clin Invest 1993;91:301-307), in whom infusions of slightly Diabetes 199544: 16-19; Wang Z. et al., J. Clin. Invest. 1995 Supraphysiological doses of GLP-1 may completely norna 95:417-421). The hormone interacts directly with the B-cells lise blood glucose values in spite of poor metabolic control via the GLP-1 receptor (Thorens B., Proc Natl AcadSci 1992: and secondary failure to sulphonylurea (Nauck M A. et al., 89:8641-4645, U.S. Pat. Nos. 5,670,360 and 6,051.689, Diabetologia 1993; 36:741-744). The importance of the glu which are incorporated by reference herein) which belongs to cagonostatic effect is illustrated by the finding that GLP-1 the glucagon/VIP/calcitonin family of G-protein-coupled also lowers blood glucose in type-I diabetic patients without 7-transmembrane spanning receptors. The importance of the residual P-cell secretory capacity (Creutzfeldt W. et al., Dia GLP-1 receptor in regulating insulin secretion was illustrated betes Care 1996; 19:580-586). in recent experiments in which a targeted disruption of the 0059 GLP-1 is involved in increasing beta-cell mass as GLP-1 receptor gene was carried out in mice. Animals well as regulating beta-cell differentiation, beta-cell prolif homozygous for the disruption had greatly deteriorated glu eration and beta-cell survival (Stoffers DA, Horm Metab Res. cose tolerance and fasting hyperglycaemia, and even het 2004 November-December: 36(11-12):811-21), and has a erozygous animals were glucose intolerant (Scrocchi L., et al., role in increasing proinsulin gene transcription and biosyn Diabetes 1996: 45: 21A). The signal transduction mechanism thesis. (Fehmann HC, et al., Endocrine Reviews, 1995; 16:390-410) 0060. In addition to its effects on the pancreatic islets, primarily involves activation of adenylate cyclase, but eleva GLP-1 has powerful actions on the gastrointestinal tract. tions of intracellular Ca" are also essential (Fehmann HC, et Infused in physiological amounts, GLP-1 potently inhibits al., Endocrine Reviews, 1995; 16:390-410; Gromada J, et al., pentagastrin-induced as well as meal-induced gastric acid Diabetes 1995; 44; 767-774). A model of GLP-1 receptor secretion (Schjoldager BT G. et al., Dig. Dis. Sci. 1989; ligand interaction is shown in Lopez de Maturana, R. et al. 35:703-708; Wettergren A, et al., Dig Dis Sci 1993: 38:665 (2003).J. Biol. Chem. 278, 10195-10200. Lopez de Maturana 673). It also inhibits gastric emntying rate and pancreatic etal. indicate that the N-terminal domain of the receptor binds enzyme secretion (Wettergren A., et al., Dig Dis Sci 1993; to the conserved face of the central helix of exendin-4, GLP-1, 38:665-673). Similar inhibitory effects on gastric and pancre and exendin (9-39). The N-terminal regions of exendin-4 and atic secretion and motility may be elicited in humans upon GLP-1 interact with the extracellular loops and/or the trans perfusion of the ileum with carbohydrate- or lipid-containing membrane regions of the GLP-1 R. Also the N-terminal solutions (Layer P. et al., Dig Dis Sci 1995; 40: 1074-1082: domain of the receptor interacts with the Trp-cage portion of Layer P. et al., Digestion 1993:54:385-386). Concomitantly, the exendin-4 and exendin (9-39). Neidigh et al. Nature Struc GLP-1 secretion is greatly stimulated, and it has been specu tural Biology (2002) 9(6):425-430 describe the Trp-cage lated that GLP-1 may be at least partly responsible for this structure of Exendin-4 and mutants thereof. so-called “ileal-brake' effect (Layer P. et al., Digestion 1993; 0.058. The action of the hormone is best described as a 54: 385-386). In fact, recent studies suggest that, physiologi potentiation of glucose stimulated insulin release (Fehmann cally, the ileal-brake effects of GLP-1 may be more important HC, et al., Endocrine Reviews, 1995; 16:390-410), but the than its effects on the pancreatic islets. Thus, in dose response mechanism that couples glucose and GLP-1 stimulation is not studies GLP-1 influences gastric emptying rate at infusion US 2013/0096050 A1 Apr. 18, 2013

rates at least as low as those required to influence islet secre Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala tion (Nauck M, et al., Gut 1995; 37 (suppl. 2): A124). Trp-Leu-Val-Lys-Gly-Arg-X, wherein X is NH for GLP-1 0061 GLP-1 seems to have an effect on food intake. Intra (7-36) and X is Gly for GLP-1 (7-37). ventricular administration of GLP-1 profoundly inhibits food 0068 WO 91/11457 discloses analogues of the active intake in rats (Schick R R, Vorm Walde T. Zimmermann J. P. GLP-1 peptides 7-34, 7-35, 7-36, and 7-37 which can also be Schusdziarra V. Classen M. Glucagon-like peptide 1-a novel useful as GLP-1 moieties. brain peptide involved in feeding regulation. in Ditschuneit 0069 EP 0708179-A2 discloses GLP-1-like polypeptides H. Gries FA. Hauner H. Schusdziarra V. Wechsler JG (eds.) and derivatives that include an N-terminal imidazole group Obesity in Europe. John Libbey & Company Ltd., 1994; pp. and optionally an unbranched C-C acyl group in attached 363-367: 42). This effect seems to be highly specific. Thus, to the lysine residue in position 34. N-terminally extended GLP-1 (PG 72-107) amide is inactive 0070 EP 06996.86-A2 discloses certain N-terminal trun and appropriate doses of the GLP-1 antagonist, exendin 9-39. cated fragments of GLP-1 that are reported to be biologically abolish the effects of GLP-1. Acute, peripheral administra active. tion of GLP-1 does not inhibit food intake acutely in rats 0071. In some embodiments the compositions, pharma (Turton MD, et al., Nature 1996: 379: 69-72). However, it ceutical compositions comprise analogs, wherein the analog remains possible that GLP-1 secreted from the intestinal amino acid sequence is based upon the GLP-1 fragments, L-cells may also act as a satiety signal. polypeptides, and functional deriviatives disclosed above. 0062. Not only the insulinotropic effects but also the (0072 Another example of a peptide is T-20 (DP-178) effects of GLP-1 on the gastrointestinal tract are preserved in which is a peptide corresponding to amino acids 638 to 673 of diabetic patients (Willms B, et al., Diabetologia 1994; 37. the HIV-1 transmembrane protein (TM) gp41, the car Suppl. 1: A118), and may help curtailing meal-induced glu boxyl-terminal helical segment of the extracellular portion of cose excursions, but, more importantly, may also influence gp41. The extracellular portion of gp41 has another alpha.- food intake. Administered intravenously, continuously for helical region which is the amino-terminal proposed Zipper one week, GLP-1 at 4 ng/kg/min has been demonstrated to domain, DP-107, DP-107 exhibits potent antiviral activity by dramatically improve glycaemic control in NIDDM patients inhibiting viral fusion. It is a 38 amino acid peptide, corre without significant side effects (Larsen J, et al., Diabetes sponding to residues 558 to 595 of the HIV-1 transmem 1996: 45, suppl. 2: 233A). The peptide is fully active after brane gp41 protein. Studies with DP-107 have proven both Subcutaneous administration (Ritzel R. et al., Diabetologia are non-toxic in in vitro studies and in animals. U.S. Pat. No. 1995; 38: 720-725), but is rapidly degraded mainly due to 5,656,480, which is incorporated by reference herein, degradation by dipeptidyl peptidase IV-like enzymes (Dea describes DP-107 and its antiviral activity. In some embodi con CF, et al., J. Clin Endocrinol Metab 1995: 80: 952-957: ments the compositions, pharmaceutical compositions com Deacon CF, et al., Diabetes 44: 1126–1131). prise analogs, wherein the analog amino acid sequence is 0063. The amino acid sequence of GLP-1 is disclosed in based upon the DP-107 fragments, polypeptides, and func Schmidt a. al. (Diabetologia 28 704-707 (1985). Human tional deriviatives disclosed. GLP-1 is a 30-31 amino acid residue peptide originating from (0073 T-20 inhibits entry of HIV into cells by acting as a preproglucagon which is synthesized, i.a. in the L-cells in the viral fusion inhibitor. The fusion process of HIV is well distal ileum, in the pancreas and in the brain. Processing of characterized. HIV binds to CD4 receptor via gp120, and preproglucagon to GLP-1 (7-36)amide, GLP-1 (7-37) and upon binding to its receptor, gp120 goes through a series of GLP-2 occurs mainly in the L-cells. Although the interesting conformational changes that allows it to bind to its corecep pharmacological properties of GLP-1 (7-37) and analogues tors, CCR5 or CXCR4. After binding to both receptor and thereof have attracted much attention in recent years only coreceptor, gp120 exposes gp41 to begin the fusion process. little is known about the structure of these molecules. The gp41 has two regions named heptad repeat 1 and 2 (HR1 and secondary structure of GLP-1 in micelles has been described 2). The extracellular domain identified as HR1 is an B.-helical by Morton et al. (Biochemistry 33: 3532-3539 (1994)), but in region which is the amino-terminal of a proposed Zipper normal solution, GLP-1 is considered a very flexible mol domain. HR1 comes together with HR2 of gp41 to form a ecule. Derivatisation of this relatively small and very flexible hairpin. The structure that it is formed is a C-helix bundle that molecule resulted in compounds whose plasma profile were places the HIV envelope in the proximity of the cellular highly protracted and still had retained activity. membrane causing fusion between the two membranes. T-20 0064 GLP-1 and analogues of GLP-1 and fragments prevents the conformational changes necessary for viral thereof are useful i.a. in the treatment of Type 1 and Type 2 fusion by binding the first heptad-repeat (HR1) of the gp41 diabetes and obesity. transmembrane glycoprotein. Thus, the formation of the 0065 WO 87/06941 discloses GLP-1 fragments, includ 6-helix bundle is blocked by T-20's binding to the HR1 region ing GLP-1 (7-37), and functional derivatives thereof and to of gp41. The DP107 and DP178 domains (i.e., the 1-HR1 and their use as an insulinotropic agent. GLP-1 (7-37), certain HR2 domains) of the HIV gp41 protein non-covalently com derivatives thereof and the use thereof to treat Diabetes mel plex with each other, and their interaction is required for the litus in a mammal are disclosed in U.S. Pat. No. 5,120,712, normal infectivity of the virus. Compounds that disrupt the which is incorporated by reference herein. interaction between DP107 and DP178, and/or between 0066 WO 90/11296 discloses GLP-1 fragments, includ DP107-like and DP178-like peptides are antifusogenic, ing GLP-1 (7-36), and functional derivatives thereof which including antiviral. have an insulinotropic activity which exceeds the insulino 007.4 DP-178 acts as a potent inhibitor of HIV-1 mediated tropic activity of GLP-1(1-36) or GLP-1 (1-37) and to their CD-4 cell-cell fusion (i.e., syncytial formation) and infec use as insulinotropic agents. tion of CD-4 cells by cell-free virus. Such anti-retroviral 0067. The amino acid sequence of GLP-1 (7-36) and GLP activity includes, but is not limited to, the inhibition of HIV 1(7-37) is: His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser transmission to uninfected CD-4" cells. DP-178 act at low US 2013/0096050 A1 Apr. 18, 2013

concentrations, and it has been proven that it is non-toxic in in anti-HIV activity, and castanospermine as an inhibitor of vitro studies and in animals. The amino acid conservation glycoprotein processing. In some embodiments, the pharma within the DP-178-corresponding regions of HIV-1 and ceutical compositions comprises an analog of T20, wherein HIV-2 has been described. the analog amino acid sequence is based upon the T20 frag 0075 Potential uses for DP-178 peptides are described in ments, polypeptides, and functional deriviatives disclosed U.S. Pat. Nos. 5,464,933 and 6,133,418, as well as U.S. Pat. above. In some embodiments, the pharmaceutical composi Nos. 6,750,008 and 6,824,783, all of which are incorporated tion comprises an analog of T20, wherein the analog amino by reference herein, for use in inhibition of fusion events acid sequence is based upon the T20 fragments, polypeptides, associated with HIV transmission. and functional deriviatives disclosed above and one other 0076) Portions and homologs of DP178 and DP-107 as anti-viral agent. In some embodiments the pharmaceutical well as modulators of DP178/DP107, DP178-like/DP107 composition of the claimed invention comprises one another like or HR1/HR2 interactions have been investigated that anti-viral agent chosen from the following: reverse tran show antiviral activity, and/or show anti-membrane fusion Scriptase inhibitors, integrase inhibitors, protease inhibitors, capability, or an ability to modulate intracellular processes cytokine antagonists, and chemokine receptor modulators involving coiled-coil peptide structures in retroviruses other described U.S. Pat. Nos. 6,855,724; 6,844,340; 6,841,558: than HIV-1 and nonretroviral viruses. Viruses in such studies 6,833,457; 6,825,210; 6,811,780; 6,809,109; 6,806,265; include, simian immunodeficiency virus (U.S. Pat. No. 6,017, 6,768,007; 6,750,230; 6,706,706; 6,696,494; 6,673,821; 536), respiratory synctial virus (U.S. Pat. Nos. 6.228,983; 6,673,791; 6,667,314; 6,642,237; 6,599,911; 6,596,729: 6,440,656; 6,479,055; 6,623,741), Epstein-Barr virus (U.S. 6,593,346; 6,589,962: 6,586,430; 6,541,515; 6,538,002: Pat. Nos. 6,093,794; 6,518,013), parainfluenza virus (U.S. 6,531,484; 6,511,994; 6,506,777; 6,500,844; 6,498,161; Pat. No. 6,333,395), influenza virus (U.S. Pat. Nos. 6,068, 6,472.410; 6,432,981; 6,410,726; 6,399,619; 6,395,743: 973; 6,060,065), and measles virus (U.S. Pat. No. 6,013,263). 6,358,979; 6,265,434; 6,248,755; 6,245,806; and 6,172,110, All of which are incorporated by reference herein. which are incorporated by reference. 0077. A commercially available form of DP-178 is FuZeon.(R). (enfuvirtide, Roche Laboratories Inc. and Trim 0080 Potential delivery systems for DP-178 include, but eris, Inc.). FuZeon. R. has an acetylated N terminus and a are not limited to those described in U.S. Pat. Nos. 6,844,324 carboxamide as the C-terminus, and is described by the fol and 6,706,892. In addition, a process for producing T20 in lowing primary amino acid sequence: CHCO-YTSLIH inclusion bodies was described in U.S. Pat. No. 6,858,410. SLIEESQNQQEKNEQELLELDKWASLWNWF-NH. It is I0081 T20/DP178, T21/DP107, and fragments thereof used in combination with other antivirals in HIV-1 patients have also been found to interact with N-formyl peptide recep that show HIV-1 replication despite ongoing antiretroviral tor (FPR members). T-20 activates the N-formyl peptide therapy. receptor present in human phagocytes (Suet al. (1999) Blood 0078 U.S. Pat. Nos. 5,464,933 and 6,824,783, which are 93(11):3885-3892) and is a chemoattractant and activator of incorporated by reference herein, describes DP-178, DP-178 monocytes and neutrophils (see U.S. Pat. No. 6,830,893). The fragments and homologs, including, but not limited to, mol FPR class receptors are G-protein-coupled, STM receptors ecules with amino and carboxy terminal truncations, Substi that bind the chemoattractant fMLP (N-formyl-methionyl tutions, insertions, deletions, additions, or macromolecular leucyl-phenylalanine) and are involved in monocyte chemo carrier groups as well as DP-178 molecules with chemical taxis and the induction of a host immune response to a patho groups such as hydrophobic groups present at their amino gen. The prototype FPR class receptor, FPR, binds fMLP with and/or carboxy termini. Additional variants, include but are high affinity and is activated by low concentrations offMLP. not limited to, those described in U.S. Pat. No. 6,830,893 and The binding of FPR by fMLP induces a cascade of G protein the derivatives of DP-178 disclosed in U.S. Pat. No. 6,861, mediated signaling events leading to phagocytic cell adhe 059. A set of T-20 hybrid polypeptides are described in U.S. Sion, chemotaxis, release of oxygen intermediates, enhanced Pat. Nos. 6,656,906, 6,562,787, 6,348,568 and 6,258,782, phagocytosis and bacterial killing, as well as MAP kinase and a DP-178-toxinfusion is described in U.S. Pat. No. 6,627, activation and gene transcription. (Krump et al., J Biol Chem 197. In some embodiments the compositions, pharmaceutical 272:937 (1997); Prossnitz et al., Pharmacol Ther 74:73 compositions comprise analogs, wherein the analog amino (1997); Murphy, Annu. Rev. Immuno. 12: 593 (1994); and acid sequence is based upon the T-20 and DP-178 fragments, Murphy, The N-formyl peptide chemotactic receptors, polypeptides, and functional deriviatives disclosed above. Chemoattractant ligands and their receptors. CRC Press, 0079 HAART (Highly Active Anti-Retroviral Therapy) is Boca Raton, p. 269 (1996)). Another FPR class receptor is the the standard of therapy for HIV which combines drugs from highly homologous variant of FPR, named FPRL1 (also a few classes of antiretroviral agents to reduce viral loads. referred to as FPRH2 and LXA4R). FPRL1 was originally U.S. Pat. No. 6,861,059, which is incorporated by reference cloned as an orphan receptor (Murphy et al., J. Biol. Chem. herein, discloses methods of treating HIV-1 infection or 267:7637-7643 (1992); Ye et al., Biochem. Biophys. Res. inhibiting HIV-1 replication employing DP-178 or DP-107 or Commun., 184:582-589 (1992); Bao et al., Genomics, derivatives thereof, in combination with at least one other 13:437-440 (1992); Gao, J. L. and P. M. Murphy, J. Biol. antiviral therapeutic agent Such as a reverse transcriptase Chem., 268:25395-25401 (1993); and Nomura et al., Int. inhibitor (e.g. AZT, ddI, ddC, ddA, d4T, 3TC, or other Immunol. 5:1239-1249 (1993)) but was subsequently found dideoxynucleotides or dideoxyfluoronucleosides) or an to mediate Ca' mobilization in response to high concentra inhibitor of HIV-1 protease (e.g. indinavir; ritonavir). Other tions offMLP. (Yeet al., Biochem. Biophys. Res. Commun., antivirals include cytokines (e.g., rIFN.alpha., rFN.beta. 184:582-589 (1992); and Gao, J. L. and P. M. Murphy, J. Biol. rIFN-gamma.), inhibitors of viral mRNA capping (e.g. rib Chem. 268:25395-25401 (1993)). In some embodiments, the avirin), inhibitors of HIV protease (e.g. ABT-538 and invention relates to a method of modulating an FPR member MK-639), amphotericin B as a lipid-binding molecule with or CCR5 by: US 2013/0096050 A1 Apr. 18, 2013

I0082) a) contacting the FPR member or CCR5 molecule 10:797-803 (1989); and Grandy, Schimiczek et al., Regul with a T20 analog, wherein said analog comprises an Pept 51:151-9 (1994), which are incorporated by reference C.-amino acid and at least one B-amino acid; herein. 0083 b) measuring the association of the T20 analog to the I0088 PYY {3-36} has a sequence identical to PYY over FPR member or CCR5 in the presence and absence of an amino acids 3 to 36. PYY {3-36 contains approximately unknown compound; and 40% of total peptideYY-like immunoreactivity in human and 0084 c) comparing the rate of association of the T20 ana canine intestinal extracts and about 36% of total plasma pep log to the FPR member or CCR5 in the presence of an tide YY immunoreactivity in a fasting state to slightly over unknown compound to the rate of association of the T20 50% following a meal. It is apparently a dipeptidyl peptidase analog to the FPR member or CCR5 in the absence of an IV (DPP4) cleavage product of peptide YY. Peptide YY unknown compound. {3-36} is reportedly a selective ligand at the Y2 and Y5 I0085. The chemokine receptor CCR5 is another G-pro receptors, which appear pharmacologically unique in prefer tein-coupled, STM receptor and is a major fusion-cofactor ring N-terminally truncated (i.e. C terminal fragments of) exploited by most primary isolates of the human immunode neuropeptide Yanalogs. A PYYagonist may bind to a PYY ficiency virus type 1 (HIV-1). (Al Khatib et al., Science 1996, receptor with higher or lower affinity, demonstrate alonger or 272: 1955; Doranz et al., Cell 1996, 85:1149; Deng et al., shorter half-life in vivo or in vitro, or be more or less effective Nature 1996, 381:661; Dragic et al., Nature 1996: 381:667; than native PYY. In some embodiments a functional fragment Horuk, Immunol Today, 20:89 (1999); Dimitrov and Broder, of PYY {3-36} is a fragment of the above sequence that “HIV and Membrane Receptors. HIV and membrane fusion: shares the immunoreactivity in human and canine intestinal Medical Intelligence Unit, Landes Bioscience, Austin, Tex., eXtractS. 1997:99; and Berger, AIDS 11, SupplA:S3 (1997)). Individu I0089. Current antiobesity drugs have limited efficacy and als that fail to express CCR5 are largely resistant to HIV-1 numerous side effects. Crowley, V. E. Yeo, G. S. & O'Rahilly, infection. (Liu et al., Cell 1996, 86:367-77; Huang, Y. Nat S., Nat. Rev. Drug Discov 1, 276-86 (2002). With obesity Med 1996, 2:1240; Dean, et al., Science, 273:1856 (1996)). reaching epidemic proportions worldwide, there is a pressing Due to its prominent role in HIV-1 fusion and entry, investi need for the development of adequate therapeutics in this gators have focused considerable research on developing area. In recent years, hormones and neuropeptides involved in molecules that interrupt the interaction between the HIV-1 the regulation of appetite, body energy expenditure, and fat envelope and CCR5. Chemokine ligands and antibodies spe mass accumulation Such as PYY have emerged as potential cific for CCR5, for example, have been shown to inhibit antiobesity drugs. See McMinn, J. E. Baskin, D. G. & HIV-1 entry and replication. (Cocchi et al., Science, 270: 1811 Schwartz, M. W., Obes Rev 1:37-46 (2000), Drazen, D. L. & (1995); Wu et al., J Exp Med, 186: 373 (1997); Proudfoot et Woods, S. C., Curr Opin Clin Nutr Metab Care 6:621-629 al., J Biol Chem,271:2599 (1996); Arenzana-Seisdedos et al., (2003), which are incorporated by reference herein. Nature, 383:400 (1996); Gong et al., J Biol Chem, 273:4289 (0090. According to Satterham et al., Nature 418:650-654 (1998)). U.S. Pat. No. 6,808,877 discusses DP-178 and its (2002), which is hereby incorporated by reference, the pep role in phosphorylation and downregulation of CCR5 and/or tide YY 3-36 system may provide a therapeutic target for the inhibition of HIV infection by acting as a ligand to the the treatment of obesity. International Publication No. WO N-formyl peptide receptor. 02/47712 and U.S. Patent Application Publication No. 2002/ I0086 Peptide YY (PYY) is a thirty six amino acid long 014 1985 disclose methods for treating obesity and diabetes peptide, first isolated from porcine intestinal tissue and with peptideYY and peptideYYagonists, such as peptideYY mainly localized in intestinal endocrine cells. PYY is secreted {3-36}. U.S. Patent Application Publication No. postprandially by endocrine cells of the distal gastrointestinal 2005.0002927 describes the use of at least one Y2 receptor tract and acts at the hypothalamus signaling satiety. See Bat binding peptide, such as peptide YY. Neuropeptide Y (NPY) terham, R. L. et al., Nature 418:650-654 (2002), which is or Pancreatic Peptide (PP) for treating a variety of diseases incorporated by reference herein. It has many biological and conditions in mammalian Subjects Such as obesity and activities, including a range of activities within the digestive epilipsy. In some embodiments the compositions, pharma system and potent inhibition of intestinal electrolyte and fluid ceutical compositions comprise analogs, wherein the analog secretion. Like its relatives, neuropeptide Y (NPY) and pan amino acid sequence is based upon the PPY or the peptideYY creatic polypeptide (PP), peptideYY (PYY) is bent into hair (3-36) fragments, polypeptides, and functional deriviatives pin configuration that is important in bringing the free ends of disclosed above. In some embodiments, the invention relates the molecule together for binding to the receptors. to a pharmaceutical composition that comprise a PPY or 0087 Recent studies have shown that fasting and post peptide YY (3-36) analog, wherein the analog amino acid prandial PYY levels are low in obese subjects, which may sequence is based upon the fragments, polypeptides, and account for their high appetite and food consumption. When functional deriviatives disclosed above for treatment of obe administered intravenously, it suppresses appetite and food sity, diabetes, seizures associated with temporal lobe epi intake in both lean and obese subjects (Batterham, R. L. et al., lepsy, ulcers, irritable bowel disease and inflammatory bowel N Engl J Med 349:941-948 (2003)). Other peptides from the disease according to the dosing regimens disclosed below. pancreatic peptide (PP) family, like peptide YY fragments 0091. In some embodiments, the compositions of the (e.g. PYY {3-36), and PYYagonists (including those not in claimed invention comprise analog of PYY(3-36), AC the PP family) also suppress appetite. Its oral activity, how 162352, Neuropeptide Y (NPY) (U.S. Pat. No US 2005/ ever, is negligible due to its low absorption and rapid degra 0.136036A1). dation in the gastrointestinal tract. PYY 3-36 is identified 0092. In addition, treatment with DPP-IV inhibitors pre as Ile Lys pro Glu Ala Pro Gly Glu ASp Ala Ser Pro Glu Glu vents degradation of Peptide YY which has been linked to Leu Asn Arg Tyr Tyr Ala Ser Leu Arg His Tyr Leu Asn Leuval gastrointestinal conditions such as ulcers, irritable bowel dis Thr Arg Glin Arg Tyr; Eberlein, Eysselein et al., Peptides ease and inflammatory bowel disease. Peptide YY and its US 2013/0096050 A1 Apr. 18, 2013

analogs or agonists have been used to manipulate endocrine nin), including those described in U.S. Pat. No. 5,739,106, regulation of cell proliferation, nutrient transport, and intes which is hereby incorporated by reference. The CCK used is tinal water and electrolyte secretion. (U.S. Pat. No. 5,604, preferably CCKoctopeptide (CCK-8). Leptin is discussed in, 203; WO9820885A1 EP692971A 1: U.S. Pat. No. 5,912, for example, Pelleymounter, C. et al., Science 269: 540-543 227, which are incorporated by reference herein). A role for (1995), Halaas, G. et al., Science 269: 543-6 (1995) and peptide YY in the regulation of intestinal motility, secretion, Campfield, S. et al., Science 269: 546-549 (1995). Suitable and blood flow has also been Suggested, as well as its use in a CCKagonist includes those described in U.S. Pat. No. 5,739, treatment of malabsorptive disorders. Analogs of PYY have 106, which is hereby incorporated by reference. Suitable been reported that emulate and enhance the duration, effect, exendins include exendin-3 and exendin-4, and exendinago biological activity and selectivity of the natural peptide in the nist compounds include, for example, those described in PCT treatment of pancreatic tumors (See U.S. Ser. No. 5,574,010, Publications WO 99/07404, WO 99/25727, and WO incorporated herein by reference). 99/25728, all of which are hereby incorporated by reference. 0093. Other suitable PYY agonists include those According to one embodiment, the composition of the present described in International Publication No. WO 98/20885, invention includes at least one delivery agent compound, which is hereby incorporated by reference. PYY, a PYYagonist, or a mixture thereof, at least one amylin 0094. In one aspect, the invention provides a method of agonist, and a CCKagonist. Suitable combinations of amylin treating obesity in an obese or overweight animal by admin agonist and CCKagonist include, but are not limited to, those istering a therapeutically effective amount of PYY analog, a described in U.S. Pat. No. 5,739,106, which is hereby incor PYY agonist analog, or a mixture thereof with at least one porated by reference. delivery agent compound and to a subject in need thereof. 0097. In some embodiments, the pharmaceutical compo While “obesity' is generally defined as a body mass index sitions comprises an analog of the polypeptides disclosed over 30, for purposes of this disclosure, any Subject, including below, wherein the analogamino acid sequence is based upon those with a body mass index of less than 30, who needs or fragments, polypeptides, and functional deriviatives with wishes to reduce body weight is included in the scope of 70%, 75%, 85%, 90%. 95%, 98%, or 99% sequence homol “obese.” Subjects who are insulin resistant, glucose intoler ogy to the following polypeptides disclosed below: ant, or have any form of diabetes mellitus (e.g., type 1, 2 or 0.098 Adrenocorticotropic hormone (ACTH) peptides gestational diabetes) can benefit from this method. including, but not limited to, ACTH, human; ACTH 1-10; 0095. In other aspects, the invention features methods of ACTH 1-13, human; ACTH 1-16, human; ACTH 1-17; reducing food intake, treating diabetes mellitus, and improv ACTH 1-24, human; ACTH 4-10; ACTH 4-11; ACTH 6-24: ing lipid profile (including reducing LDL cholesterol and ACTH 7-38, human; ACTH 18-39, human; ACTH, rat; triglyceride levels and/or changing HDL cholesterol levels) ACTH 12-39, rat; beta-cell tropin (ACTH 22-39); biotinyl comprising administering to a Subject in need thereofathera ACTH 1-24, human; biotinyl-ACTH 7-38, human; corticos peutically effective amount of a PYY analog, a PYYagonist tatin, human; corticostatin, rabbit: {Met(02), DLys, Phe analog, or a mixture thereof with at least one delivery agent ACTH 4-9, human; Met(0),DLys, Phe ACTH 4-9, compound. In some embodiments, the methods of the inven human: N-acetyl, ACTH 1-17, human; and ebiratide. tion are used to treat conditions or disorders which can be 0099 Adrenomedullin peptides including, but not limited alleviated by reducing nutrient availability in a subject in need to, adrenomedullin, adrenomedulin 1-52, human; adrenom thereof, comprising administering to said subject in need edullin 1-12, human; adrenomedullin 13-52, human; thereofatherapeutically effective amount of a PYY analog, a adrenomedulin 22-52, human; pro-adrenomedullin 45-92, PYY agonist analog, or a mixture thereof with at least one human; pro-adrenomedullin 153-185, human; adrenomedul delivery agent compound. Such conditions and disorders lin 1-52, porcine; pro-adrenomedullin (N-20), porcine; include, but are not limited to, hypertension, dyslipidemia, adrenomedullin 1-50, rat; adrenomedullin 11-50, rat; and cardiovascular disease, eating disorders, insulin-resistance, proAM-N20 (proadrenomedullin N-terminal 20 peptide), rat. obesity, and diabetes mellitus of any kind. 0100 Allatostatin peptides including, but not limited to, 0096 Suitable PYY agonist analogs may be derived or allatostatin I; allatostatin II; allatostatin III; and allatostatin based upon the amino acid sequence of PYY agonists that IV. have a potency in one of the assays described in WO 02/47712 0101 Amylin peptides including, but not limited to, and U.S. patent Publication No. 2002/014 1985 (which is acetyl-amylin 8-37, human; acetylated amylin 8-37, rat; herein incorporated by reference and discloses the activity of AC187 amylin antagonist; AC253 amylin antagonist; AC625 food intake, gastric emptying, pancreatic secretion, or weight amylin antagonist; amylin 8-37, human; amylin (IAPP), cat: reduction assays) which is greater than the potency of NPY in amylin (insulinoma or islet amyloid polypeptide(IAPP)): that same assay. APYY analog and/or a PYYagonist analog amylin amide, human; amylin 1-13 (diabetes-associated pep with the delivery agent compound may be administered sepa tide 1-13), human; amylin 20-29 (IAPP 20-29), human; rately or together with one or more other compounds and AC625 amylin antagonist; amylin 8-37, human; amylin compositions that exhibit a long term or short-term action to (IAPP), cat; amylin, rat; amylin 8-37, rat; biotinyl-amylin, reduce nutrient availability, including, but not limited to other rat; and biotinyl-amylin amid; human. compounds and compositions that comprise an amylin or 0102 Amyloid beta-protein fragment peptides including, amylin agonist, a cholecystokinin (CCK) or CCK agonist, a but not limited to, Alzheimer's disease beta-protein 12-28 leptin (OB protein) or leptin agonist, an exendin or exendin (SP17): amyloid beta-protein 25-35; amyloid beta/A4-pro agonist, or a GLP-1 or GLP-1 agonist as described in U.S. tein precursor 328-332; amyloid beta/A4 protein precursor Patent Publication 2005.0009748. Suitable amylin agonists (APP) 319-335; amyloid beta-protein 1-43; amyloid beta include, for example, (25.28.29Pro-)-human amylin (also protein 1-42; amyloid beta-protein 1-40; amyloid beta-pro known as “pramlintide', and described in U.S. Pat. Nos. tein 10-20; amyloid beta-protein 22-35; Alzheimer's disease 5,686,511 and 5.998.367), calcitonin (e.g., salmon calcito beta-protein (SP28); beta-amyloid peptide 1-42, rat; beta US 2013/0096050 A1 Apr. 18, 2013 amyloid peptide 1-40, rat; beta-amyloid 1-11: beta-amyloid pneumophila, leishmania; leprosy, lyme disease; malaria 31-35; beta-amyloid 32-35; beta-amyloid 35-25; beta-amy immunogen; measles; meningitis; meningococcal; Meningo loid/A4 protein precursor 96-110; beta-amyloid precursor coccal polysaccharide group A; Meningococcal polysaccha protein 657-676; beta-amyloid 1-38; (Gln)-Alzheimer's ride group C; mumps; mumps virus; mycobacteria; Mycobac disease beta-protein; (Gln')-beta-amyloid 1-40; (Gln’)- terium tuberculosis, Neisseria, Neisseria gonorrhea, beta-amyloid 6-40; non-A beta component of Alzheimer's Neisseria meningitidis; Ovine blue tongue; Ovine encephali disease amyloid (NAC); P3, (Abeta 17-40) Alzheimer's dis tis; papilloma; parainfluenza; paramyxoviruses; Pertussis; ease amyloid.beta.-peptide; and SAP (serum amyloid P.com plague; pneumococcus; Pneumocystis carinii; pneumonia; ponent) 194-204. poiiovirus; proteus species; Pseudomonas aeruginosa; 0103 Angiotensin peptides including, but not limited to, rabies; respiratory syncytial virus; rotavirus; rubella; salmo A-779; Ala-Pro-Gly-angiotensin II; (Ile Val)-angiotensin nellae; schistosomiasis; Shigellae; simian immunodeficiency II; angiotensin III antipeptide; angiogenin fragment 108-122; virus; Smallpox, Staphylococcus aureus, Staphylococcus angiogenin fragment 108-123; angiotensin I converting species; Streptococcus pneumoniae, Streptococcus pyo enzyme inhibitor, angiotensin I, human; angiotensin I con genes, Streptococcus species; Swine influenza; tetanus; Tre Verting enzyme Substrate; angiotensin I 1-7, human; angio ponema pallidum; typhoid; vaccinia; Varicella-Zoster virus; peptin; angiotensin II, human; angiotensin II antipeptide; and vibrio cholerae. angiotensin II 1-4, human; angiotensin II 3-8, human; angio 010.6 Anti-microbial peptides including, but not limited tensin II 4-8, human; angiotensin II 5-8, human; angiotensin to, buforin I; buforin II; cecropin A; cecropin B; cecropin PI, III (Des-Asp-angiotensin II), human; angiotensin III porcine; gaegurin 2 (Rana rugosa); gaegurin 5 (Rana rug inhibitor ({Ile'}-angiotensin III); angiotensin-converting Osa); indolicidin; protegrin-(PG)-I; magainin 1; and magai enzyme inhibitor (Neothunnus macropterus); Asn. Val nin 2; and T-22 Tyr', Lys7-poly-phemusin II peptide. angiotensin I, goosefish; {ASn", Val, ASn-angiotensin I, 0107 Apoptosis related peptides including, but not lim salmon; (Asn', Val, Gly)-angiotensin I, eel: {Asn', Val ited to, Alzheimer's disease beta-protein (SP28); calpain angiotensin I 1-7, eel, goosefish, Salmon; {ASn". Val-angio inhibitor peptide; capsase-1 inhibitor V: capsase-3, substrate tensin II; biotinyl-angiotensin I, human; biotinyl-angiotensin IV: caspase-1 inhibitor I, cell-permeable; caspase-1 inhibitor II, human; biotinyl-Ala-Ala-Ala-angiotensin II: Des VI: caspase-3 Substrate III, fluorogenic; caspase-1 Substrate Asp'}-angiotensin I, human: {p-aminophenylalanine-an V, fluorogenic; caspase-3 inhibitor I, cell-permeable: giotensin II; renin Substrate (angiotensinogen 1-13), human; caspase-6 ICE inhibitor III: Des-Ac, biotin-ICE inhibitor preangiotensinogen 1-14 (renin Substrate tetradecapeptide), III; IL-1B converting enzyme (ICE) inhibitor II; IL-1B con human; renin Substrate tetradecapeptide (angiotensinogen verting enzyme (ICE) substrate IV: MDL 28170; and 1-14), porcine: {Sar'}-angiotensin II, (Sar)-angiotensin II MG-132. 1-7 amide: {Sar", Ala-angiotensin II: Sar', Ile-angio 0.108 Atrial natriuretic peptides including, but not limited tensin II: Sar", Thr}-angiotensin II; (Sar", Tyr(Me)")-an to, alpha-ANP (alpha-chANP), chicken; anantin: ANP 1-11, giotensin II (Sarmesin); Sar", Val, Ala-angiotensin II: rat: ANP 8-30, frog: ANP 11-30, frog: ANP-21 (fANP-21), {Sar", Ile-angiotensin III; synthetic tetradecapeptide renin frog: ANP-24 (fANP-24), frog: ANP-30, frog: ANP fragment substrate (No. 2); {Val-angiotensin III: {Val-angiotensin 5-28, human, canine: ANP-7-23, human: ANP fragment 7-28, II: {Val-angiotensin I, human: {Val-angiotensin I: {Val, human, canine; alpha-atrial natriuretic polypeptide 1-28, Asn-angiotensin I, bullfrog; and Val, Ser}-angiotensin human, canine; A71915, rat; atrial natriuretic factor 8-33, rat; I, fowl. atrial natriuretic polypeptide 3-28, human; atrial natriuretic 0104 Antibiotic peptides including, but not limited to, polypeptide 4-28, human, canine; atrial natriuretic polypep Ac-SQNY: bactenecin, bovine; CAP 37 (20-44); car tide 5-27; human; atrial natriuretic aeptide (ANP), eel; atrio bormethoxycarbonyl-DPro-DPhe-OBzl; CD36 peptide P peptin I, rat, rabbit, mouse; atriopeptin II, rat, rabbit, mouse; 139-155; CD36 peptide P93-110:cecropin A-melittin hybrid atriopeptin III, rat, rabbit, mouse; atrial natriuretic factor peptide (CA(1-7)M(2-9)NH); cecropin B, free acid; CYS (raNF), rat, auriculin A (rat ANF 126-149); auriculin B (rat (BZl)84 CD fragment 81-92; defensin (human) HNP-2; der ANF 126-150); beta-ANP (1-28, dimer, antiparallel); beta maseptin; immunostimulating peptide, human; lactoferricin, rANF 17-48; biotinyl-alpha-ANP1-28, human, canine; bioti bovine (BLFC); and magainin spacer. nyl-atrial natriuretic factor (biotinyl-rANF), rat; cardiodilatin 0105 Antigenic polypeptides, which can elicit an 1-16, human; C-ANF 4-23, rat: Des-Cys', Cys'}-atrial enhanced immune response, enhance an immune response natriuretic factor 104-126, rat; Met(O)' ANP 1-28, and or cause an immunizingly effective response to diseases human: (Mpr’.DAla)ANP 7-28, amide, rat; prepro-ANF and/or disease causing agents including, but not limited to, 104-116, human; prepro-ANF26-55 (proANF 1 -30), human; adenoviruses; anthrax; Bordetella pertussus; botulism; prepro-ANF 56-92 (proANF 31-67), human; prepro-ANF bovine rhinotracheitis; Branhamella Catarrhalis; canine 104-123, human: {Tyr'}-atriopeptin I, rat, rabbit, mouse; hepatitis; canine distemper; Chlamydiae; cholera; coccidi {Tyr'}-atriopeptin II, rat, rabbit, mouse; {Tyr-prepro ANF omycosis; cowpox, cytomegalovirus; Dengue fever, dengue 104-123, human; urodilatin (CDD/ANP 95-126); ventricular toxoplasmosis; diphtheria; encephalitis; enterotoxigenic E. natriuretic peptide (VNP), eel; and ventricular natriuretic coli: Epstein Barr virus; equine encephalitis; equine infec peptide (VNP), rainbow trout. tious anemia; equine influenza; equine pneumonia; equine 0109 Bag cell peptides including, but not limited to, alpha rhinovirus; Escherichia Coli; feline leukemia; flavivirus; bag cell peptide; alpha-bag cell peptide 1-9; alpha-bag cell globulin; haemophilus influenza type b: Haemophilus influ peptide 1-8; alpha-bag cell peptide 1-7; beta-bag cell factor, enzae, Haemophilus pertussis, Helicobacter pylori; hemo and gamma-bag cell factor. philus; hepatitis; hepatitis A: hepatitis B; Hepatitis C; herpes 0110 Bombesin peptides including, but not limited to, viruses; HIV: HIV-1 viruses; HIV-2 viruses; HTLV; influ alpha-s1 casein 101-123 (bovine milk); biotinyl-bombesin: enza, Japanese encephalitis; Klebsiellae species: Legionella bombesin 8-14; bombesin: Leu'-psi (CH-NH)Leu''}- US 2013/0096050 A1 Apr. 18, 2013 bombesin: D-Phe, Des-Met''}-bombesin 6-14 ethylamide: morphin 1-3, amide; beta-casomorphin, bovine; beta-caso (DPhe') bombesin; DPhe'.Leu''}-bombesin: Tyr morphin 1-4, bovine; beta-casomorphin 1-5, bovine; beta bombesin; and (Tyr'.DPhe')-bombesin. casomorphin 1-5, amide, bovine; beta-casomorphin 1-6. 0111 Bone GLA peptides (BGP) including, but not lim bovine: {DAla-beta-casomorphin 1-3, amide, bovine: ited to, bone GLA protein; bone GLA protein 45-49; {Glu'', {DAla’.Hyp'Tyr}-beta-casomorphin 1-5 amide: {DAla, Gla''''}-osteocalcin 1-49, human; myclopeptide-2 (MP-2); DProTyr}-beta-casomorphin 1-5, amide: {DAla.Tyr osteocalcin 1-49 human; osteocalcin 37-49, human; and beta-casomorphin 1-5, amid; bovine: {DAla'.Tyr}-beta {Tyr, Phe''} bone GLA protein 38-49, human. casomorphin 1-5, amide, bovine: {DAla, (pCl)Phe-beta 0112 Bradykinin peptides including, but not limited to, casomorphin, amide, bovine: {DAla-beta-casomorphin {Ala', des-Pro-bradykinin; bradykinin; bradykinin 1-4, amide, bovine: {DAla-beta-casomorphin 1-5, bovine; (Bowfin. Gar); bradykinin potentiating peptide; bradykinin {DAla-beta-casomorphin 1-5, amide, bovine; DAIa, 1-3; bradykinin 1-5; bradykinin 1-6; bradykinin 1-7; brady Met}-beta-casomorphin 1-5, bovine: {DPro-beta-caso kinin 2-7:bradykinin 2-9; {DPhe7 bradykining (Des-Arg)- morphin 1-5, amid; bovine: {DAla-beta-casomorphin 1-6, bradykin in: {Des-Arg'}-Lys-bradykin in (Des-Arg'}- bovine: {DPro-beta-casomorphin 1-4, amide: (Des-Tyr")- kallidin); {D-N-Me-Phe-bradykinin; {Des-Arg, Leu beta-casomotphin, bovine; (DAla'.Tyr)-beta-casomorphin bradykinin; Lys-bradykinin (kallidin); Lys-(Des-Arg, 1-5, amid; bovine: {DAla, (pCOPhe-beta-casomorphin, Leu)-bradykinin ({Des-Arg", Leu-kallidin); Lys'- amide, bovine: {DAla-beta-casomorphin 1-4, amide, Hyp}-bradykinin; ovokinin; (Lys", Ala)-bradykinin; Met bovine: {DAla-beta-casomorphin 1-5, bovine: {DAla Lys-bradykinin; peptide K12 bradykinin potentiating pep beta-casomorphin 1-5, amid; bovine: {DAla Met}-beta-ca tide: {(pCl)Phe-bradykinin; T-kinin (Ile-Ser-bradykinin); somorphin 1-5, bovine: {DPro-beta-casomorphin 1-5, {This, D-Phe7}-bradykinin; Tyr'}-bradykinin; Tyr amid; bovine: {DAla-beta-casomorphin 1-6, bovine; bradykinin; {Tyr}-bradykinin; and kallikrein. {DPro-beta-casomorphin 14, amide: {Des-Tyr'}-beta-ca 0113 Brain natriuretic peptides (BNP) including, but not sornorphin, bovine; and (Val)-beta-casomorphin 1-4, amide, limited to, BNP 32, canine; BNP-like Peptide, eel; BNP-32, bovine. human; BNP-45, mouse; BNP-26, porcine; BNP-32, porcine: I0120 Chemotactic peptides including, but not limited to, biotinyl-BNP-32, porcine; BNP-32, rat; biotinyl-BNP-32, defensin 1 (human) HNP-1 (human neutrophil peptide-1); rat; BNP45 (BNP 51-95, 5K cardiac natriuretic peptide), rat; and N-formyl-Met-Leu-Phe. and){Tyr'}-BNP 1-32, human. I0121 Cholecystokinin (CCK) peptides including, but not 0114 C-peptides including, but not limited to, C-peptide; limited to, caerulein; cholecystokinin; cholecystokinin-pan and {Tyr'}-C-peptide, human. creozymin, CCK-33, human; cholecystokinin octapeptide 14 0115 C-type natriuretic peptides (CNP) including, but not (non-sulfated) (CCK 26-29, unsulfated); cholecystokinin limited to, C-type natriuretic peptide, chicken: C-type natri octapeptide (CCK26-33); cholecystokinin octapeptide (non uretic peptide-22 (CNP-22), porcine, rat, human; C-type sulfated) (CCK 26-33, unsulfated); cholecystokinin hep natriuretic peptide-53 (CNP-53), human: C-type natriuretic tapeptide (CCK 27-33); cholecystokinin tetrapeptide (CCK peptide-53 (CNP-53), porcine, rat; C-type natriuretic pep 30-33); CCK-33, porcine: CR 1409, cholecystokinin antago tide-53 (porcine, rat) 1-29 (CNP-531-29); prepro-CNP 1-27, nist; CCK flanking peptide (unsulfated); N-acetylcholecys rat; prepro-CNP 30-50, porcine, rat; vasonatrin peptide tokinin, CCK 26-30, sulfated; N-acetyl cholecystokinin, (VNP); and {Tyr'}-C-type natriuretic peptide-22 ({Tyr'}- CCK 26-31, sulfated: N-acetylcholecystokinin, CCK26-31, CNP-22). non-sulfated; prepro CCK fragment V-9-M; and proglumide. 0116 Calcitonin peptides including, but not limited to, 0.122 Colony-stimulating factor peptides including, but biotinyl-calcitonin, human; biotinyl-calcitonin, rat; biotinyl not limited to, colony-stimulating factor (CSF); GMCSF: calcitonin, Salmon, calcitonin, chicken, calcitonin, eel; calci MCSF; and G-CSF. tonin, human; calcitonin, porcine; calcitonin, rat; calcitonin, salmon; calcitonin 1-7. human; calcitonin 8-32, Salmon; kata I0123 Corticortropin releasing factor (CRF) peptides calcin (PDN-21) (C-procalcitonin); and N-proCT (amino including, but not limited to, astressin; alpho.-helical CRF terminal procalcitonin cleavage peptide), human. 12-41; biotinyl-CRF, ovine; biotinyl-CRF, human, rat; CRF, 0117 Calcitonin gene related peptides (CGRP) including, bovine: CRF, human, rat; CRF, ovine; CRF, porcine; but not limited to, acetyl-alpha-CGRP 19-37, human; alpha {Cys''}-CRF, human, rat; CRF antagonist (alphO-helical CGRP 19-37, human; alpha-CGRP 23-37, human; biotinyl CRF 9-41); CRF 6-33, human, rat: {DPro-CRF, human, rat; CGRP human; biotinyl-CGRP II, human; biotinyl-CGRP, ID-Phe', Nle'-CRF 12-41, human, rat; eosinophilotactic rat; beta-CGRP rat; biotinyl-beta-CGRP rat; CGRP rat; peptide; Met(0)}-CRF, ovine: {NIe', Tyr-CRF, ovine: CGRP human; calcitonin C-terminal adjacent peptide: prepro CRF 125-151, human; sauvagine, frog; Tyr'}-CRF, CGRP 1-19, human; CGRP 20-37, human; CGRP 8-37, human, rat: {Tyr-CRF, ovine: Tyr-CRF 34-41, ovine: human; CGRP II, human; CGRP rat; CGRP 8-37, rat; CGRP {Tyr'}-urocortin; urocortin amide, human; urocortin, rat; 29-37, rat; CGRP30-37, rat; CGRP31-37, rat; CGRP32-37, urotensin I (Catostomus commerSoni); urotensin II; and uro rat; CGRP 33-37, rat; CGRP 31-37, rat; ({Cys(Acm)''}- tensin II (Rana ridibunda). CGRP: elcatonin; Tyr-CGRP human: {Tyr'}-CGRP II, 0.124 Cortistatin peptides including, but not limited to, human: {Tyr'}-CGRP 28-37, rat: {Tyr'}-CGRP rat; and cortistatin 29; cortistatin 29 (1-13); {Tyr'}-cortistatin 29; {Tyr}-CGRP 22-37, rat. pro-cortistatin 28–47; and pro-cortistatin 51-81. 0118 CART peptides including, but not limited to, CART, 0.125 Cytokine peptides including, but not limited to, human; CART 55-102, human; CART, rat; and CART tumor necrosis factor; and tumor necrosis factor-.beta. 55-102, rat. (TNF-beta.). 0119 Casomorphin peptides including, but not limited to, 0.126 Dermorphin peptides including, but not limited to, beta-casomorphin, human; beta-casomorphin 1-3, beta-caso dermorphin and dermorphin analog 1-4. US 2013/0096050 A1 Apr. 18, 2013

0127 Dynorphin peptides including, but not limited to, endothelin-2 (ET-2), human, canine; endothelin-3 (ET-3), big dynorphin (prodynorphin 209-240), porcine; biotinyl human, rat, porcine, rabbit; biotinyl-endothelin-3 (biotinyl dynorphin A (biotinyl-prodynorphin 209-225); {DAla, ET-3); prepro-endothelin-1 (94-109), porcine; BQ-518; DArgdynorphin A 1-13, porcine: {D-Ala-dynorphin A, BQ-610; BQ-788; endothelium-dependent relaxation porcine: {D-Ala-dynorphin A amide, porcine: {D-Ala'}- antagonist; FR13.9317: IRL-1038; JKC-30 1: JICC-302: dynorphin A 1-13, amide, porcine: {D-Ala-dynorphin A PD-145065; PD-142893; sarafotoxin S6a (atractaspis engad 1-9, porcine: {DArg'}-dynorphin A 1-13, porcine: {DArg densis); Sarafotoxin S6b (atractaspis engaddensis); Sarafo dynorphin A 1-13, porcine: {Des-Tyr'}-dynorphin A 1-8; toxin S6c (atractaspis engaddensis): {Lys-Sarafotoxin S6c; {D-Pro'}-dynorphin A 1-11, porcine; dynorphin A amide, sarafotoxin S6d; big endothelin-1, human; biotinyl-big porcine, dynorphin A 1-6, porcine; dynorphin. A 1-7, porcine; endothelin-1, human; big endothelin-1 (1-39), porcine; big dynorphin A 1-8, porcine; dynorphin A 1-9, porcine; dynor endothelin-3 (22-41), amide, human; big endothelin-1 (22 phin A 1-10, porcine; dynorphin A 1-10 amide, porcine; 39), rat; big endothelin-1 (1-39), bovine; big endothelin-1 dynorphin A 1-11, porcine; dynorphin A 1-12, porcine; (22-39), bovine; big endothelin-1 (19-38), human; big endot dynorphin A 1-13, porcine; dynorphin A 1-13 amide, porcine; helin-1 (22-38), human; big endothelin-2, human; big endot DAKLI (dynorphin A-analogue kappa ligand); DAKLI-bi helin-2 (22-37), human; big endothelin-3, human; big endot otin (Arg'''}-dynorphin A (1-13)-Gly-NH(CH)NH-bi helin-1, porcine; big endothelin-1 (22-39) (prepro otin); dynorphin A 2-17, porcine; dynorphin 2-17, amide, endothelin-1 (74-91); big endothelin-1, rat; big endothelin-2 porcine, dynorphin A 2-12, porcine, dynorphin A 3-17. (1-38), human; big endothelin-2 (22-38), human; big endot amide, porcine, dynorphin A 3-8, porcine; dynorphin A 3-13, helin-3, rat; biotinyl-big endothelin-1, human; and (Tyr')- porcine; dynorphin A 3-17, porcine; dynorphin A 7-17, por prepro-endothelin (110-130), amide, human. cine; dynorphin A 8-17, porcine, dynorphin A 6-17, porcine; 0.130 ETa receptor antagonist peptides including, but not dynorphin A 13-17, porcine; dynorphin A (prodynorphin limited to, (BQ-123); BE18257B}: {BE-18257A}/{W- 209-225), porcine; dynorphin B 1-9; MeTyr', MeArg, 7338A}:{BQ-485}: FR13.9317; PD-151242; and TTA-386. D-Leu-dynorphin 1-8 ethyl amide: {(nMe)Tyr'} dynor I0131 ETb receptor antagonist peptides including, but not phin A 1-13, amid; porcine; Phe7-dynorphin A 1-7, por limited to, BQ-3020: {RES-701-3); and IRL-1720} cine: {Phe7-dynorphin A 1-7, amide, porcine; and prodynor I0132) Enkephalin peptides including, but not limited to, phin 228-256 (dynorphin B 29) (leumotphin), porcine. adrenorphin, free acid; amidorphin (proenkephalin A (104 0128 Endorphin peptides including, but not limited to, 129)-NII2), bovine: BAM-12P (bovine adrenal medulla alpha-neo-endorphin, porcine; beta-neoendorphin; Ac-beta enkephalin: {D-Ala, D-Leu-enkephalin: {D-Ala., endorphin, camel, bovine, Ovine; Ac-beta-endorphin 1-27. D-Met-enkephalin: {DAla-Leu-enkephalin, amide: camel, bovine, ovine; Ac-beta-endorphin, human; Ac-beta {DAla, Leu, Arg-enkephalin: Des-Tyr'.DPen-en endorphin 1-26, human; Ac-beta-endorphin 1-27, human; kephalin: {Des-Tyr'.DPen, Pen-enkephal in: {Des-Tyr Ac-gamma-endorphin (Ac-beta-lipotropin 61-77); acetyl-al Leu-enkephalin: {D-Pen’-enkephalin: {DPen, Pen-en pha-endorphin; alpha-endorphin (beta-lipotropin 61-76): kephalin; enkephalinase substrate: {D-Pen, pCI-Phe", alpha-neo-endorphin analog; alpha-neo-endorphin 1-7; D-Pen-enkephalin; Leu-enkephalin; Leu-enkephalin, {Arg-alpha-neoendorphin 1-8; beta-endorphin (beta-lipo amide; biotinyl-Leu-enkephalin: {D-Ala-Leu-enkephalin; tropin 61-91), camel, bovine, ovine; beta-endorphin 1-27. {D-Ser-Leu-enkephalin-Thr (delta-receptor peptide) (DS camel, bovine, Ovine; beta-endorphin, equine; beta-endor LET); (D-Thr)-Leu-enkephalin-Thr (DTLET); Lys-Leu phin (beta-lipotropin 61-91), human; beta-endorphin (1-5)+ enkephalin: {MetArg-enkephalin; (MetArg-enkepha (16-31), human; beta-endorphin 1-26, human; beta-endor lin-Arg: {Met. Arg'.Phe'}-enkephalin, amide; Met phin 1-27, human; beta-endorphin 6-31, human; beta enkephalin; biotinyl-Met-enkephalin: {D-Ala-Met endorphin 18-31, human; beta-endorphin, porcine; beta enkephalin: {D-Ala-Met-enkephalin, amide; Met endorphin, rat; beta-lipotropin 1-10, porcine; beta-lipotropin enkephalin-Arg-Phe, Met-enkephalin, amide: {Ala-Met 60-65; beta-lipotropin 61-64; beta-lipotropin 61-69; beta-li enkephalin, amide: {DMet, Pro-enkephalin, amide: potropin 88-91; biotinyl-beta-endorphin (biotinyl-bets-lipo {DTrp-Met-enkephalin, amide, metorphinamide (adrenor tropin 61-91); biocytin-beta-endorphin, human; gamma-en phin); peptide B. bovine; 3200-Dalton adrenal peptide E. dorphin (beta-lipotropin 61-77); {DAla-alpha-neo bovine; peptide F. bovine; preproenkephalin B 186-204. endorphin 1-2, amide: (DAla)-beta-lipotropin 61-69; human; spinorphin, bovine; and thiorphan (D.L.3-mercapto (DAla)-gamma-endorphin: {Des-Tyr'}-beta-endorphin, 2-benzylpropanoyl-glycine). human: {Des-Tyr'}-gamma-endorphin (beta-lipotropin 0.133 Fibronectin peptides including, but not limited to 62-77); (Leu)-beta-endorphin, camel, bovine, ovine: {Met, platelet factor-4 (58-70), human; echistatin (Echis carinatus): Lys-alpha-neo-endorphin 1-6; Met, Lys7-alpha-neo E. P. L. Selectin conserved region; fibronectin analog: endorphin 1-7; and {Met, Lys, Arg-alpha-neo-endorphin fibronectin-binding protein; fibrinopeptide A, human; 1-7. {Tyr'}-fibrinopeptide A, human; fibrinopeptide B, human; 0129. Endothelin peptides including, but not limited to, {Glu'}-fibrinopeptide B, human: {Tyr'}-fibrinopeptide B, endothelin-1 (ET-1); endothelin-1 (Biotin-Lys; endothe human; fibrinogen beta-chain fragment of 24-42; fibrinogen lin-1 (1-15), human; endothelin-1 (1-15), amide, human; Ac binding inhibitor peptide; fibronectin related peptide (col endothelin-1 (16-21), human; Ac-DTrp-endothelin-1 lagen binding fragment); fibrinolysis inhibiting factor; (16-21), human; Ala''}-endothelin-1 (Dprl, Asp")-en FN—C/H-1 (fibronectin heparin-binding fragment); FN—C/ dothelin-1: {Ala-endothelin-3, human; Ala'-endothe H-V (fibronectin heparin-binding fragment); heparin-bind lin-1, human; (Asn')-endothelin-1, human: {Res-701-1}- ing peptide; laminin pentapeptide, amide; Leu-Asp-Val-NH2 endothelin B receptor antagonist; Suc-Glu, Ala'''}- (LDV-NH), human, bovine, rat, chicken; necrofibrin, endothelin-1 (8-21), IRL-1620; endothelin-C-terminal human; necrofibrin, rat; and platelet membrane glycoprotein hexapeptide: {D-Valf-big endothelin-1 (16-38), human; IIB peptide 296-306. US 2013/0096050 A1 Apr. 18, 2013

0134 Galanin peptides including, but not limited to, gala pro-releasing factor, human; biotinyl-growth hormone nin, human; galanin 1-19, human; preprogalanin 1-30. releasing factor, human; growth hormone releasing factor human; preprogalanin 65-88, human; preprogalanin 89-123, 1-29, amide, human: {D-Ala-growth hormone releasing human; galanin, porcine; galanin 1-16, porcine, rat; galanin, factor 1-29, amide, human: {N-Ac-Tyr', D-Arg-GRF 1-29, rat; biotinyl-galanin, rat; preprogalanin 28-67, rat; galanin amide: {His', Nle''}-growth hormone releasing factor 1-32, 1-13-bradykinin 2-9, amide: M40, galanin 1-13-Pro-Pro amide; growth hormone releasing factor 1-37, human; growth (Ala-Leu) 2-Ala-amide, C7, galanin 1-13-spantide-amide; hormone releasing factor 140, human; growth hormone GMAP 1-41, amide; GMAP 16-41, amide; GMAP 25-41, releasing factor 1-40, amide, human; growth hormone releas amide; galantide; and entero-kassinin. ing factor 30-44, amide, human; growth hormone releasing 0135 Gastrin peptides including, but not limited to, gas factor, mouse; growth hormone releasing factor, Ovine; trin, chicken; gastric inhibitory peptide (GIP), human; gastrin growth hormone releasing factor, rat; biotinyl-growth hor I, human; biotinyl-gastrin I, human; big gastrin-1, human; mone releasing factor, rat; GHRP-6 ({His', Lys-GHRP): gastrin releasing peptide, human; gastrin releasing peptide hexarelin (growth hormone releasing hexapeptide); and 1-16, human; gastric inhibitory polypeptide (GIP), porcine; {D-Lys-GFIRP-6. gastrin releasing peptide, porcine; biotinyl-gastrin releasing 0140 GTP-binding protein fragment peptides including, peptide, porcine; gastrin releasing peptide 14-27, porcine, but not limited to, Arg-GTP-binding protein fragment, Gs human; little gastrin, rat; pentagastrin; gastric inhibitory pep alpha; GTP-binding protein fragment, G beta; GTP-binding tide 1-30, porcine; gastric inhibitory peptide 1-30, amide, protein fragment, GAlpha; GTP-binding protein fragment, porcine; (Tyr-gastric inhibitory peptide 23-42, human; and Go Alpha; GTP-binding protein fragment, Gs Alpha; and gastric inhibitory peptide, rat. GTP-binding protein fragment, G Alpha i2. 0.136 Glucagon peptides including, but not limited to, 0141 Guanylin peptides including, but not limited to, gua {Des-His-Glu-glucagon, exendin-4, glucagon, human; nylin, human; guanylin, rat; and uroguanylin. biotinyl-glucagon, human; glucagon 19-29, human; gluca 0142. Inhibin peptides including, but not limited to, gon 22-29, human: {Des-His'-Glu-glucagon, amide; glu inhibin, bovine; inhibin, alpha-subunit 1-32, human: {Tyr'}- cagon-like peptide 1, amide; glucagon-like peptide 1, human; inhibin, alpha-Subunit 1-32, human; seminal plasma inhibin glucagon-like peptide 1 (7-36); glucagon-like peptide 2, rat; like peptide, human: {Tyr'}-seminal plasma inhibin-like biotinyl-glucagon-like peptide-1 (7-36) (biofinyl-preproglu peptide, human; inhibin, alpha-Subunit 1-32, porcine; and cagon 78-107, amide); glucagon-like peptide 2, human; inter {Tyr'}-inhibin, alpha-subunit 1-32, porcine. vening peptide-2; Oxyntomodulin/glucagon 37; and valosin 0143 Insulin peptides including, but not limited to, insu (peptide VQY), porcine. lin, human; insulin, porcine; IGF-I, human; insulin-like 0.137 Gn-RH associated peptides (GAP) including, but growth factor II (69-84); pro-insulin-like growth factor 11 not limited to, Gn-RH associated peptide 25-53, human; Gn (68-102), human; pro-insulin-like growth factor II (105-128), RH associated peptide 1-24, human; Gn-RH associated pep human; Asp''}-insulin, human; Lys'}-insulin, human; tide 1-13, human; Gn-RH associated peptide 1-13, rat; gona {Leu'}-insulin, human: {Val''}-insulin, human; dotropin releasing peptide, follicular, human: {Tyr'}-GAP {Ala'-insulin, human: {Asp'', pro'-insulin, human; ({Tyr'}-Gn-RH Precursor Peptide 14-69), human; and {Lys’, Pro’-insulin, human: Leu'. Pro’}-insulin, proopiomelanocortin (POMC) precursor 27-52, porcine. human: Val', Pro’-insulin, insulin, human; Ala’, 0138 Growth factor peptides including, but not limited to, Pro'-insulin, human: {Gly''}-insulin, human; cell growth factors; epidermal growth factors; tumor growth {Gly'Gln'}-insulin, human: Ala'-insulin, human; factor; alpha-TOP; beta-TF: alpha-TGF 34-43, rat; EGF, {Ala'Gln'} insulin, human: {Gln'-insulin, human; human; acidic fibroblast growth factor; basic fibroblast {Gln'-insulin, human: {Gly'Gln'-insulin, human; growth factor; basic fibroblast growth factor 13-18; basic (GIY-2 Gln Glu-insulin, human: {Gln. Glu?-in fibroblast growth factor 120-125; brain derived acidic fibro sulin, human; B22-B30 insulin, human; B23-B30 insulin, blast growth factor 1-11: brain derived basic fibroblast growth human; B25-B30 insulin, human; B26-B30 insulin, human; factor 1-24; brain derived acidic fibroblast growth factor 102 B27-B30 insulin, human; B29-B30 insulin, human; the A 111: Cys(Acm'')}-epidermal growth factor 20-31; epi chain of human insulin, and the B chain of human insulin. dermal growth factor receptor peptide 985-996; insulin-like 0144. Interleukin peptides including, but not limited to, growth factor (IGF)-I, chicken; IGF-I, rat; IGF-I, human: Des interleukin-1 beta 165-181, rat; and interleukin-8 (IL-8, (1-3) IGF-I, human; R3 IGF-I, human; R3 IGF-I, human; CINC/gro), rat. long R3 IGF-I, human; adjuvant peptide analog; anorexigenic 0145 Lamimin peptides including, but not limited to, peptide; Des (1-6) IGF-II, human; R6 IGF-II, human; IGF-I laminin; alpha1 (I)-CB3 435-438, rat; and laminin binding analogue; IGF1 (24-41); IGF1 (57-70); IGFI (30-41); IGF inhibitor. II; IGF II (33-40): Tyr-IGF II (33-40); liver cell growth 0146 Leptin peptides including, but not limited to, leptin factor; midkine; midkine 60-121, human: N-acetyl, alpha 93-105, human; leptin 22-56, rat; Tyr-leptin 26-39, human; TGF 34-43, methyl ester, rat; nerve growth factor (NOF), and leptin 116-130, amide, mouse. mouse; platelet-derived growth factor; platelet-derived 0147 Leucokinin peptides including, but not limited to, growth factor antagonist; transforming growth factor-alpha, leucomyosuppressin (LMS); leucopyrokinin (LPK); leucoki human; and transforming growth factor-I, rat. nin I; leucokinin II; leucokinin III; leucokinin IV; leucokinin 0139 Growth hormone peptides including, but not limited VI; leucokinin VII; and leucokinin VIII. to, growth hormone (hGH), human; growth hormone 1-43, 0.148 Luteinizing hormone-releasing hormone peptides human; growth hormone 6-13, human; growth hormone including, but not limited to, antide; Gn-RH II, chicken; releasing factor, human; growth hormone releasing factor, luteinizing hormone-releasing hormone (LH-RH) (GnRH): bovine; growth hormone releasing factor, porcine; growth biotinyl-LH-RH; cetrorelix (D-20761); D-Ala-LH-RH: hormone releasing factor 1-29, amide, rat; growth hormone {Gln)-LH-RH (Chicken LH-RH); (DLeu, Val") LH-RH US 2013/0096050 A1 Apr. 18, 2013

1-9, ethylamide: (D-Lys)-LH-RH; D-Phe, Pro, D-Phe urechistachykinin II; Xenopsin-related peptide I: Xenopsin LH-RH; DPhe, DAla LH-RH: {Des-Gly-LH-RH, related peptide II; pedal peptide (Pep), aplysia; peptide F1, ethyl amide: {D-Ala'. Des-Gly'}-LH-RH, ethyl amide: lobster, phyllomedusin; polistes mastoparan; proctolin; ran {DTrp-LH-RH, ethyl amide: D-Trp. Des-Gly-LH atensin; Ro I (Lubber Grasshopper, Romalea microptera); Ro RH, ethylamide (Deslorelin): {DSer(But), Des-Gly'}-LH II (Lubber Grasshopper, Romalea microptera); SALMF RH, ethyl amide; ethyl amide; leuprolide; LH-RH 4-10; LH amide 1 (S1); SALMFamide 2 (S2); and SCPA. RH 7-10; LH-RH, free acid; LH-RH, lanprey; LH-RH, (O155 Neuropeptide Y (NPY) peptides including, but not salmon; Lys-LH-RH; (Trp'.Leu) LH-RH, free acid; and limited to, (Leu, Pro neuropeptide Y. human; neuropep {(t-Bu)DSer', (Aza)Gly-LH-RH. tide F (Moniezia expansa); B1 BP3226 NPY antagonist; Bis 0149 Mastoparan peptides including, but not limited to, (31/31') (Cys', TrP, Nva} NPY 31-36); neuropeptide Y, mastoparan; mas7; mas8; mas 17; and mastoparan X. human, rat; neuropeptide Y 1-24 amide, human; biotinyl 0150. Mast cell degranulating peptides including, but not neuropeptide Y: {D-Tyr’7, D-Thr-NPY 27-36; Des limited to, mast cell degranulating peptide HR-1; and mast 10-17 (cyclo 7-21) (Cys7', Pro-NPY. C2-NPY; Leu', cell degranulating peptide HR-2. Pro neuropeptide Y. human neuropeptide Y, free acid, 0151 Melanocyte stimulating hormone (MSH) peptides human; neuropeptide Y, free acid, porcine; prepro NPY including, but not limited to, (Ac-Cys, DPhe"Cys' alpha 68-97, human: N-acetyl-Leu, Leu'. NPY 24-36; neu MSH 4-13, amide; alpha-melanocyte stimulating hormone; ropeptide Y. porcine: {D-TrP}-neuropeptide Y. porcine; alpha-MSH, free acid; beta-MSH, porcine; biotinyl-alpha {D-TrPNPY 1-36, human: Leu'7.DTrP} neuropeptide melanocyte stimulating hormone; biotinyl-(Nle, D-Phe7} Y. human: Leu, Pro-NPY, porcine: NPY 2-36, porcine: alpha-melanocyte stimulating hormone: {Des-Acetyl-al NPY 3-36, human; NPY 3-36, porcine; NPY 13-36, human: pha-MSH: {DPhe-alpha-MSH, amide: gamma-1-MSH, NPY 13-36, porcine; NPY 16-36, porcine; NPY 18-36, por amide: Lys'}-gamma-1-MSH, amide: MSH release inhibit cine; NPY 20-36: NFY 22-36; NPY 26-36; Pro-NPY ing factor, amide: {Nle'}-alpha-MSH, amide: {Nle", 1-36, human; Pro-neuropeptide Y. porcine: PYX-1; D-Phe-alpha-MSH: N-Acetyl, Nle.DPhe7) alpha-MSH PYX-2; T4-NPY(33-36)}4; and Tyr(OMe)''}-neuropep 4-10, amide; beta-MSH, human; and gamma-MSH. tide Y. human. 0152 Morphiceptin peptides including, but not limited to, 0156 Neurotropic factor peptides including, but not lim morphiceptin (beta-casomorphin 14 amide); (D-Pro)-mor ited to, glial derived neurotropic factor (GDNF); brain phiceptin; and {N-MePhe, D-Pro-morphiceptin. derived neurotropic factor (BDNF); and ciliary neurotropic 0153. Motilin peptides including, but not limited to, moti factor (CNTF). lin, canine; motilin, porcine; biotinyl-motilin, porcine; and 0157, Orexin peptides including, but not limited to, orexin {Leu'}-motilin, porcine. A: orexin B, human; orexin B, rat, mouse. 0154 Neuro-peptides including, but not limited to, Ac 0158 Opioid peptides including, but not limited to, alpha Asp-Glu; achatina cardio-excitatory peptide-1 (ACEP-1) casein fragment 90-95; BAM-18F; casomokinin L. casoxin (Achatina fillica); adipokinetic hormone (AKH) (Locust); D; crystalline; DALDA: dermenkephalin (deltorphin) (Phy adipokinetic hormone (Heliothis zea and Manduca sexta); lomedusa sauvagei): {D-Ala-deltorphin I: {D-Ala-del alytesin; Tabanus atratus adipokinetic hormone (Taa-AKH); torphin II; endomorphin-1; endomorphin-2; kyotorphin; adipokinetic hormone II (Locusta migratoria); adipokinetic {DArg-kyotorphin; morphine tolerance peptide; morphine hormone II (Schistocera gregaria); adipokinetic hormone III modulating peptide, C-terminal fragment; morphine modu (AKH-3); adipokinetic hormone G (AKH-G) (Gryllus lating neuropeptide (A-18-F NH); nociceptin orphanin bimaculatus); allatotropin (AT) (Manduca sexta); allatotro FQ} (ORL1 agonist); TIPP; Tyr-MIF-1: Tyr-W-MIF-1; valor pin 6-13 (Manduca sexta); APGW amide (Lynnaea stagna phin; LW-hemorphin-6, human; Leu-Valorphin-Arg; and lis); buccalin; cerebellin: {Des-Ser'}-cerebellin; corazonin Z-Pro-D-Leu. (American Cockroach Periplaneta americana); crustacean 0159. Oxytocin peptides including, but not limited to, cardioactive peptide (CCAP); crustacean erythrophore; DF2 {Asu}-oxytocin; oxytocin; biotinyl-oxytocin; {Thr, Gly (Procambarus clarkii); diazepam-binding inhibitor frag oxytocin; and tocinoic acid ({Ile-pressinoic acid). ment, human; diazepam binding inhibitor fragment (ODN); 0160 PACAP (pituitary adenylating cyclase activating eledoisin related peptide; FMRF amide (molluscan cardioex peptide) peptides including, but not limited to, PACAP 1-27. citatory neuropeptide); Gly-Pro-Glu (GPE), human; gran human, ovine, rat; PACAP (1-27)-Gly-Lys-Arg-NH. human; uliberin R; head activator neuropeptide: {His'}-corazonin; {Des-Gln-PACAP 6-27, human, ovine, rat; PACAP38, Stick insect hypertrehalosaemic factor II; Tabanus atratus frog; PACAP27-NH, human, ovine, rat; biotinyl-PACAP27 hypotrehalosemic hormone (Taa-HoTH); isoguvacine hydro NH, human, ovine, rat; PACAP 6-27, human, ovine, rat; chloride; bicuculline methiodide; piperidine-4-sulphonic PACAP38, human, ovine, rat; biotinyl-PACAP38, human, acid; joining peptide of proopiomelanocortin (POMC). ovine, rat; PACAP 6-38, human, ovine, rat; PACAP27-NH. bovine; joining peptide, rat; KSAYMRF amide (Predivivus); human, ovine, rat; biotinyl-PACAP27-NH, human, ovine, kassinin; kinetensin; levitide; litorin; LUQ 81-91 (Aplysia rat; PACAP 6-27, human, Ovine, rat; PACAP38, human, californica); LUQ 83-91 (Aplysia Californica); myoactive ovine, rat; biotinyl-PACAP38, human, ovine, rat; PACAP peptide I (Periplanetin CC-1) (Neuro-homone D); myoactive 6-38, human, ovine, rat; PACAP38 16-38, human, ovine, rat; peptide II (Periplanetin CC-2); myomodulin; neuron specific PACAP38 31-38, human, ovine, rat; PACAP38 31-38, peptide; neuron specific enolase 404-4-(3, rat; neuropeptide human, ovine, rat; PACAP-related peptide (PRP), human; FF; neuropeptide K, porcine; NEI (prepro-MCH 131-143) and PACAP-related peptide (PRP), rat. neuropeptide, rat; NGE (prepro-MCH 110-128) neuropep 0.161 Pancreastatin peptides including, but not limited to, tide, rat; NFI (Procambarus clarkii); PBAN-1 (Bombyx mori); chromostatin, bovine; pancreastatin (hPST-52) (chromogra Hez-PBAN (Heliothis zea); SCPB (cardioactive peptide from nin A 250-301, amide); pancreastatin 24-52 (hPST-29), aplysia); secretoneurin, rat; uperolein, urechistachykinin I; human; chromogranin. A 286-301, amide, human; pancre US 2013/0096050 A1 Apr. 18, 2013 astatin, porcine; biotinyl-pancreastatin, porcine; Nle-pan rat; prolactin-releasing peptide 20, rat; prolactin-releasing creastatin, porcine: {Tyr".Nle-pancreastatin, porcine; peptide 31, bovine; and prolactin-releasing peptide 20, {Tyr'}-pancreastatin, porcine; parastatin 1-19 (chromogra bovine. nin A347-365), porcine; pancreastatin (chromogranin A264 (0167 Peptide YY (PYY) peptides including, but not lim 3,4-amide, rat; biotinyl-pancreastatin (biotinyl-chromogra ited to, PYY. human: PYY 3-36, human; biotinyl-PYY. nin A 264-3,4-amide: {Tyr'}-pancreastatin, rat; human: PYY. porcine, rat; and Leu, Pro-PYY. human. pancreastatin 26-51, rat; and pancreastatin 33-49, porcine. 0168 Renin substrate peptides including, but not limited 0162 Pancreatic polypeptides including, but not limited to, acetyl, angiotensinogen 1-14, human; angiotensinogen to, pancreatic polypeptide, avian: pancreatic polypeptide, 1-14, porcine; renin substrate tetradecapeptide, rat: {Cys human; C-fragment pancreatic polypeptide acid, human; renin substrate tetradecapeptide, rat: {Leu}-renin substrate C-fragment pancreatic polypeptide amide, human; pancreatic tetradecapeptide, rat; and Val-renin substrate tetrade polypeptide (Rana temporaria); pancreatic polypeptide, rat; capeptide, rat. and pancreatic polypeptide, salmon. 0169. Secretin peptides including, but not limited to, 0163 Parathyroid hormone peptides including, but not secretin, canine; secretin, chicken; secretin, human; biotinyl limited to, Asp''-parathyroid hormone 39-84, human; secretin, human; secretin, porcine; and secretin, rat. (Asp'')-parathyroid hormone 53-84, human: {Asn'}-par 0170 Somatostatin (GIF) peptides including, but not lim athyroid hormone 1-84, hormone: {Asn'}-parathyroid hor ited to. BIM-23027; biotinyl-somatostatin: biotinylated cor mone 64-84, human: {ASn, Leu'}-parathyroid hormone tistatin 17, human; cortistatin 14, rat; cortistatin 17, human; 1-34, human: {Cys--parathyroid hormone 1-34, human; {Tyr'}-cortistatin 17, human; cortistatin 29, rat: {D-Trp hypercalcemia malignancy factor 1-40; {Leu'}-parathyroid somatostatin: {DTrp, DCys''}-somatostatin: {DTrp, hormone 1-34, human: Lys(biotinyl)'.Nle', Tyr-par Tyr''}-somatostat in: {D-Trp''}-somatostatin; NTB (Nal athyroid hormone 1-34 amide: {Nle', Tyr-parathyroid triben): {Nle-somatostatin 1-28; octreotide (SMS hormone 1-34 amide: {Nle', Tyr-parathyroid hormone 201-995); prosomatostatin 1-32, porcine; {Tyr'}-somatosta 3-34 amide, bovine: {Nle', Tyr-parathyroid hormone tin: {Tyr'}-somatostatin: {Tyr'}-somatostatin 28 (1-14): 1-34, human: {Nle', Tyr-parathyroid hormone 1-34 {Tyr''}-somatostatin: {Tyr'}, D-Trp-somatostatin; soma amide human: {Nle', Tyr-parathyroid hormone 3-34 to statin: Somatostatin antagonist; somatostatin-25; Soma amide, human: {Nle'', Tyr-parathyroid hormone 7-34 tostatin-28; somatostatin 28 (1-12); biotinyl-somatostatin amide, bovine; Nle', Tyr-parathyroid hormone 1-34 28; Tyr'}-somatostatin-28: {Leu, D-Trp., Tyr amide, rat; parathyroid hormone 44-68, human; parathyroid somatostatin-28; biotinyl-Leu, D-Trp’, Tyr hormone 1-34, bovine; parathyroid hormone 3-34, bovine; Somatostatin-28; Somatostatin-28 (1-14); and somatostatin parathyroid hormone 1-31 amide, human; parathyroid hor analog, RC-160. mone 1-34, human; parathyroid hormone 13-34, human; par 0171 Substance P peptides including, but not limited to, G athyroid hormone 1-34, rat; parathyroid hormone 1-38, protein antagonist-2: Ac-Arg, Sar, Met(02)''}-substance human; parathyroid hormone 1-44, human; parathyroid hor P 6-11; Arg-substance P. Ac-Trp-3,5-bis(trifluoromethyl) mone 28–48, human; parathyroid hormone 39-68, human; benzyl ester; Ac-Arg, Sar, Met(O2)''}-substance P 6-11; parathyroid hormone 39-84, human; parathyroid hormone {D-Ala-substance P 4-11: {Tyr, D-Phe7, D-His-Sub 53-84, human; parathyroid hormone 69-84, human; parathy stance P 6-11 (sendide); biotinyl-substance P. biotinyl roid hormone 70-84, human: Pro-peptide YY (PYY), NTE:Arg-substance P. (Tyr-substance P. Sar, Met human: {Tyr'}-hypercalcemia malignancy factor 1-40; (O2)''}-substance P: D-Pro, DTrp'}-substance P: {Tyr'}-parathyroid hormone 1-44, human: {Tyr'}-parathy {D-Pro, O-Trp-substance P 4-11; substance P 4-11: roid hormone 1-34, human: {Tyr'}-parathyroid hormone {DTrp°7'-substance P: {(Dehydro)Pro’. Pro-substance 1-34, human; Tyr'7-parathyroid hormone 27-48, human; P: Dehydro-Pro-substance P 4-11: {Glp.(Me)Phe, {Tyr-parathyroid hormone 7-34 amide, bovine: {Tyr Sar-substance P 5-11: {Glp.Sar-substance P 5-11; parathyroid hormone 43-68, human: {Tyr, Asn'}-parathy {Glp}-substance P 5-11; hepta-substance P (substance P roid hormone 52-84, human; and {Tyr-parathyroid hor 5-11); hexa-substance P(substance P 6-11); MePhe.Sar}- mone 63-84, human. substance P: {Nle''}-substance P; Octa-substance P(sub 0164 Parathyroid hormone (PTH)-related peptides stance P 4-11); {pGlu'}-hexa-substance P({pGlu-sub including, but not limited to, PTHrP (Tyr-PTHrP 1-36 stance P 6-11): {pClu, D-Pro-substance P 6-11: {(pNO) amide), chicken; hHCF-(1-34)-NH. (humoral hypercalcemic Phe’Nle''}-substance P; penta-substance P (substance P factor), human; PTH-related protein 1-34, human; biotinyl 7-11); Pro-substance P, GR73632, substance P 7-11; PTH-related protein 1-34, human: {Tyr'}-PTH-related pro {Sar-substance P 4-11; Sar-substance P. septide tein 1-34, human; Tyr-PTH-related protein 1-34 amide, ({pGlu'. Pro-substance P 6-11); spantide I; spantide II; human; PTH-related protein 1-37, human; PTH-related pro substance P. substance P, cod; substance P. trout; substance P tein 7-34 amide, human; PTH-related protein 38-64 amide, antagonist; Substance P-Gly-Lys-Arg; Substance P 1-4; Sub human; PTI-1-related protein 67-86 amide, human; PTH stance P 1-6; substance P 1-7; substance P 1-9; deca-Sub related protein 107-111, human, rat, mouse; PTH-related pro stance P (substance P 2-11); nona-substance P (substance P tein 107-111 free acid; PTH-related protein 107-138, human: 3-11); substance Ptetrapeptide (substance P 8-11); substance and PTH-related protein 109-111, human. P tripeptide (substance P 9-11); substance P. free acid; sub 0.165 Peptide T peptides including, but not limited to, stance P methyl ester, and {Tyr.Nle''} substance P. peptide T: {D-Ala-peptideT; and D-Ala'}-peptide T 0172 Tachykinin peptides including, but not limited to, amide. {Ala, beta-Ala neurokinin A 4-10; eledoisin; 0166 Prolactin-releasing peptides including, but not lim locustatachykinin I (Lam-TK-I) (Locusta migratoria); ited to, prolactin-releasing peptide 31, human; prolactin-re locustatachykinin II (Lora-TK-II) (Locusta migratoria); neu leasing peptide 20, human; prolactin-releasing peptide 31, rokinin A 4-10; neurokinin A (neuromedin L. Substance K); US 2013/0096050 A1 Apr. 18, 2013 20 neurokinin A, cod and trout; biotinyl-neurokinin A (biotinyl peptide 11-28, human, porcine, rat, Ovine; vasoactive intesti neuromedin L. biotinyl-substance K); Tyr-neurokinin A; nal peptide (cod, Gadus morhua); vasoactive intestinal pep {Tyr-substance K: FR64349; Lys, Gly-(R)-gamma-lac tide 6-28; vasoactive intestinal peptide antagonist; vasoactive tam-Leu-neurokinin A 3-10; GR83074; GR87389: intestinal peptide antagonist (Ac-Tyr', D-Phe-GHRF GR94800; Beta-Ala-neurokinin A 4-10; Nle'}-neuro 1-29 amide); vasoactive intestinal peptide receptorantagonist kinin A 4-10; Trp', beta-Ala-neurokinin A 4-10; neuroki (4-Cl-D-Phe, Leu'7-VIP); and vasoactive intestinal peptide nin B (neuromedin K); biotinyl-neurokinin B (biotinyl-neu receptor binding inhibitor, L-8-K. Additional constructs romedin K); MePhe-neurokinin B; Pro'}-neurokinin B; include but are not limited to, Ala'''' VIP Ala (''' {Tyr'}-neurokinin B; neuromedin B, porcine; biotinyl-neu 1922.24.25.27.28 VIP, {K, R16, L27}-VIP(1-7)/GRF(8-27), romedin B, porcine; neuromedin B-30, porcine; neuromedin Ro25-1553, Ro25-1392, BAY55-9837, R3P65, Maxadilan, B-32, porcine; neuromedin B receptor antagonist; neurome PG97-269, PG 99-465, Max.d4., and M65 (Dickson & Fin din C, porcine; neuromedin N. porcine; neuromedin (U-8), layson, Pharmacology & Therapeutics, Volume 121, Issue 3, porcine; neuromedin (U-25), porcine; neuromedin U, rat; March 2009, Pages 294-316). neuropeptide-gamma (gamma-preprotachykinin 72-92); PG 0176 Vasopressin (ADH) peptides including, but not lim KII; phyllolitorin: {Leu-phyllolitorin (Phyllomedusa sau ited to, Vasopressin; (ASu'', Arg-vasopressin; vasotocin, vagei); physalaemin, physalaemin 1-11: Scyliorhinin II, {Asu'...Arg-vasotocin: {Lys-vasopressin; pressinoic amide, dogfish; Senktide, selective neurokinin B receptor acid: {Arg-desamino vasopressin desglycinamide: peptide: {Ser'}-neuromedin C; beta-preprotachykinin 69-91, {Arg-vasopressin (AVP): {Arg-vasopressin desglycina human; beta-preprotachykinin 111-129, human; tachyplesin mide; biotinyl-Arg-vasopressin (biotinyl-AVP): I; Xenopsin, and Xenopsin 25 (Xenin 25), human. {D-Arg-vasopressin; desamino-Arg-vasopressin; desa 0173 Thyrotropin-releasing hormone (TRH) peptides mino-(D-Arg-vasopressin (DDAVP); (deamino-D-3-(3'- including, but not limited to, biotinyl-thyrotropin-releasing pyridyl-Ala)}-Arg-vasopressin: {1-(beta-Mercapto-beta, hormone: {GIu'}-TRH: His-Pro-diketopiperazine: {3-Me beta-cyclopentamethylene propionic acid), 2-(O-methyl)ty His-TRH; pGlu-Gln-Pro-amide; pGlu-His; Phe-TRH: rosine-Arg-vasopressin; vasopressin metabolite neu prepro TRH 53-74; prepro TRH 83-106; prepro-TRH 160 ropeptide pGlu, Cys'}; vasopressin metabolite neuropep 169 (Ps4, TRH-potentiating peptide); prepro-TRH 178-199, tide pGlu, Cys}: {Lys-deamino vasopressin thyrotropin-releasing hormone (TRH); TRH, free acid; TRH desglycinamide: Lys-vasopressin: Mpr'.Val'.DArg SH Pro; and TRH precursor peptide. vasopressin; Phe, Ile, ORn-vasopressin (Phe, Orn 0.174 Toxin peptides including, but not limited to, omega vasotocin); Arg-vasotocin, and {d(CH), Tyr(Me), agatoxin TK, agelenin, (spider, Agelena opulenta); apamin Orn-vasotocin. (honeybee, Apis mellifera); calcicudine (CaC) (green 0177 Virus related peptides including, but not limited to, mamba, Dedroaspis angusticeps); calciseptine (black viral membrane fusion proteins, fluorogenic human CMV mamba, Dendroaspis polylepis polylepis); charybdotoxin protease substrate; HCV core protein 59-68; HCV NS4A (ChTX) (Scorpion, Leiurus quinquestriatus var. hebraeus); protein 1840 (JT strain); HCV NS4A protein 21-34 (JT chlorotoxin; conotoxin GI (marine Snail, Conus geographus); strain); hepatitis B virus receptor binding fragment; hepatitis conotoxin GS (marine Snail, Conus geographus); conotoxin B virus pre-S region 120-145: {Ala''}-hepatitis B virus MI (Marine Conus magus); alpha-conotoxin EI, Conus pre-S region 120-131; herpesvirus inhibitor 2: HIV envelope ermineus; alpha-conotoxin SIA: alpha-conotoxin ImI; alpha protein fragment 254-274; HIV gag fragment 129-B; HIV conotoxin SI (cone snail, Conus striatus); micro-conotoxin substrate; P 18 peptide; peptide T: {3.5 diiodo-Tyr' peptide GIIIB (marine Snail, Conus geographus); omega-conotoxin T; R15K HIV-1 inhibitory peptide; T20; T21; V3 decapeptide GVIA (marine Snail, Conus geographus); omega-conotoxin P 18-110; and virus replication inhibiting peptide. MVIIA (Conus magus); omega-conotoxin MVIIC (Conus magus); omega-conotoxin SVIB, (cone snail, Conus stria 0.178 The human hormone glucagon is a 29-amino acid tus); endotoxin inhibitor; geographutoxin I (GTX-I) (mu.- peptide hormone produced in the A-cells of the pancreas. The Conotoxin GIIIA); iberiotoxin (IbTX) (scorpion, Buthus hormone belongs to a multi-gene family of structurally tamulus): kaliotoxin 1-37; kaliotoxin (Scorpion, Androctonus related peptides that include secretin, gastric inhibitory pep mauretanicus mauretanicus); mast cell-degranulating pep tide, vasoactive intestinal peptide and glicentin. These pep tide (MCD-peptide, peptide 401); margatoxin (MgTX) (scor tides variously regulate carbohydrate metabolism, gas pion, Centruriodes Margaritatus); neurotoxin NSTX-3 trointestinal mobility and secretory processing. The principal (Papua New Guinean spider, Nephilia maculata); PLTX-II recognized actions of pancreatic glucagon, however, are to (spider, Plectreurys tristes); scyllatoxin (leiurotoxin I); and promote hepatic glycogenolysis and glyconeogenesis, result stichodactyla toxin (ShK). ing in an elevation of blood Sugar levels. In this regard, the (0175 Vasoactive intestinal peptides (VIP/PHI) including, actions of glucagon are counter regulatory to those of insulin but not limited to, VIP, human, porcine, rat, ovine; VIP-Gly and may contribute to the hyperglycemia that accompanies Lys-Arg-NH; biotinyl-PHI (biotinyl-PHI-27), porcine; Diabetes mellitus (Lund, P. K., et al., Proc. Natl. Acad. Sci. {Glp' VIP 16-28, porcine; PHI (PHI-27), porcine; PHI U.S.A., 79:345-349 (1982)}. (PHI-27), rat; PHM-27 (PHI), human; prepro VIP 81-122, 0179 Glucagon has been found to be capable of binding to human; preproVIP/PHM 111-122; prepro VIP/PHM specific receptors which lie on the Surface of insulin produc 156-170; biotinyl-PHM-27 (biotinyl-PHI), human; vasoac ing cells. Glucagon, when bound to these receptors, stimu tive intestinal contractor (endothelin-beta); vasoactive intes lates the rapid synthesis of cAMP by these cells. cAMP, in tinal octacosa-peptide, chicken; vasoactive intestinal peptide, turn, has been found to stimulate insulin expression {Kor guinea pig, biotinyl-VIP, human, porcine, rat; vasoactive man, L.Y., et al., Diabetes, 34:717-722 (1985). Insulin acts intestinal peptide 1-12, human, porcine, rat; vasoactive intes to inhibit glucagon synthesis {Ganong, W. F., Review of tinal peptide 10-28, human, porcine, rat; vasoactive intestinal Medical Physiology, Lange Publications, Los Altos, Calif., p. US 2013/0096050 A1 Apr. 18, 2013

273 (1979)}. Thus, the expression of glucagon is carefully No. 5,482,926, WO 91/12018, U.S. Pat. No. 5,288,703). regulated by insulin, and ultimately by the serum glucose However, none of the above peptide hormones possess the level. efficacy or specificity of GLP-2 in promoting proliferation of 0180. The glucagon gene is initially translated from a 360 the intestine epithelium. GLP-2 acts synergistically with the base pair precursor to form the polypeptide, preproglucagon peptide hormones IGF-I and/or GH to promote the prolifera (Lund, et al., Proc. Natl. Acad. Sci. U.S.A. 79:345-349 (1982) tion of cells in the large intestine. Furthermore, the intesti 1. This polypeptide is Subsequently processed to form pro notrophic effects on the Small and large intestines of this glucagon. Patzelt, C., et al., Nature, 282:260-266 (1979) dem combination therapy are greater than that seen with any one of onstrated that proglucagon was Subsequently cleaved into alone. Coadministration of GLP-2 with IGF-2 to promote glucagon and a second polypeptide. Subsequent work by growth of Small and/or large intestine tissue is discussed in Lund, P. K., et al. Supra, Lopez L. C., et al., Proc. Natl. Acad. U.S. Pat. No. 5,952,301. Sci. U.S.A., 80:5485-5489 (1983), and Bell, G. I., et al., 0.184 Nucleic acid encoding the GLP-2 receptor has been Nature 302:716–718 (1983), demonstrated that the progluca isolated and methods to identify GLP-2 receptoragonists are gon molecule was cleaved immediately after lysine-arginine described (U.S. patent application Ser. No. 08/767.224 and dipeptide residues. Studies of proglucagon produced by U.S. Ser. No. 08/845,546). GLP-2's role indiseases involving channel catfish (Ictalurus punctata) indicated that glucagon the esophagus and the stomach, in assisting patients at risk of from this animal was also proteolytically cleaved after adja developing a malfunctioning of the upper gastrointestinal cent lysine-arginine dipeptide residues {Andrews P. C., et al., tract, and in increasing tissue growth in the upper gastrointes J. Biol. Chem., 260:3910-3914 (1985), Lopez, L. C., et al., tinal tract have been discussed (see U.S. Pat. No. 6,051,557). Proc. Natl. Acad. Sci. U.S.A.,80:5485-5489 (1983)}. Bell, G. GLP-2 receptor agonists act to enhance functioning of the I., et al., Supra, discovered that mammalian proglucagon was large intestine. (U.S. Pat. No. 6,297.214). GLP-2 and peptidic cleaved at lysine-arginine or arginine-arginine dipeptides, agonists of GLP-2 can cause proliferation of the tissue of and demonstrated that the proglucagon molecule contained large intestine. GLP-2 may also be useful to treat or prevent three discrete and highly homologous peptide molecules inflammatory conditions of the large intestine, including which were designated glucagon, glucagon-like peptide 1 inflammatory bowel diseases (U.S. Pat. No. 6,586,399). (GLP-1) and glucagon-like peptide 2 (GLP-2). Lopez, et al., 0185. A very wide variety of non-naturally encoded amino concluded that glucagon-like peptide 1 was 37 amino acid acids are suitable for use in the present invention. Any number residues long and that glucagon-like peptide 2 was 34 amino of non-naturally encoded amino acids can be introduced into acid residues long. Analogous studies on the structure of rat an analog. In general, the introduced non-naturally encoded preproglucagon revealed a similar pattern of proteolytic amino acids are substantially chemically inert toward the 20 cleavage between adjacent lysine-arginine or arginine-argin common, genetically-encoded amino acids (i.e., alanine, ine dipeptide residues, resulting in the formation of glucagon, arginine, asparagine, aspartic acid, cysteine, glutamine, GLP-1 and GLP-2 Heinrich, G., et al., Endocrinol. 115: glutamic acid, glycine, histidine, isoleucine, leucine, lysine, 2176-2181 (1984)}. methionine, phenylalanine, proline, serine, threonine, tryp 0181. Glucagon-like peptide-2 (GLP-2) is a 33 amino acid tophan, tyrosine, and Valine). In some embodiments, the non peptide expressed in a tissue-specific manner from the pleio naturally encoded amino acids include side chain functional tropic glucagon gene. GLP-2 shows remarkable homology in groups that react efficiently and selectively with functional terms of amino acid sequence to glucagon and Glucagon-like groups not found in the 20 common amino acids (including peptide-1 (GLP-1). Further, different mammalian forms of but not limited to, azido, ketone, aldehyde and aminooxy GLP-2 are highly conserved. The sequence of human GLP-2, groups) to form stable conjugates. For example, an analog is as follows: His-Ala-Asp-Gly-Ser-Phe-Ser-Asp-Glu-Met that includes a non-naturally encoded amino acid containing ASn-Thr-Ile-Leu-Asp-ASn-Leu-Ala-A-la-Arg-Asp-Phe-Ile an azido functional group can be reacted with a polymer Asn-Trp-Leu-Ile-Gln-Thr-Lys-Ile-Thr-Asp. Further, a large (including but not limited to, polyethylene glycol) or, alter number of agonist GLP-2 peptides that are described in PCT natively, a second polypeptide containing an alkyne moiety to Application PCT/CA97/00252, filed Apr. 11, 1997. Analogs form a stable conjugate resulting for the selective reaction of are described in U.S. Pat. No. 6,051,557, and examples of the azide and the alkyne functional groups to form a Huisgen GLP-2 variants are found in U.S. Pat. Nos. 5,990,077 and {3+2} cycloaddition product. 6,184,201. 0186. In some embodiments, the composition or pharma 0182 Recently it was demonstrated that GLP-2 is an intes ceutical compositions of the claimed invention comprises an tinotrophic peptide hormone (Drucker et al., (1996) PNAS, analog of a polypeptide, wherein the analog amino acid 93:7911-7916). When given exogenously, GLP-2 can pro sequence is based upon the fragments, polypeptides, and duce a marked increase in the proliferation of Small intestinal functional deriviatives disclosed herein and wherein the ana epithelium of the test mice, apparently with no undesirable log compruises at least one or a plurality of non-natural amino side effects. Subsequently it was shown that peptide analogs acids and at least one or a plurality off-amino acid residues. of native GLP-2 with certain modifications to the peptide A non-natural amino acid typically possesses an R group that sequence possess enhanced intestinotrophic activity (U.S. is any substituent other than one component of the twenty patent application Ser. No. 08/669,791). Moreover, GLP-2 natural amino acids, and may be suitable for use in the present has also been shown to increase D-Glucose maximal trans invention. Because the non-naturally encoded amino acids of port rate across the intestinal basolateral membrane (Cheese the invention typically differ from the natural amino acids man and Tseng (1996) American Journal of Physiology 271: only in the structure of the side chain, the non-naturally G477-G482). encoded amino acids form amide bonds with other amino 0183) A number of peptide hormones (IGF-2, IGF-1, GH), acids, including but not limited to, natural or non-naturally structurally unrelated to GLP-2, have been demonstrated to encoded, in the same manner in which they are formed in have varying degrees of intestinotrophic activity. (U.S. Pat. naturally occurring polypeptides. However, the non-natural US 2013/0096050 A1 Apr. 18, 2013 22 amino acids have side chain groups that distinguish them and Sundberg (Third Edition, Parts A and B, 1990, Plenum from the natural amino acids. For example, R optionally Press, New York). See, also, U.S. Patent Application Publi comprises an alkyl-, aryl-, acyl-, keto-, azido-, hydroxyl-, cations 2003/0082575 and 2003/0108885, which is incorpo hydrazine, cyano-, halo-, hydrazide, alkenyl, alkynl, ether, rated by reference herein. In addition to unnatural (or non thiol, seleno-, sulfonyl-, borate, boronate, phospho, natural)amino acids that contain novel side chains, unnatural phosphono, phosphine, heterocyclic, enone, imine, aldehyde, amino acids that may be suitable for use in the present inven ester, thioacid, hydroxylamine, amino group, or the like or tion also optionally comprise modified backbone structures, any combination thereof. Other non-naturally occurring including but not limited to, as illustrated by the structures of amino acids of interest that may be suitable for use in the Formula II and 111 of U.S. Patent Application Publication present invention include, but are not limited to, amino acids 2010-0048871, wherein Ztypically comprises OH, NH, SH, comprising a photoactivatable cross-linker, spin-labeled NH R', or S-R'; X and Y, which can be the same or differ amino acids, fluorescent amino acids, metal binding amino ent, typically comprise S or O, and R and R', which are acids, metal-containing amino acids, radioactive amino acids, optionally the same or different, are typically selected from amino acids with novel functional groups, amino acids that the same list of constituents for the R group described above covalently or noncovalently interact with other molecules, for the unnatural amino acids as well as hydrogen. For photocaged and/or photoisomerizable amino acids, amino example, unnatural amino acids of the invention optionally acids comprising biotin or a biotin analogue, glycosylated comprise Substitutions in the amino or carboxyl group as amino acids such as a Sugar Substituted serine, other carbo illustrated by Formulas II and III. Unnatural amino acids of hydrate modified amino acids, keto-containing amino acids, this type include, but are not limited to, C.-hydroxy acids, amino acids comprising polyethylene glycol or polyether, C-thioacids, C.-aminothiocarboxylates, including but not lim heavy atom Substituted amino acids, chemically cleavable ited to, with side chains corresponding to the common twenty and/or photocleavable amino acids, amino acids with an elon natural amino acids or unnatural side chains. In addition, gated side chains as compared to natural amino acids, includ Substitutions at the C-carbon optionally include, but are not ing but not limited to, polyethers or long chain hydrocarbons, limited to, L, D, or C-O-disubstituted amino acids such as including but not limited to, greater than about 5 or greater D-glutamate, D-alanine, D-methyl-O-tyrosine, aminobutyric than about 10 carbons, carbon-linked Sugar-containing amino acid, and the like. Other structural alternatives include cyclic acids, redox-active amino acids, amino thioacid containing amino acids, such as proline analogues as well as 3, 4, 6, 7, 8, amino acids, and amino acids comprising one or more toxic and 9 membered ring proline analogues, 13 amino acids Such moiety. as substituted B-alanine. 0187 Exemplary non-natural amino acids that may be 0189 In some embodiments, the composition or pharma suitable for use in the present invention and that are useful for ceutical compositions of the claimed invention comprises an reactions with water soluble polymers include, but are not analog of a polypeptide, wherein the analog amino acid limited to, those with carbonyl, aminooxy, hydrazine, sequence is based upon the fragments, polypeptides, and hydrazide, semicarbazide, azide and alkyne reactive groups. functional deriviatives disclosed herein and wherein the ana In some embodiments, non-naturally encoded amino acids log comprises at least one or a plurality of unnatural amino comprise a saccharide moiety. Examples of such amino acids acid or non-natural amino acid and at least one or a plurality include N-acetyl-L-glucosaminyl-L-serine, N-acetyl-L-ga off-amino acid residues, wherein the unnatural amino acids lactosaminyl-L-serine, N-acetyl-L-glucosaminyl-L-threo based on natural amino acids, such as tyrosine, glutamine, nine, N-acetyl-L-glucosaminyl-L-asparagine and O-man phenylalanine, and the like, and are suitable for use in the nosaminyl-L-serine. Examples of Such amino acids also present invention. Tyrosine analogs include, but are not lim include examples where the naturally-occurring N- or O-link ited to, para-Substituted tyrosines, ortho-Substituted age between the amino acid and the saccharide is replaced by tyrosines, and meta Substituted tyrosines, where the Substi a covalent linkage not commonly found in nature—including tuted tyrosine comprises, including but not limited to, a keto but not limited to, an alkene, an oxime, a thioether, an amide group (including but not limited to, an acetyl group), a ben and the like. Examples of Such amino acids also include Zoyl group, an amino group, a hydrazine, anhydroxyamine, a saccharides that are not commonly found in naturally-occur thiol group, a carboxy group, an isopropyl group, a methyl ring proteins such as 2-deoxy-glucose, 2-deoxygalactose and group, a Co-Co straight chain or branched hydrocarbon, a the like. saturated or unsaturated hydrocarbon, an O-methyl group, a 0188 Many of the non-naturally encoded amino acids polyether group, a nitro group, an alkynyl group or the like. In provided herein are commercially available, e.g., from addition, multiply Substituted aryl rings are also contem Sigma-Aldrich (St. Louis, Mo., USA), Novabiochem (a divi plated. Glutamine analogs that may be suitable for use in the sion of EMD Biosciences, Darmstadt, Germany), or Peptech present invention include, but are not limited to, C.-hydroxy (Burlington, Mass., USA). Those that are not commercially derivatives, cyclic derivatives, and amide substituted available are optionally synthesized as provided herein or glutamine derivatives. Example phenylalanine analogs that using standard methods known to those of skill in the art. In may be suitable for use in the present invention include, but Some embodiments, the invention relates to a method of are not limited to, para-Substituted phenylalanines, ortho manufacturing a polypeptide analog wherein the polypeptide Substituted phenyalanines, and meta-substituted phenylala analog is manufactured using a synthesis technique disclosed nines, where the Substituent comprises, including but not in the following references, which are incorporated herein by limited to, a hydroxy group, a methoxy group, a methyl reference: For organic synthesis techniques, see, e.g., group, anallyl group, an aldehyde, an azido, an iodo, abromo, Organic Chemistry by Fessendon and Fessendon, (1982, Sec a keto group (including but not limited to, an acetyl group), a ond Edition, Willard Grant Press, Boston Mass.); Advanced benzoyl, an alkynyl group, or the like. Specific examples of Organic Chemistry by March (Third Edition, 1985, Wiley and unnatural amino acids that may be suitable for use in the Sons, New York); and Advanced Organic Chemistry by Carey present invention include, but are not limited to, ap-acetyl-L- US 2013/0096050 A1 Apr. 18, 2013 phenylalanine, an O-methyl-L-tyrosine, an L-3-(2-naphthyl) provided herein or as provided in various publications or alanine, a 3-methyl-phenylalanine, an O-4-allyl-L-tyrosine, a using standard methods known to those of skill in the art. For 4-propyl-L-tyrosine, a tri-O-acetyl-GlcNAc J3-serine, an organic synthesis techniques, see, e.g., Organic Chemistry by L-Dopa, a fluorinated phenylalanine, an isopropyl-L-pheny Fessendon and Fessendon, (1982, Second Edition, Willard lalanine, a p-azido-L-phenylalanine, a p-acyl-L-phenylala Grant Press, Boston Mass.); Advanced Organic Chemistry by nine, a p-benzoyl-L-phenylalanine, an L-phosphoserine, a March (Third Edition, 1985, Wiley and Sons, New York); and phosphonoSerine, a phosphonotyrosine, a p-iodo-phenylala Advanced Organic Chemistry by Carey and Sundberg (Third nine, a p-bromophenylalanine, a p-amino-L-phenylalanine, Edition, Parts A and B, 1990, Plenum Press, New York). an isopropyl-L-phenylalanine, and a p-propargyloxy-pheny Additional publications describing the synthesis of unnatural lalanine, and the like. Examples of structures of a variety of amino acids include, e.g., WO 2002/085923 entitled “In vivo unnatural amino acids that may be suitable for use in the incorporation of Unnatural Amino Acids.” Matsoukas et al., present invention are provided in, for example, WO 2002/ (1995).J.Med. Chem., 38,4660-4669; King, F. E. & Kidd, D. 085923 entitled “In vivo incorporation of unnatural amino A. A. (1949) A New Synthesis of Glutamine and of Y-Dipep acids. See also Kiicket al., (2002). Incorporation of azides tides of Glutamic Acid from Phthylated Intermediates. J. into recombinant proteins for chemoselective modification Chem. Soc., 3315-3319; Friedman, O. M. & Chattenji, R. by the Staudinger ligation, PNAS 99:19-24, for additional (1959) Synthesis of Derivatives of Glutamine as Model Sub methionine analogs. strates for Anti-Tumor Agents. J. Am. Chem. Soc. 81, 3750 0190. The chemical moieties via unnatural amino acids 3752; Craig, J. C. et al. (1988) Absolute Configuration of the that can be incorporated into analogs offer a variety of advan Enantiomers of 7-Chloro-4 {{4-(diethylamino)-- tages and manipulations of the protein. For example, the methylbutylaminoquinoline (Chloroquine). J. Org. Chem. unique reactivity of a keto functional group allows selective 53, 1167-1170; Azoulay, M., Vilmont, M. & Frappier, F. modification of proteins with any of a number of hydrazine (1991) Glutamine analogues as Potential Antimalarials, Eur. or hydroxylamine-containing reagents in vitro and in vivo. A J. Med. Chem. 26, 201-5; Koskinen, A. M. P. & Rapoport, H. heavy atom unnatural amino acid, for example, can be useful (1989) Synthesis of 4-Substituted Prolines as Conformation for phasing X-ray structure data. The site-specific introduc ally Constrained Amino Acid Analogues. J. Org. Chem. 54. tion of heavy atoms using unnatural amino acids also pro 1859-1866; Christie, B. D. & Rapoport, H. (1985) Synthesis vides selectivity and flexibility in choosing positions for of Optically Pure Pipecolates from L-Asparagine. Applica heavy atoms. In some embodiments, the composition orphar tion to the Total Synthesis of (+)-Apovincamine through maceutical compositions of the claimed invention comprises Amino Acid Decarbonylation and Iminium Ion Cyclization. an analog of a polypeptide, wherein the analog amino acid J. Org. Chem. 50:1239-1246; Barton et al., (1987) Synthesis sequence is based upon the fragments, polypeptides, and of Novel alpha-Amino-Acids and Derivatives Using Radical functional deriviatives disclosed herein and wherein the ana Chemistry: Synthesis of L- and D-alpha-Amino-Adipic log comprises at least one or a plurality of unnatural amino Acids, L-alpha-aminopimelic Acid and Appropriate Unsatur acid or non-natural amino acid and at least one or a plurality ated Derivatives. Tetrahedron 43:4297-4308; and, Subas of B-amino acid residues, wherein the unnatural amino is a inghe et al., (1992) Quisqualic acid analogues: synthesis of photoreactive unnatural amino acid chosen from (including beta-heterocyclic 2-aminopropanoic acid derivatives and but not limited to, amino acids with benzophenone and ary their activity at a novel quisqualate-sensitized site. J. Med. lazides (including but not limited to, phenylazide) side Chem. 35:4602-7. See also, patent applications entitled “Pro chains), for example, allow for efficient in vivo and in vitro tein Arrays, filed Dec. 22, 2003, Ser. No. 10/744,899 and Ser. photocrosslinking of protein. Examples of photoreactive No. 60/435,821 filed on Dec. 22, 2002. unnatural amino acids include, but are not limited to, p-azido 0193 In some embodiments, the composition comprises a phenylalanine and p-benzoyl-phenylalanine. The protein transcription factor analog wherein the total number of with the photoreactive unnatural amino acids can then be B-amino acids in the analog is from about 10 percent to about crosslinked at will by excitation of the photoreactive group 60 percent of the total number of amino acids of the analog. In providing temporal control. In one example, the methyl group Some embodiments, the composition comprises an enkephlin of an unnatural amino can be substituted with an isotopically analog wherein the total number of B-amino acids in the labeled, including but not limited to, methyl group, as a probe analog is from about 10 percent to about 60 percent of the of local structure and dynamics, including but not limited to, total number of amino acids of the analog. In some embodi with the use of nuclear magnetic resonance and vibrational ments, the composition comprises an LHRH analog wherein spectroscopy. Alkynyl or azido functional groups, for the total number off-amino acids in the analog is from about example, allow the selective modification of proteins with 10 percent to about 60 percent of the total number of amino molecules through a 3+2} cycloaddition reaction. acids of the analog. In some embodiments, the composition 0191) A non-natural amino acid incorporated into a comprises a neuropeptide analog wherein the total number of polypeptide at the amino terminus can be composed of an R B-amino acids in the analog is from about 10 percent to about group that is any Substituent other than one used in the twenty 60 percent of the total number of amino acids of the analog. In natural amino acids and a second reactive group different Some embodiments, the composition comprises an glycoin from the NH group normally present in C-amino acids. A tegrin analog wherein the total number of 3-amino acids in similar non-natural amino acid can be incorporated at the the analog is from about 10 percent to about 60 percent of the carboxyl terminus with a second reactive group different total number of amino acids of the analog. In some embodi from the COOH group normally present in C-amino acids. ments, the composition comprises an integrin analog wherein 0.192 Many of the unnatural amino acids suitable for use the total number off-amino acids in the analog is from about in the present invention are commercially available, e.g., from 10 percent to about 60 percent of the total number of amino Sigma (USA) or Aldrich (Milwaukee, Wis., USA). Those that acids of the analog. In some embodiments, the composition are not commercially available are optionally synthesized as comprises a glucagon or glucagon-like peptide analog US 2013/0096050 A1 Apr. 18, 2013 24 wherein the total number of B-amino acids in the analog is prises an insulin analog wherein the total number off-amino from about 10 percent to about 60 percent of the total number acids in the analog is from about 10 percent to about 60 of amino acids of the analog. In some embodiments, the percent of the total number of amino acids of the analog. In composition comprises an antithrombotic peptides analog Some embodiments, the composition comprises a growth fac wherein the total number of B-amino acids in the analog is tor analog wherein the total number of 3-amino acids in the from about 10 percent to about 60 percent of the total number analog is from about 10 percent to about 60 percent of the of amino acids of the analog. In some embodiments, the total number of amino acids of the analog. Any of the com composition comprises a vassopressin analog wherein the positions above may be used in the methods disclosed in this total number off-amino acids in the analog is from about 10 instant specification. percent to about 60 percent of the total number of amino acids 0194 In some embodiments, the composition comprises a of the analog. In some embodiments, the composition com VIP analog wherein the total number of B-amino acids in the prises a cytokine or interleukin analog wherein the total num analog is from about 10 percent to about 60 percent of the ber off-amino acids in the analog is from about 10 percent to total number of amino acids of the analog. In some embodi about 60 percent of the total number of amino acids of the ments, the composition comprises a VIP analog wherein the analog. In some embodiments, the composition comprises an total number of B-amino acids in the analog is from about 12 interferon analog wherein the total number off-amino acids percent to about 50 percent of the total number of amino acids in the analog is from about 10 percent to about 60 percent of of the analog. In some embodiments, the composition com the total number of amino acids of the analog. In some prises a VIP analog wherein the total number of B-amino embodiments, the composition comprises an endothlin ana acids in the analog is from about 14 percent to about 50 log wherein the total number off-amino acids in the analog is percent of the total number of amino acids of the analog. In from about 10 percent to about 60 percent of the total number Some embodiments, the composition comprises a VIP analog of amino acids of the analog. In some embodiments, the wherein the total number of B-amino acids in the analog is composition comprises an natriuretic hormone analog from about 16 percent to about 50 percent of the total number wherein the total number of B-amino acids in the analog is of amino acids of the analog. In some embodiments, the from about 10 percent to about 60 percent of the total number composition comprises a VIP analog wherein the total num of amino acids of the analog. In some embodiments, the ber off-amino acids in the analog is from about 18 percent to composition comprises an extracellular kinase ligand analog about 50 percent of the total number of amino acids of the wherein the total number of B-amino acids in the analog is analog. In some embodiments, the composition comprises a from about 10 percent to about 60 percent of the total number VIP analog wherein the total number of B-amino acids in the of amino acids of the analog. In some embodiments, the analog is from about 20 percent to about 50 percent of the composition comprises an angiotensin enzyme inhibitor ana total number of amino acids of the analog. In some embodi log wherein the total number off-amino acids in the analog is ments, the composition comprises a VIP analog wherein the from about 10 percent to about 60 percent of the total number total number of B-amino acids in the analog is from about 30 of amino acids of the analog. In some embodiments, the percent to about 50 percent of the total number of amino acids composition comprises an antiviral peptide analog wherein of the analog. In some embodiments, the composition com the total number off-amino acids in the analog is from about prises a VIP analog wherein the total number of B-amino 10 percent to about 60 percent of the total number of amino acids in the analog is from about 40 percent to about 50 acids of the analog. In some embodiments, the composition percent of the total number of amino acids of the analog. In comprises a thrombin analog wherein the total number of Some embodiments, the composition comprises a VIP analog B-amino acids in the analog is from about 10 percent to about wherein the total number of B-amino acids in the analog is 60 percent of the total number of amino acids of the analog. In from about 45 percent to about 50 percent of the total number Some embodiments, the composition comprises a Substance P of amino acids of the analog. In some embodiments, the analog wherein the total number of B-amino acids in the composition comprises a VIP analog wherein the total num analog is from about 10 percent to about 60 percent of the ber off-amino acids in the analog is from about 40 percent to total number of amino acids of the analog. In some embodi about 45 percent of the total number of amino acids of the ments, the composition comprises a substance G analog analog. In some embodiments, the composition comprises a wherein the total number of B-amino acids in the analog is VIP analog wherein the total number of B-amino acids in the from about 10 percent to about 60 percent of the total number analog is from about 30 percent to about 40 percent of the of amino acids of the analog. In some embodiments, the total number of amino acids of the analog. In some embodi composition comprises a Somatotropin analog wherein the ments, the composition comprises a VIP analog wherein the total number off-amino acids in the analog is from about 10 total number of B-amino acids in the analog is from about 35 percent to about 60 percent of the total number of amino acids percent to about 40 percent of the total number of amino acids of the analog. In some embodiments, the composition com of the analog. In some embodiments, the composition com prises a Somatostatin analog wherein the total number of prises a VIP analog wherein the total number of B-amino B-amino acids in the analog is from about 10 percent to about acids in the analog is from about 20 percent to about 30 60 percent of the total number of amino acids of the analog. In percent of the total number of amino acids of the analog. In Some embodiments, the composition comprises a GnRHana Some embodiments, the composition comprises a VIP analog log wherein the total number off-amino acids in the analog is wherein the total number of B-amino acids in the analog is from about 10 percent to about 60 percent of the total number from about 10 percent to about 20 percent of the total number of amino acids of the analog. In some embodiments, the of amino acids of the analog. In some embodiments, the composition comprises abradykinin analog wherein the total composition comprises a VIP analog wherein the total num number of B-amino acids in the analog is from about 10 ber off-amino acids in the analog is from about 15 percent to percent to about 60 percent of the total number of amino acids about 20 percent of the total number of amino acids of the of the analog. In some embodiments, the composition com analog. In some embodiments, the composition comprises a US 2013/0096050 A1 Apr. 18, 2013

VIP analog wherein the total number of B-amino acids in the secretin analog and one other active agent, wherein the secre analog is from about 20 percent to about 25 percent of the tin analog comprises at least one C.-amino acid and at least one total number of amino acids of the analog. In some embodi B-amino acid. ments, the composition comprises a VIP analog wherein the 0.198. In another embodiment of the invention, the phar total number off-amino acids in the analog is from about 25 maceutical composition comprises a VIP analog and one percent to about 30 percent of the total number of amino acids other active agent, wherein the VIP analog comprises at least of the analog. In some embodiments, the composition com one O-amino acid and at least one B-amino acid. prises a VIP analog wherein the total number of B-amino 0199 The invention further relates to uses of a composi acids in the analog is from about 30 percent to about 35 tion comprising a secretin analog in the preparation of a percent of the total number of amino acids of the analog. medicament for treating or preventing pulmonary hyperten Sion, primary arterial hypertension, pulmonary hypertension 0.195. In some embodiments, the composition comprises a associated to post-ventricular septal defect, idiopathic pull VIP analog, wherein the ratio of total B-amino acids in the monary fibrosis, idiopathic pulmonary arterial hypertension, analog is from 1 to 3 B-amino acids for every 7 amino acids of CREST syndrome—Calcinosis; Raynaud's disease; loss of the analog. In some embodiments, the composition comprises muscle control of the Esophagus; Sclerodactyly; Telangiecta a VIP analog, wherein the ratio of total B-amino acids in the sia, Acute respiratory distress, congestive heart failure, analog is from 2 to 43-amino acids for every 7 amino acids of chronic obstructed pulmonary disorder, asthma, chronic the analog. In some embodiments, the composition comprises obstructive pulmonary disease, sarcoidosis, Small lung cell a VIP analog, wherein the ratio of total B-amino acids to cancer, autoimmune disease, inflammatory disease, sepsis, amino acids in the analog is from 3 to 5 B-amino acids for Hirschsprung's Disease, sexual dysfunction, erectile dys every 7 amino acids of the analog. In some embodiments, the function, Parkinson's disease, Alzheimer's disease, circadian composition comprises a VIP analog, wherein the ratio of rhythm dysfunction, pain, colorectal cancer, hepatocellular total B-amino acids to amino acids in the analog is from 4 to cancer, elevated blood pressure levels, elevated blood glucose 6 B-amino acids for every 7 amino acids of the analog. In levels, hyperglycemia, diabetes, insulin resistance, metabolic Some embodiments, the composition comprises a VIP analog, acidosis, obesity, Type I diabetes, Type II diabetes Multiple wherein the ratio of total B-amino acids to amino acids in the Sclerosis, osteoporosis, Sjogren's syndrome, pancreatitis, analog is from 5 to 7 B-amino acids for every 7 amino acids of uVeoretinitis, osteoporosis, female sexual dysfunction. The the analog. In some embodiments, the composition comprises invention further relates to use of a composition comprising a a VIP analog, wherein the ratio of total B-amino acids to VIP analog in the preparation of a medicament for treating or amino acids in the analog is 1 B-amino acid for every 7 amino preventing pulmonary hypertension, primary arterial hyper acids of the analog. In some embodiments, the composition tension, pulmonary hypertension associated to post-ventricu comprises a VIP analog, wherein the ratio of total B-amino lar septal defect, idiopathic pulmonary fibrosis, idiopathic acids to amino acids in the analog is 23-amino acids for every pulmonary arterial hypertension, CREST syndrome—Calci 7 amino acids of the analog. In some embodiments, the com nosis; Raynaud's disease; loss of muscle control of the position comprises a VIP analog, wherein the ratio of total Esophagus; Sclerodactyly; Telangiectasia, Acute respiratory B-amino acids to amino acids in the analog is 33-amino acids distress, congestive heart failure, chronic obstructed pulmo for every 7 amino acids of the analog. In some embodiments, nary disorder, asthma, chronic obstructive pulmonary dis the composition comprises a VIP analog, wherein the ratio of ease, sarcoidosis, Small lung cell cancer, autoimmune dis total B-amino acids to amino acids in the analog is 43-amino ease, inflammatory disease, sepsis, Hirschsprung's Disease, acids for every 7 amino acids of the analog. In some embodi sexual dysfunction, erectile dysfunction, Parkinson's dis ments, the composition comprises a VIP analog, wherein the ease, Alzheimer's disease, circadian rhythm dysfunction, ratio of total B-amino acids to amino acids in the analog is 5 pain, colorectal cancer, hepatocellular cancer, elevated blood B-amino acids for every 7 amino acids of the analog. In some pressure levels, elevated blood glucose levels, hyperglyce embodiments, the composition comprises a VIP analog, mia, diabetes, insulin resistance, metabolic acidosis, obesity, wherein the ratio of total B-amino acids to amino acids in the Type I diabetes, Type II diabetes Multiple Sclerosis, analog is 6 B-amino acids for every 7 amino acids of the osteoporosis, Sjogren's syndrome, pancreatitis, uveoretinitis, analog. osteoporosis, female sexual dysfunction. 0200. In some embodiments, the invention relates to meth 0196. In another embodiment of the invention, the com ods of manufacturing any one of the aforementioned compo position comprises a VIP analog, wherein the analog com sitions, pharmaceutical compositions, or a pharmaceutical prises a repetitive pattern of 3-amino acids from the amino salt derived therefrom comprising catalyzing a reaction terminus to the carboxy-terminus selected from the between at least one O-amino acid with at least one B-amino following: C.C.C.C.C.C.B., C.C.C.C.C.B.C., C.C.C.C. BC.C., C.C.C. BC.C.C. acid. C.C. foC.C.C., C.B.C.C.C.C.C., BC.C.C.C.C.C. C.C.C.C.O.Bf3, C.C.C.C. BBC. 0201 The invention also relates to methods of treating or C.C.O.Bf3C.C., C.C.Bf3C.C.C. C. BBC.C.C.C., BBC.C.C.C.C., BC.C.C.C.C. B. preventing pulmonary hypertension, primary arterial hyper BC.C.C.O.BC, BC.C.C. BC.C., BC.C. BC.C.C., BC foC.C.C., C. BC.C.C.C. B. tension, pulmonary hypertension associated to post-ventricu CBC.C.O.BC, CBC.C. BC.C. C. BC.BC.C.C., C.C.f3C.C.C.B., C.O.BC.C.BC. lar septal defect, idiopathic pulmonary fibrosis, idiopathic C.O.?ofo.C., C.C.O.BC.O.B., C.C.C. BC. BC, and C.C.C.O.BC.B. pulmonary arterial hypertension, CREST syndrome—Calci 0197) Some embodiments of the claimed invention nosis; Raynaud's disease; loss of muscle control of the include pharmaceutical compositions. In some embodiments, Esophagus; Sclerodactyly; Telangiectasia, Acute respiratory the pharmaceutical composition comprises any of the afore distress, congestive heart failure, chronic obstructed pulmo mentioned compositions in combination with a pharmaceu nary disorder, asthma, chronic obstructive pulmonary dis tically acceptable carrier. In another embodiment of the ease, sarcoidosis, Small lung cell cancer, autoimmune dis invention, the pharmaceutical composition comprises a ease, inflammatory disease, sepsis, Hirschsprung's Disease, US 2013/0096050 A1 Apr. 18, 2013 26 sexual dysfunction, erectile dysfunction, Parkinson's dis 0215 c) comparing the rate of association of the secretin ease, Alzheimer's disease, circadian rhythm dysfunction, analog to the human secretin receptor in the presence of an pain, colorectal cancer, hepatocellular cancer, elevated blood unknown compound to the rate of association of the secretin pressure levels, elevated blood glucose levels, hyperglyce analog to the human secretin receptor in the absence of an mia, diabetes, insulin resistance, metabolic acidosis, obesity, unknown compound. Type I diabetes, Type II diabetes Multiple Sclerosis, 0216. The present invention also relates to methods of osteoporosis, Sjogren's syndrome, pancreatitis, uveoretinitis, identifying a modulator of human osteoporosis, female sexual dysfunction comprising admin 0217 VIP receptor activity comprising: istrating any one of the compositions orpharmaceutical com 0218 a) contacting a human VIP receptor with the VIP positions comprising a secretin family analog, or a pharma analog, wherein the analog comprises an O-amino acid and at ceutical salt derived therefrom, to a subject in need thereof. least one B-amino acid; 0202 The present invention also relates to methods of 0219 b) measuring the association of the VIP analog to the inhibiting secretion of TNF-C. in a subject comprising admin human VIP receptor in the presence and absence of an istering a composition comprising a vasoactive intestinal pep unknown compound; and tide (VIP) analog to a subject, wherein said analog comprises 0220, c) comparing the rate of association of the VIP ana an O-amino acid and at least one B-amino acid. In some log to the human VIP receptor in the presence of an unknown embodiments, the method comprises administering the com compound to the rate of association of the VIP analog to the position comprising any of the percentages off-amino acids. human VIP receptor in the absence of an unknown com 0203 The present invention is also directed towards kits pound. comprising any of the aforementioned compositions or phar maceutical compositions comprising a secretin analog, BRIEF DESCRIPTION OF DRAWINGS wherein the secretin analog comprises an O-amino acid and at least one B-amino. The present invention is directed toward 0221 FIG. 1 shows MALDI-TOF data of a purified VIP kits comprising any of the aforementioned compositions or analogue which illustrates the expected mass (within a rea pharmaceutical compositions comprising a VIP analog, sonable tolerance) of both singly charged and doubly charged wherein the VIP analog comprises an O-amino acid and at species of the analogue after chemical synthesis, cleavage least on B-amino acid. In some embodiments, the kit further from resin, and Subsequent purification of the analogue comprises a vehicle for administration of the composition. through a C18HPLC column. 0204 The present invention also relates to methods of 0222 FIG. 2 presents circular dichroism data of a VIP identifying a modulator of human receptor activity compris analogue diluted in a 10 mM sodium phosphate buffer at pH ing: of 7.5. The signal exhibited for the structure of the VIP ana logue is similar to previously characterized C.-amino acid/B 0205 a) contacting a human receptor with a secretin ana amino acid peptides of similar backbone length and concen log, wherein the analog comprises an O-amino acid and at tration, which indicates a substantial helical content (Home least one B-amino acid; et. al., J. Am. Chem. Soc., 2007, 129 (14), pp. 4178-4180; 0206 b) measuring the association of the Secretin analog Home et al. PNAS, Sep. 1, 2009, vol. 106, no. 35, 14751 to the human receptor in the presence and absence of an 14756). unknown compound; and 0223 FIG. 3 illustrates in vitro functional ECso data of a 0207 c) comparing the rate of association of the secretin VIP analogue tested in the presence of VIPR1 (VPAC) or analog to the human receptor in the presence of an unknown VIPR2 (VPAC) receptors as compared to the binding of compound to the rate of association of the secretin analog to wild-type VIP protein to the same receptors. The data show the human receptor in the absence of an unknown compound. that the analogue achieves full activation of VIPR1 (~100%, 0208. The present invention also relates to methods of relative to maximum activation), but has an ECso at a concen identifying a modulator of animal receptor activity compris tration higher than the ECs of wild-type VIP protein. ing: 0224 FIG. 4 illustrates data from an in vitro antagonist 0209 a) contacting an animal receptor with a secretin inhibition assay in which competition for VIPR1 (VPAC) or analog, wherein the analog comprises an O-amino acid and at VIPR2 (VPAC) was measured by the amount of VIP ana least one B-amino acid; logue capable of inhibiting the association of wild-type VIP 0210 b) measuring the association of the Secretin analog to its receptors. to the animal receptor in the presence and absence of an unknown compound; and DETAILED DESCRIPTION OF ILLUSTRATIVE 0211 c) comparing the rate of association of the secretin EMBODIMENTS analog to the animal receptor in the presence of an unknown 0225. Various terms relating to the methods and other compound to the rate of association of the secretin analog to aspects of the present invention are used throughout the speci the animal receptor in the absence of an unknown compound. fication and claims. Such terms are to be given their ordinary 0212. The present invention also relates to methods of meaning in the art unless otherwise indicated. Other specifi identifying a modulator of human secretin receptor activity cally defined terms are to be construed in a manner consistent comprising: with the definition provided herein. 0213 a) contacting a human secretin receptor with a secre 0226. As used in this specification and the appended tin analog, wherein the analog comprises an O-amino acid and claims, the singular forms “a,” “an,” and “the include plural at least one B-amino acid; referents unless the content clearly dictates otherwise. 0214 b) measuring the association of the Secretin analog 0227. The term “about as used herein when referring to a to the human secretin receptor in the presence and absence of measurable value Such as an amount, a temporal duration, and an unknown compound; and the like, is meant to encompass variations of +20%, +10%, US 2013/0096050 A1 Apr. 18, 2013 27

+5%, +1%, or +0.1% from the specified value, as such varia aminoisobutyric acid, 3-Aminobutyric acid, and 2-hydroxy tions are appropriate to perform the disclosed methods. 4(4-nitrophenyl)butyric acid. In some embodiments, the ana 0228. The term “active state' refers to the conformation or log has a polypeptide backbone of identicallength and similar set of conformations of a polypeptide that allows functional homology to the polypeptides disclosed in Tables 1, 2, 3, domain or domains of the polypeptide to associate or disas and/or 4. In some embodiments, the analog is about 70%, Sociate with another compound, macromolecule, or ligand. In 75%, 80%, 85%, 90%. 95%, 98%, or 99% homolgous to at Some embodiments, the association or disassociation of the least one of the polypeptides disclosed in Tables 1,2,3, and/or polypeptide with another compound, macromolecule, or 4. In some embodiments, the analog is an agonist or antago ligand may propagate or inhibit a biologic signal. nist of one or more of the following receptors: VPAC1, 0229. The terms “amino acid' refer to a molecule contain VPAC2, or PAC1. In some embodiments, the analog is a ing both an amino group and a carboxyl group bound to a fragment of one of the polypeptides disclosed in Tables 1, 2, carbon which is designated the C-carbon. Suitable amino 3, and 4 and shares the same or improved biological or bio acids include, without limitation, both the D- and L-isomers chemical activity as compared to the biological or biochemi of the naturally-occurring amino acids, as well as non-natu cal activity of the polypeptides disclosed in Tables 1, 2, 3, rally occurring amino acids prepared by organic synthesis or and/or 4 upon which the analog amino acid sequence is other metabolic routes. in Some embodiments, a single derived. In some embodiments, the analog is an agonist or “amino acid might have multiple sidechain moieties, as antagonist of the receptor of the full-length, naturally trans available per an extended aliphatic or aromatic backbone lated or naturally occurring polypeptide upon which the scaffold. Unless the context specifically indicates otherwise, the term amino acid, as used herein, is intended to include amino acid sequence of the agonist orantagonist is derived. In amino acid analogs. Some embodiments, the analog is an agonist or antagonist of 0230. The term “analog refers to any polypeptide com the receptor of the polypeptides disclosed in Tables 1, 2, 3, prising at least one O-amino acid and at least one B-amino and/or 4. In such embodiments, the amino acid sequence of acid residue, wherein the polypeptide is structurally similar to the agonists or antagonists are derived from the amino acid a naturally occurring full-length protein and shares the bio sequence of the polypeptides disclosed in Tables 1, 2, 3, chemical or biological activity of the naturally occurring and/or 4. In some embodiments the analog of the present full-length protein upon which the analog is based. In some invention is modified by a bioactive lipid moiety on at least embodiments, an analog is any polypeptide comprising at one amino acid residue of the analog. In Such embodiments, least one B-amino acid residue, wherein the polypeptide is the lipid moieties may be chosen from the following lipid structurally similar to a naturally occurring full-length pro molecules: LPA, progesterone, prostanoids, S1P, LPA, can tein and shares the biochemical or biological activity of the nabinoids, 2-arachidonylglycerol. In some embodiments, the naturally occurring full-length protein upon which the analog side chain or terminal end of the amino acid residues of the is based and wherein the addition of one or more B-amino acid polypeptides disclosed in Tables 1, 2, 3, and/or 4 may be residues constrains an alpha helical structure in the polypep modified with the bioreactive lipid moieties. In some embodi tide. In some embodiments, an analog is any polypeptide ments, the analogs of the present invention are derived from comprising at least one B-amino acid residue, wherein the one of the following sequences: polypeptide is structurally similar to a naturally occurring full-length protein and shares the biochemical or biological activity of the naturally occurring full-length protein upon HSDGIFTDSYSRYRKOMAVKKYLAAVLGKRYKORVKNK-NH; which the analog is based. In some embodiments, the non HSDGIFTDSYSRYRKOMAVKKYLAAVL-NH; natural amino acid residue is a monomer of an aliphatic polypeptide. In some embodiments the aliphatic analogs are HSDGTFTSELSRLRDSARLQRLLQGLV-NH; chosen from oligoureas, azapeptides, pyrrolinones, C.-ami noxy-peptides, and Sugar-based peptides. In some embodi HSDGTFTSDYSKYLDSRRAQDFVQWLMNT-NH; ments, the composition comprises a non-natural B-amino HADGVFTSDFSKLLGQLSAKKYLESLM-NH acid. In some embodiments, the analog is a fragment of the full-length protein upon which the analog is based. In some 0231. The term "O-amino acid refers to any and all natu embodiments, fragments are from about 5 to about 75 amino ral and unnatural O-amino acids and their respective residues acids in length as compared to the naturally occurring, fully (i.e., the form of the amino acid when incorporated into a translated and fully processed protein sequences. In some polypeptide molecule), without limitation. In some embodi embodiments, the analogs comprise a fragment of a naturally ments, “C.-amino acid explicitly encompasses the conven translated full-length protein that induces the biochemical or tional and well-known naturally occurring amino acids, as biological activity of a biological pathway of a Subject at a well as all synthetic variations, derivatives, and analogs level equivalent to or increased as compared to the activity thereof. In some embodiments, “C.-amino acid means ala induced by a naturally occurring full-length protein upon nine, arginine, asparagine, aspartic acid, cysteine, glutamine, which the analog is derived. In some embodiments, the ana glutamic acid, glycine, histidine, isoleucine, Ieucine, lysine, log is a truncated polypeptide as compared to the full-length, methionine, phenylalanine, proline, serine, threonine, tryp naturally translated or naturally occurring polypeptide upon tophan, tyrosine, and/or valine. In some embodiments, which the truncated polypeptide is derived. In some embodi C.-amino acids also include analogs such as N-methylated ments, the analog is a synthetic polypeptide, wherein at least C.-amino acids, hydroxylated C.-amino acids, and aminoxy one of the amino acid residues of the polypeptide comprises acids. In some embodiments, C.-amino refers to include at least one non-natural side chain. In some embodiments, the N-alkyl C.-amino acids (such as N-methylglycine), hydroxy analogs of the invention comprise at least one non-natural lysine, 3-hydroxyproline, 4-hydroxyproline, nor-valine, nor amino acid chosen from one of the following structures: leucine, and ornithine. US 2013/0096050 A1 Apr. 18, 2013 28

0232. The terms “B-amino acid' and “B-amino acid resi —(CH), NHC(=O)R', -(CH2), NHS(=O) due' refer to any and all -amino acids and their respective CH. R. -(CH2)-O-(CH2), R. —(CH),— residues (i.e., the form of the amino acid when incorporated S-(CH2).R. -(CH2), S(=O)-(CH2), R. into a polypeptide molecule), without limitation. In some (CH2)—S(=O) (CH), R5, (CH2)—NH embodiments, the terms “B-amino acid refers to those (CH), R. —(CH)-N-(CH2), R}, —(CH),— B-amino acids described in U.S. Pat. No. 6,060,585, issued NHC(=O)-(CH), R, and —(CH), NHS(=O) May 9, 2000, incorporated herein by reference, and those (CH), R; wherein each R" is independently selected described in allowed U.S. Pat. No. 6,683,154, issued Jan. 27, from the group consisting of hydrogen, C-Calkyl, alkenyl, 2004; U.S. Pat. No. 6,710,186, issued Mar. 23, 2004; and U.S. or alkynyl: mono- or bicyclic aryl, mono- or bicyclic het Pat. No. 6,727,368, issued Apr. 27, 2004, all of which are eroaryl having up to Sheteroatoms selected from N, O, and S; incorporated herein by reference. Further still, cyclic imino mono- or bicyclic aryl-C-Calkyl, mono- or bicyclic het carboxylic acids and gem-di-substituted cyclic imino car eroaryl-C-Calkyl; and wherein R is selected from the boxylic acids (both of which are a type of cyclically-con group consisting of hydroxy, C-Calkyloxy, aryloxy, het strained B-amino acid) may also be used in the invention. In eroaryloxy, thio, C-Calkylthio, C-Calkylsulfinyl, some embodiments, the term “B-amino acid refers to resi C-Calkylsulfonyl, arylthio, arylsulfinyl, arylsulfonyl, het dues disclosed in U.S. Pat. No. 6,958,384, issued Oct. 25, 2005, incorporated herein by reference. Further still, these eroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, amino, B-residues may also take the form of the gem-di-substituted mono- or di-C-Calkylamino, mono- or diarylamino, mono cyclic imino acids disclosed in U.S. Pat. No. 6,710,186, incor or diheteroarylamino, N-alkyl-N-arylamino, N-alkyl-N-het porated herein by reference. In some embodiments, the terms eroarylamino, N-aryl-N-heteroarylamino, aryl-C- “B-amino acid refers to B-homo amino acids. In some Calkylamino, carboxylic acid, carboxamide, mono- or embodiments the B-amino acids refers to the selection of an di-C-Calkylcarboxamide, mono- or diarylcarboxamide, amino acid chosen from the following: mono- or diheteroarylcarboxamide, N-alkyl-N-arylcarboxa mide, N-alkyl-N-heteroarylcarboxamide, N-aryl-N-het eroarylcarboxamide, Sulfonic acid, Sulfonamide, mono- or di-C-Calkylsulfonamide, mono- or diarylsulfonamide, mono- or diheteroarylsulfonamide, N-alkyl-N-arylsulfona R-HN C-O-R2 R-HN C-O-R2 mide, N-alkyl-N-heteroarylsulfonamide, N-aryl-N-heteroar ylsulfonamide, urea; mono- di- or tri-substituted urea, wherein the Substitutent(s) is selected from the group consist ing of C-Calkyl, aryl, heteroaryl; O-alkylurethane, O-ary lurethane, and O-heteroarylurethane; and m is an integer of from 2-6 and n is an integer of from 0-6; and when R is bonded to a nitrogenatom, R is independently selected from the group consisting of those listed above for when R is attached to a carbonatom, and further selected from the group consisting of S(=O). CH. R. —C(=O) R' S (=O) -(CH2).R. and —C(=O)-(CH2), R: wherein R* and Rare as defined hereinabove, and m is an R-HN C-O-R2 and integer of from 2-6 and n is an integer of from 0-6: provided that when the B-amino acid is of formula R is not hydrogen; racemic mixtures thereof, isolated or enriched enantiomers N S1X thereof; isolated or enriched diastereomers thereof, and salts R3 thereof. In some embodiments the B-amino acids refers to the O selection of an amino acid chosen from the following: R-HN C-O-R.

O O RS N R-HN C-O-R2 R-HN C-O-R2

R" is selected from the group consisting hydrogen and an amino protecting group; R is selected from the group con R3. R3AN sisting of hydrogen and a carboxyprotecting group; and when R is bonded to a carbonatom, R is selected from the group consisting of hydrogen, hydroxy, linear or branched C-C- alkyl, alkenyl, or alkynyl: mono- or bicyclic aryl, mono- or R-HN C-O-R2 bicyclic heteroaryl having up to 5 heteroatoms selected from N, O, and S. mono- or bicyclic aryl-C-C-alkyl, mono- or bicyclic heteroaryl-C-C-alkyl, -(CH2), —OR, -(CH2), SR, —(CH), S(=O)—CH. R. . —(CH2)—S(=O). CH R, (CH2), NR'R'', US 2013/0096050 A1 Apr. 18, 2013 29

-continued heteroaryl-C-C-alkyl, -(CH2), —OR. -(CH2), O 1-SR, -(CH2), S(=O)—CH2—R, -(CH2), R-HN C-O-R2 and 1—S(=O). CH. R. -(CH), NR'R'',

A-1 N (=O)–(CH), R. —(CH2)—S(=O) -(CH2) R3 f R5, (CH2), NH (CH2), R5, (CH2). 1-N-(CH2), R2, -(CH2), NHC(=O)— R-HN C-O-R. (CH2), R. and -(CH2), NHS(=O)2 -(CH2) R: 0236 wherein R is independently selected from the group consisting of hydrogen, C-C-alkyl, alkenyl, RS N or alkynyl: mono- or bicyclic aryl, mono- or bicyclic heteroaryl having up to 5 heteroatoms selected from N, O, and Si mono- or bicyclic aryl-C-C-alkyl, In some embodiments the f-amino acids refers to the follow mono- or bicyclic heteroaryl-C-C-alkyl; and ing formula: 0237 wherein R is selected from the group consist ing of hydroxy, C-C-alkyloxy, aryloxy, heteroary loxy, thio, C-C-alkylthio, C-C-alkylsulfinyl,

ACPC C-C-alkylsulfonyl, arylthio, arylsulfinyl, arylsulfo nyl, heteroarylthio, heteroarylsulfinyl, heteroaryl Sulfo-nyl, amino, mono- or di-C-C alkylamino, mono- or diarylamino, mono- or diheteroarylamino, N-alkyl-N-arylamino, N-alkyl-N-heteroarylamino, N-aryl-N-heteroarylamino, aryl-C-C-alkylamino, carboxylic acid, carboxamide, mono- or di-C-C- In some embodiments the B-amino adds refers to the follow alkylearboxa-mide, mono- or diarylcarboxamide, ing formula: mono- or dihet-eroarylcarboxamide, N-alkyl-N-aryl carboxamide, N-alkyl-N-hetero mylcarboxamide, N-aryl-N-het-eroarylcarboxamkte, sulfonic acid, sul fonamide, mono- or di-C-C-alkylsulfonamide, mono- or dia-rylsulfonamide, mono- or diheteroaryl sulfonamide, N-alkyl-N-arylsulfonamide, N-alky 1-N-heteroaryl-sulfonamide, N-aryl-N-heteroarylsul fonamide, urea; mono- di- or tri-substituted urea, wherein the sub-situtent(s) is selected from the group An APC residue within an consisting of C-C-alkyl, aryl, heteroaryl; O-alky undefined peptide chain, lurethane, O-arylurethane, and O-heteroarylurethane; under neutral aqueous conditions and (the ring N is protonated). 0238 m is an integer of from 2-6 and n is an integer of from 0-6: 0239 the substituents on heteroatoms of the ring wherein the NH and/or COOH groups are replaced with being inde-pendently selected from the group consist functional peptide bonds. ing of S(=O)? CH. R. C(=O) R' S 0233. In some embodiments the term “B-amino acid (=O)2 (CH2), R. and —C(=O)-(CH2), — refers to: R; wherein RandR areas defined hereinabove, and m is an integer of from 2-6 and n is an integer of from (I) 0-6: H X- - - - Y O 0240 provided that when X & Y together with the carbons to which they are bonded define a five- or R-N-CH-CH-C-O-R2 six-membered cycloalkyl ora five-membered hetero cyclic ring having one nitrogen as the sole heteroa 0234 wherein X and Y combined, together with the tom, and the nitrogen is bonded to a carbon atom carbon atoms to which they are bonded, define a substi adjacent to the carboxy carbon of Formula I, the tuted or unsub-situted C-C cycloalkyl, cycloalkenyl or cycloalkyl or heterocyclic ring is substituted; heterocyclic ring having one or more nitrogen atoms as 0241) R' is selected from the group consisting hydro the sole heteroatom; gen and an amino protecting group; 0235 the substituents on carbon atoms of the rings (0242 R is selected from the group consisting of being independently selected from the group consisting hydrogen and a carboxy protecting group; of linear or branched C-C-alkyl, alkenyl, or alkynyl: 0243 racemic mixtures thereof, isolated or enriched mono- or bicyclic aryl, mono- or bicyclic heteroaryl enanti-omers thereof; isolated or enriched diastere having up to 5 heteroatoms selected from N, O, and S; omers thereof mono- or bicyclic aryl-C-C-alkyl, mono- or bicyclic 0244 and salts thereof. US 2013/0096050 A1 Apr. 18, 2013 30

0245. In some embodiments the term “B-amino acid -continued refers to selection of an amino acid chosen from the follow ing: Bor B. In some embodiments the term “B-amino acid” R O R R O refers to selection of an amino acid chosen from the follow 1ng: N N H R H R li R R |B?'-residue B?'-residue R O A O N wherein R. R', R", and R" is an amine, hydroxy, hydroxyl, R carbonyl, H. =O. —OH, -COOH, - N, —CH, —CH B -St.id 2-(Sle id X, halo, aryl, arylalkoxy, arylalkyl, alkynyl, alkenyl, alky lene, alkyl, alkyl-halo, arylamido, alkylheterocycle, alky lamino, alkylguanidino, alkanol, alkylcarboxy, cycloalkyl, R O A O heteroaryl, heteroarylalkyl, heteroarylalkoxy, or heterocy A.H orkyR clyl; R |B-residue |B’’-residue wherein X is any substituent. R O R R O 0247. In some embodiments the term “B-amino acid refers to selection of an amino acid chosen from the follow 1ng: A.H A.H R R |B-residue |B-residue R O R R O luy a N O R H R H R' -residue f’-residue R R B. |B?'-residue B?'-residue Buy A wherein R. R', R", and R" are any substituent. A.H N R R 0246. In some embodiments the term “B-amino acid |B-residue |B’’-residue refers to selection of an amino acid chosen from the follow R O R R O ing:

H H R R R O A O |B-residue |B-residue R O R R O

R f-residue f’-residue H R H R li R R O |B?'-residue B?'-residue R O

NR a N H R wherein R. R', R", and R" are any substituent, provided that: R (i)R is not O, N, or halo when the R is in a B-residue, (ii) R |B-residue |B’’-residue and R' are not O, N, or halo when the R and R' are in a B-residue; (iii) R is not O, N, or halo when the R is in a Bf-residue; (iv) RandR are not O, N, orhalo when the Rand R O R R O R" are in a B-residue; (v) R" is not O, N, or halo when the R" is in a B’’-residue; (vi) Rand R' are not O, N, or halo N N H H when the R and Rare in a B’’-residue. R R 0248. In some embodiments the term “B-amino acid |B-residue |B-residue refers to selection of an amino acid chosen from the follow ing: US 2013/0096050 A1 Apr. 18, 2013 31

(CH), Rs —(CH2), —NH-(CH2)—Rs —(CH), 1—N—{(CH), Rs —(CH), NHC(=O)-(CH2) R O A O —Rs, and —(CH2), —NHS(=O) (CH) Rs: wherein R is independently selected from the group consist ing of hydrogen, C-C-alkyl, alkenyl, or alkynyl: mono- or R bicyclic aryl, mono- or bicyclic heteroaryl having up to 5 f-residue f’-residue heteroatoms selected from N, O, and S: mono- or bicyclic aryl-C-C-alkyl, mono- or bicyclic heteroaryl-C-C-alkyl; and wherein Rs is selected from the group consisting of R O A O hydroxy, C-C-alkyloxy, aryloxy, heteroaryloxy, thio. A N N ry C-C-alkylthio. C-C-alkylsulfinyl, C-C-alkylsulfonyl, H R R arylthio, arylsulfinyl, arylsulfonyl, heteroarylthio, heteroar |B-residue |B’’-residue ylsulfinyl, heteroarylsulfonyl, amino, mono- or di-C-C- R O R R O alkylamino, mono- or diarylamino, mono- or diheteroary lamino, N-alkyl-N-arylamino, N-alkyl-N-heteroarylamino, N-aryl-N-heteroarylamino, aryl-C-C-alkylamino, car N N H H boxylic acid, carboxamide, mono- or di-C-C-alkylcarboxa R R mide, mono- or diarylcarboxamide, mono- or diheteroaryl |B-residue |B-residue carboxamide, N-alkyl-N-arylcarboxamide, N-alkyl-N- R O R O heteroarylcarboxamide, N-aryl-N-heteroarylcarboxamide, R Sulfonic acid, sulfonamide, mono- or di-C-C-alkylsulfona mide, mono- or diarylsulfonamide, mono- or diheteroarylsul N N fonamide, N-alkyl-N-arylsulfonamide, N-alkyl-N-heteroar H R H R' R R ylsulfonamide, N-aryl-N-heteroarylsulfonamide, urea; mono- di- or tri-substituted urea, wherein the substitutent(s) |B?'-residue B?'-residue is selected from the group consisting of C-C-alkyl, aryl, heteroaryl; O-alkylurethane, O-arylurethane, and O-het wherein R. R', R", and R" is an amine, hydroxy, hydroxyl, eroarylurethane; and m is an integer of from 2-6 and n is an carbonyl, H. =O, —OH, -COOH, N, —CH, —CH, integer of from 0-6; the substituents on heteroatoms of the X, halo, aryl, arylalkoxy, arylalkyl, alkynyl, alkenyl, alky ring being independently selected from the group consisting lene, alkyl, alkyl-halo, arylamido, alkylheterocycle, alky of S(=O)—CH2—R C(=O)—R S(=O) lamino, alkylguanidino, alkanol, alkylcarboxy, cycloalkyl, (CH), Rs, and —C(=O)—(CH)—Rs, wherein R heteroaryl, heteroarylalkyl, heteroarylalkoxy, or heterocy and Rs areas defined hereinabove, and m is an integer of from clyl; 2-6 and n is an integer between 0 and 6: provided that when X and Y together with the carbons to which they are bonded wherein X is any substituent; provided that: (i)R is not O, N, define a five- or six-membered cycloalkyl or a five-membered or halo when the R is in a 3-residue, (ii) Rand R' are not O. heterocyclic ring having one nitrogen as the sole heteroatom, N, orhalo when the RandR are in a B-residue; (iii)R is not and the nitrogen is bonded to a carbon atom adjacent to the O, N, or halo when the R is in a 3’-residue; (iv) RandR are carboxy carbon of Formula I, the cycloalkyl or heterocyclic not O, N, or halo when the RandR' are in a 3’-residue, (v) ring is Substituted; R is selected from the group consisting R" is not O, N, or halo when the R" is in a B’’-residue; (vi) hydrogen and an amino protecting group; R is selected from R and R' are not O, N, or halo when the R and R' are in a the group consisting of hydrogen and a carboxy protecting B’’-residue. group; racemic mixtures thereof, isolated or enriched enanti A “cyclic’ beta-amino acid is acid is an amino acid of the omers thereof; isolated or enriched diastereomers thereof; following formula I: and salts thereof. 0249. A "heterocyclic” beta-amino acid is an amino acid H X- - - -Y O of formula I, wherein X and Y combined, together with the carbon atoms to which they are bonded, define a substituted R-N-CH-CH-C-O-R2 or unsubstituted C-C cyclically or cycloalkenyl group hav ing one or more nitrogen, oxygen or Sulfur atoms as a het wherein X and Y combined, together with the carbonatoms to eroatom(s) within the cycloakyl or cycloalkenyl group; which they are bonded, define a substituted or unsubstituted wherein Substituents on carbon atoms of the cycloakyl or C-C cycloalkyl or cycloalkenyl group; wherein substituents cycloalkenyl rings being independently selected from the on carbon atoms of the rings being independently selected group consisting of linear or branched C-C-alkyl, alkenyl, from the group consisting of linear or branched C-C-alkyl, or alkynyl: mono- or bicyclic aryl, mono- or bicyclic het alkenyl, or alkynyl; mono- or bicyclic aryl, mono- or bicyclic eroaryl having up to 5 heteroatoms selected from N, O, and S; heteroaryl having up to 5 heteroatoms selected from N, O, and mono- or bicyclic aryl-C-C-alkyl, mono- or bicyclic het S; mono- or bicyclic aryl-C-C-alkyl, mono- or bicyclic eroaryl-C-C-alkyl, -(CH2), —OR. -(CH2)—SR, heteroaryl-C-C-alkyl, -(CH2)—OR —(CH2). (CH2)—S(=O)—CH2—R —(CH2)—S(=O) - SR (CH2), S(O) CH, R4, (CH)—S(=O) CH. R. —(CH)—NRR, —(CH),—NHC(D)R. —CH2—R —(CH2)—NRR —(CH2)—NHC —(CH2), —NHS(=O). CH-Ra, -(CH2)—O US 2013/0096050 A1 Apr. 18, 2013 32

(CH2), Rs.2. —(CH2)—NHC(=O)—(CH2)—Rs. some embodiments the terms beta-3 or beta-2 amino acid and —(CH), NHS(=O) (CH), Rs; wherein R is refers to 33-homo B2-homo amino acids. independently selected from the group consisting of hydro 0251 A “conservative amino acid substitution' is one in gen, C-C-alkyl, alkenyl, or alkynyl: mono- or bicyclic aryl, which the amino acid residue is replaced with an amino acid mono- or bicyclic heteroaryl having up to 5 heteroatoms residue having a similar side chain. Families of amino acid selected from N, O, and S; mono- or bicyclic aryl-C-C- residues having similar side chains have been defined in the alkyl, mono- or bicyclic heteroaryl-C-C-alkyl, and wherein art. These families include amino acids with basic side chains Rs is selected from the group consisting of hydroxy, C-C- (e.g., K. R. H), acidic side chains (e.g., 13, E), uncharged alkyloxy, aryloxy, heteroaryloxy, thio, C-C6-alkylthio. polar side chains (e.g., G. N. Q. S. T.Y. C. H), nonpolar side C-C-alkylsulfinyl, C-C-alkylsulfonyl, arylthio, arylsulfi chains (e.g., G. A. V. L. I. P. F. M. W), beta-branched side nyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroar chains (e.g., T. V. I) and aromatic side chains (e.g.Y.F. W. H). Thus, a predicted nonessential amino acid residue in a VIP ylsulfonyl, amino, mono- or di-C-C-alkylamino, mono- or analog, for example, replaced with another amino acid resi diarylamino, mono- or diheteroarylamino, N-alkyl-N-ary due from the same side chain family. Other examples of lamino, N-alkyl-N-heteroarylamino, N-aryl-N-heteroary acceptable Substitutions are substitutions based on isosteric lamino, aryl-C-C6-alkylamino, carboxylic acid, carboxam considerations (e.g. norleucine for methionine) or other prop ide, mono- or di-C-C-alkylcarboxamide, mono- or erties (e.g. 2-thienylalanine for phenylalanine). diarylcarboxamide, mono- or diheteroarylcarboxamide, 0252. As used herein, the term "derived from in the con N-alkyl-N-arylcarboxamide, N-alkyl-N-heteroarylcarboxa text of the relationship between a chemical structure oramino mide, N-aryl-N-heteroarylcarboxamide, sulfonic acid, sul acid sequence and a related chemical structure or related fonamide, mono- or di-C-C-alkylsulfonamide, mono- or amino acid sequence describes a chemical structure or amino diarylsulfonamide, mono- or diheteroarylsulfonamide, acid sequence that may be homologous to or structurally N-alkyl-N-arylsulfonamide, N-alkyl-N-heteroarylsulfona similar to the related chemical structure or related amino acid mide, N-aryl-N-heteroarylsulfonamide, urea; mono- di- or Sequence. tri-substituted urea, wherein the substitutent(s) is selected 0253) As used herein, the term “inflammatory disease' from the group consisting of C-C-alkyl, aryl, heteroaryl; refers to any disease, condition, or ailment that results from an O-alkylurethane, O-arylurethane, and O-heteroarylurethane: immune response or a pathogen infection, which in some and m is an integer of from 2-6 and n is an integer of from 0-6: instances may be characterized by one or more of pain, Swell the Substituents on heteroatoms of the ring being indepen ing, and redness of a tissue types. In some embodiments, dently selected from the group consisting of —S(=O) - inflmmatory disease refers to rheumatoid arthritis, Crohn's CH2—R C(=O)—R S(=O) -(CH2), Rs. and disease, sepsis, ulcerative colitis, irritable bowel disease, —C(=O)—(CH),—Rs, wherein R and Rs areas defined chronic irritable bowel syndrome, and allergies Such as aller hereinabove, and m is an integer of from 2-6 and n is an gic rhinitis. integer between 0 and 6: provided that when X and Y together 0254. A “non-essential amino acid residue is a residue with the carbons to which they are bonded define a five- or that can be altered from the wild-type sequence of a polypep six-membered cycloalkyl or a five-membered heterocyclic tide (e.g., a short domain of VIP) without abolishing or sub ring having one nitrogen as the sole heteroatom, and the stantially altering its essential biological or biochemical nitrogen is bonded to a carbon atom adjacent to the carboxy activity (e.g., receptor binding or activation). An "essential” carbon of Formula I, the cycloalkyl or heterocyclic ring is amino acid residue is a residue that, when altered from the Substituted; R is selected from the group consisting hydro wild-type sequence of the polypeptide, results in abolishing gen and an amino protecting group; R is selected from the or Substantially abolishing the polypeptide's essential bio group consisting of hydrogen and a carboxyprotecting group; logical or biochemical activity. racemic mixtures thereof, isolated or enriched enantiomers 0255 A“non-natural side chain” is a modified or synthetic thereof; isolated or enriched diastereomers thereof, and salts chain of atoms joined by covalent bond to the C-carbon atom, thereof. B-carbon atom, or Y-carbonatom which does not make up the 0250 In some embodiments, at least one of the B-amino backbone of the polypeptide chain of amino acids. The natu acid residues in the analog is replaced with at least one ral side chain, or R group, of alanine is a methyl group. In B-amino acid residue that is cyclically constrained via a ring Some embodiments, the non-natural side chain of the compo encompassing its f° and f carbonatoms. In another embodi sition is a methyl group in which one or more of the hydrogen ment of the invention, most or all of the inserted f-amino acid atoms is replaced by a deuterium atom. residues are cyclically constrained. In another version of the 0256 The term “polypeptide' encompasses two or more invention, at least one of the B-amino acid residues is unsub naturally or non-naturally-occurring amino acids joined by a stituted at its f° and B carbon atoms. Alternatively, all of the covalent bond (e.g., an amide bond). Polypeptides as (3-amino acid residues may be substituted at their ?and? described herein include full-length proteins (e.g., fully pro carbonatoms (with linear, branched or cyclic Substituents). In cessed pro-proteins or full-length synthetic polypeptides) as Some embodiments, the cyclic Substituents of the claimed well as shorter amino acid sequences (e.g., fragments of invention comprise side chains that are covalently bonded to naturally-occurring proteins or synthetic polypeptide frag the side chains of other contiguous amino acids. In some ments). embodiments, the cyclic substituents of the claimed invention 0257. The term “salt” refers to acidic salts formed with comprise side chains that are covalently bonded to the side inorganic and/or organic acids, as well as basic salts formed chains of other non-contiguous amino acids. In some embodi with inorganic and/or organic bases. Examples of these acids ments the cyclic substituents of the claimed invention do not and bases are well known to those of ordinary skill in the art. include side chains that are covalently bonded to the side Such acid addition salts will normally be pharmaceutically chains of other contiguous or non-contiguous amino acids. In acceptable although salts of non-pharmaceutically accept US 2013/0096050 A1 Apr. 18, 2013 able acids may be of utility in the preparation and purification for example, polyethylene glycol. In some embodiments, the of the compound in question. Salts include those formed from polypeptide of the claimed invention may be bound by poly hydrochloric, hydrobromic, Sulphuric, phosphoric, citric, tar ethylene glycol to better Solubilize the composition compris taric, lactic, pyruvic, acetic, succinic, fumaric, maleic, meth ing the peptide. anesulphonic and benzenesulphonic acids. 0261 The terms “treating” and “to treat’, mean to allevi 0258. In some embodiments, salts of the compositions ate symptoms, eliminate the causation either on a temporary comprising either a secretin or VIP analog may be formed by or permanent basis, or to prevent or slow the appearance of reacting the free base, or a salt, enantiomer or racemate symptoms. The term “treatment includes alleviation, elimi thereof, with one or more equivalents of the appropriate acid. nation of causation (temporary or permanent) of, or preven In some embodiments, pharmaceutical acceptable salts of the tion of symptoms and disorders associated with any condi present invention refer to analogs having at least one basic tion. The treatment may be a pre-treatment as well as a group or at least one basic radical. In some embodiments, treatment at the onset of symptoms. pharmaceutical acceptable salts of the present invention com 0262 “Effective amount” refers to an amount of a com prise a free amino group, a free guanidino group, a pyrazinyl pound, material, or composition, as described herein effective radical, or a pyridyl radical that forms acid addition salts. In to achieve a particular biological result such as, but not lim Some embodiments, the pharmaceutical acceptable salts of ited to, biological results disclosed, described, or exemplified the present invention refer to analogs that are acid addition herein. Such results may include, but are not limited to, the salts of the Subject compounds with (for example) inorganic effective reduction of symptoms associated with any of the acids, such as hydrochloric acid, Sulfuric acid or a phosphoric disease states mentioned herein, as determined by any means acid, or with Suitable organic carboxylic or Sulfonic acids, for suitable in the art. The effective amount of the composition example aliphatic mono- or di-carboxylic acids. Such as trif may be dependent on any number of variables, including luoroacetic acid, acetic acid, propionic acid, glycolic acid, without limitation, the species, breed, size, height, weight, Succinic acid, maleic acid, fumaric acid, hydroxymaleic acid, age, overall health of the subject, the type of formulation, the malic acid, tartaric acid, citric acid or oxalic acid, or amino mode or manner or administration, the type and/or severity of acids such as arginine or lysine, aromatic carboxylic acids, the particular condition being treated, or the need to modulate Such as benzoic acid, 2-phenoxy-benzoic acid, 2-acetoxyben the activity of the molecular pathway induced by association Zoic acid, salicylic acid, 4-aminosalicylic acid, aromatic-ali of the analog to its receptor. The appropriate effective amount phatic carboxylic acids, such as mandelic acid or cinnamic can be routinely determined by those of skill in the art using acid, heteroaromatic carboxylic acids, such as nicotinic acid routine optimization techniques and the skilled and informed or isonicotinic acid, aliphatic sulfonic acids, such as meth judgment of the practitioner and other factors evident to those ane-, ethane- or 2-hydroxyethane-Sulfonic acid, or aromatic skilled in the art. A therapeutically effective dose of the ana Sulfonic acids, for example benzene-, p-toluene- or naphtha logs described herein may provide partial or complete bio lene-2-sulfonic acid. When several basic groups are present logical activity as compared to the biological activity induced mono- or poly-acid addition salts may be formed. The reac by the wild-type or naturally occurring polypeptides upon tion may be carried out in a solvent or medium in which the which the analogs are derived. A therapeutically effective salt is insoluble or in a solvent in which the salt is soluble, for dose of the analogs described herein may provide a Sustained example, water, dioxane, ethanol, tetrahydrofuran or diethyl biochemical or biological affect and/or an increased resis ether, ora mixture of solvents, which may be removed in tance to degradation when placed in solution as compared vacuo or by freeze drying. The reaction may also be a meta with the normal affect observed when the naturally occurring thetical process or it may be carried out on an ion exchange and fully processed tranlated protein is administered to the resin. In some embodiments, the salts may be those that are same Subject. physiologically tolerated by a patient. Salts according to the 0263. The term “fragment” refers to any analog of a natu present invention may be found in their anhydrous form or as rally occurring polypeptide disclosed herein that comprises at in hydrated crystalline form (i.e., complexed or crystallized least 4 amino acids identical to the naturally occurring with one or more molecules of water). polypeptide upon which the analog is based. The term “func 0259. The term “subject' is used throughout the specifi tional fragment” refers to any fragment of any analog of a cation to describe an animal to whom treatment with the naturally occurring polypeptide disclosed herein that com compositions according to the present invention is provided prises at least 4 amino acids identical to the naturally occur or administered. For treatment of those conditions which are ring polypeptide upon which the analog is based and shares specific for a specific Subject, Such as a human being, the term the function of the naturally occurring polypeptide upon "patient may be interchangeably used. In some instances in which the analog is based. In some embodiments, the com the description of the present invention, the term “patient’ positions or pharmaceutical composition comprises an ana will refer to human patients. In some embodiments, the sub log comprising at least one 3-amino acid. wherein the analog ject may be a mammal to whom the present invention is is a fragment of VIP, a secretin family member, an interleukin, provided or administered. In some embodiments, the Subject or any of the polypeptides disclosed in the instant application. may be a non-human animal to whom the present invention is In some embodiments, the compositions or pharmaceutical provided or administered. composition comprises an analog comprising at least one 0260. The term “soluble' or “water soluble refers to solu B-amino acid, wherein the analog is a fragment of VIP, a bility that is higher than /100,000 (mg/ml). The solubility of a secretin family member, an interleukin, or any of the polypep Substance, or Solute, is the maximum mass of that Substance tides disclosed in the instant application and wherein the that can be dissolved completely in a specified mass of the fragment shares at least 4 contiguous amino acid residues solvent, such as water. “Practically insoluble' or “insoluble.” with the naturally occurring polypeptide upon which the ana on the other hand, refers to an aqueous solubility that is /10,000 log is based and wherein the fragment retains the biological (mg/ml) or less. Water soluble or soluble substances include, activity of the naturally occurring polypeptide upon which the US 2013/0096050 A1 Apr. 18, 2013 34 analog is based. In some embodiments, the VIP analog is a In some embodiments, the analog is modified with at least one fragment that comprises between about 1 to about 27 amino PEG molecule on at least one of the non-natural amino acids. acids of the naturally occurring VIP sequence. In some 0264. The term “halo” or “halogen” refers to fluorine, embodiments, the VIP analog is a fragment that comprises chlorine, bromine or iodine or a radical thereof. between about 1 to about 26 amino acids of the naturally 0265. The term “alkyl refers to a hydrocarbon chain that occurring VIP sequence. In some embodiments, the VIP ana is a straight chain or branched chain, containing the indicated log is a fragment that comprises between about 1 to about 25 number of carbon atoms. For example, C-Co indicates that amino acids of the naturally occurring VIP sequence. In some the group has from 1 to 10 (inclusive) carbon atoms in it. In embodiments, the VIP analog is a fragment that comprises the absence of any numerical designation, “alkyl is a chain between about 1 to about 24 amino acids of the naturally (straight or branched) having 1 to 20 (inclusive) carbonatoms occurring VIP sequence. In some embodiments, the VIP ana in it. In some embodiments the alkyl group is chosen from: log is a fragment that comprises between about 1 to about 23 C-Clo, C2-Clo, Ca-Clo, Cs-Co. Co-Clo, C7-Co. Co-Co amino acids of the naturally occurring VIP sequence. In some C-C2, C1-C, C1-C, C1-C5. C-C, C1-C7, C-Cs, or C-Co. embodiments, the VIP analog is a fragment that comprises 0266 The term “alkylene' refers to a divalent alkyl (i.e., between about 1 to about 22 amino acids of the naturally —R—). occurring VIP sequence. In some embodiments, the VIP ana 0267. The term “alkenyl refers to a hydrocarbon chain log is a fragment that comprises between about 1 to about 21 that is a straight chain or branched chain having one or more amino acids of the naturally occurring VIP sequence. In some carbon-carbon double bonds. The alkenyl moiety contains the embodiments, the VIP analog is a fragment that comprises indicated number of carbonatoms. For example, C-Co indi between about 1 to about 20 amino acids of the naturally cates that the group has from 2 to 10 (inclusive) carbonatoms occurring VIP sequence. In some embodiments, the VIP ana in it. The term “lower alkenyl” refers to a C-C alkenyl chain. log is a fragment that comprises between about 1 to about 19 In the absence of any numerical designation, “alkenyl' is a amino acids of the naturally occurring VIP sequence. In some chain (straight or branched) having 2 to 20 (inclusive) carbon embodiments, the VIP analog is a fragment that comprises atoms in it. between about 1 to about 18 amino acids of the naturally 0268. The term “alkynyl refers to a hydrocarbon chain occurring VIP sequence. In some embodiments, the VIP ana that is a straight chain or branched chain having one or more log is a fragment that comprises between about 1 to about 19 carbon-carbon triple bonds. The alkynyl moiety contains the amino acids of the naturally occurring VIP sequence. In some indicated number of carbonatoms. For example, C-Co indi embodiments, the VIP analog is a fragment that comprises cates that the group has from 2 to 10 (inclusive) carbonatoms between about 1 to about 17 amino acids of the naturally in it. The term “lower alkynyl refers to a C-C alkynyl occurring VIP sequence. In some embodiments, the VIP ana chain. In the absence of any numerical designation, “alkynyl log is a fragment that comprises between about 1 to about 16 is a chain (straight or branched) having about 2 to about 20 amino acids of the naturally occurring VIP sequence. In some (inclusive) carbon atoms in it. embodiments, the VIP analog is a fragment that comprises 0269. The term “aryl” refers to an aromatic ring system. In between about 1 to about 15 amino acids of the naturally Some embodiments, the aryl group of the analog include occurring VIP sequence. In some embodiments, the VIP ana substituents, wherein 0, 1, 2, 3, 4, 5, 6,7,8,9, or 10 atoms of log is a fragment that comprises between about 1 to about 14 each ring are Substituted by a Substituent. Iin some embodi amino acids of the naturally occurring VIP sequence. In some ments, the aryl group refers to a 6-carbon monocyclic or embodiments, the VIP analog is a fragment that comprises 10-carbon bicyclic aromatic ring system wherein 0, 1, 2, 3, or between about 1 to about 13 amino acids of the naturally 4 atoms of each ring are Substituted by a Substituent. occurring VIP sequence. In some embodiments, the VIP ana Examples of aryl groups include phenyl, naphthyl and the log is a fragment that comprises between about 1 to about 12 like. The term “arylalkyl or the term “aralkyl refers to alkyl amino acids of the naturally occurring VIP sequence. In some substituted with an aryl. The term “arylalkoxy' refers to an embodiments, the VIP analog is a fragment that comprises alkoxy substituted with aryl. "Arylalkyl refers to an aryl between about 1 to about 11 amino acids of the naturally group, as defined above, wherein one of the aryl group's occurring VIP sequence. In some embcdiments, the VIP ana hydrogen atoms has been replaced with an alkyl group, as log is a fragment that comprises between about 1 to about 10 defined above. Representative examples of an arylalkyl group amino acids of the naturally occurring VIP sequence. In some include, but are not limited to, 2-methylphenyl, 3-methylphe embodiments, the VIP analog is a fragment that comprises nyl, 4-methylphenyl, 2-ethylphenyl, 3-ethylphenyl, 4-eth between about 1 to about 9 amino acids of the naturally ylphenyl, 2-propylphenyl, 3-propylphenyl, 4-propylphenyl, occurring VIP sequence. In some embodiments, the VIP ana 2-butylphenyl, 3-butylphenyl, 4-butylphenyl, 2-pentylphe log is a fragment of VIP that comprises between about 1 to nyl, 3-pentylphenyl, 4-pentylphenyl, 2-isopropylphenyl, about 8 amino acids of the naturally occurring VIP sequence. 3-isopropylphenyl, 4-isopropylphenyl, 2-isobutylphenyl, In some embodiments, the VIP analog is a fragment that 3-isobutylphenyl, 4-isobutylphenyl, 2-sec-butylphenyl, comprises between about 1 to about 7 amino acids of the 3-sec-butylphenyl, 4-sec-butylphenyl, 2-t-butylphenyl, 3-t- naturally occurring VIP sequence. In some embodiments, the butylphenyl and 4-t-butylphenyl. VIP analog is a fragment that comprises between about 1 to 0270 Arylamido” refers to an aryl group, as defined about 6 amino acids of the naturally occurring VIP sequence. above, wherein one of the aryl group’s hydrogen atoms has In some embodiments, the VIP analog is a fragment that been replaced with one or more —C(O)NH groups. Repre comprises between about 1 to about 5 amino acids of the sentative examples of an arylamido group include 2-C(O) naturally occurring VIP sequence. In some embodiments, the NH-phenyl, 3-C(O)NH2-phenyl, 4-C(O)NH2-phenyl, 2-C VIP analog is a fragment that comprises between about 1 to (O)NH-pyridyl, 3-C(O)NH-pyridyl, and 4-C(O)NH about 4 amino acids of the naturally occurring VIP sequence. pyridyl. US 2013/0096050 A1 Apr. 18, 2013

0271 Alkylheterocycle” refers to an alkyl group, as carbonatoms and 1-3, 1-6, or 1-9 heteroatoms of O, N, or S if defined above, wherein one of the alkyl group's hydrogen monocyclic, bicyclic, or tricyclic, respectively), wherein 0, 1, atoms has been replaced with a heterocycle. Representative 2, 3, or 4 atoms of each ring are substituted by a Substituent. examples of an alkylheterocyclo group include, but are not Examples of heteroaryl groups include, but are not limited to, limited to, —CH2CH2-morpholine. —CH2CH2piperidine, pyridyl, furyl or furanyl, imidazolyl, benzimidazolyl pyrim —CHCHCH-morpholine, and —CHCHCH-imida idinyl, thiophenyl or thienyl, quinolinyl, indolyl, thiazolyl, Zole. and the like. 0272 “Alkylamido” refers to an alkyl group, as defined (0279. The term “heteroarylalkyl or the term “het above, wherein one of the alkyl group’s hydrogenatoms has eroaralkyl refers to an alkyl substituted with a heteroaryl. been replaced with a —C(O)NH group. Representative The term "heteroarylalkoxy' refers to an alkoxy substituted examples of an alkylamido group include, but are not limited with heteroaryl. to, —CHC(O)NH, -CHCHC(O)NH, CHCHCHC 0280. The term "heterocyclyl refers to a nonaromatic 5-8 (O)NH2, - CHCHCHCHC(O)NH2, membered monocyclic, 8-12 membered bicyclic, or 11-14 —CHCHCHCHCHC(O)NH, CHCH(C(O)NH) membered tricyclic ring system having 1-3 heteroatoms if CH, CHCH(C(O)NH2)CHCH, -CH(C(O)NH) monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if CHCH, C(CH),CHC(O)NH, CHCHNFIC(O) tricyclic, said heteroatoms selected from O, N, or S (e.g., CH, CHCH-NHC(O)CHCH, and CHCH-NHC(O) carbonatoms and 1-3, 1-6, or 1-9 heteroatoms of O, N, or S if CH=CH. monocyclic, bicyclic, or tricyclic, respectively), wherein 0, 1, 0273 “Alkylamino” refers to an alkyl group, as defined 2 or 3 atoms of each ring are substituted by a substituent. above, wherein one of the alkyl group’s hydrogenatoms has Examples of heterocyclyl groups include, but are not limited been replaced with a —NH group. Representative examples to, piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, tetrahy of an alkylamido group include, but are not limited to drofuranyl, and the like. —CH-NH. CHCH-NH. CHCHCH-NH. 0281. The term “substituent” refers to a group replacing a —CHCHCHCH-NH – CHCHCHCHCH-NH. second atom or group Such as a hydrogen atom on any mol 0274 Alkylguanidino’ refers to an alkyl group, as ecule, compound or moiety. Suitable Substituents include, defined above, wherein one of the alkyl group's hydrogen without limitation, halo, hydroxy, mercapto, oxo, nitro, atoms has been replaced with a —NH(C NH)NH group. haloalkyl, alkyl, alkaryl, aryl, aralkyl, alkoxy, thioalkoxy, Representative examples of an alkylamido group include, but aryloxy, amino, alkoxycarbonyl, amido, carboxy, alkane are not limited to —CH NH(C=NH)NH, CHCH-NH Sulfonyl, alkylcarbonyl, and cyano groups. (C=NH)NH, CHCHCH-NH. (CNH)NH, 0282. In some embodiments, the composition comprises —CHCHCHCH-NH (C—NH)NH2, an analog comprises one or more asymmetric centers and thus —CHCHCHCHCH-NH (C NH)NH2. In some occuras racemates and racemic mixtures, single enantiomers, embodiments alkyl units can be found on the Natom(s) of the individual diastereomers and diastereomeric mixtures. alkylamino or alkylguanidino groups (for example, Preparation of pure enantiomers or mixtures of desired enan —CH-NH(CH), CHN(CH)). tiomeric excess (ee) or enantiomeric purity are accomplished 0275 Alkanol refers to an alkyl group, as defined above, by one or more of the many methods of (a) separation or wherein one of the alkyl group's hydrogen atoms has been resolution of enantiomers, or (b) enantioselective synthesis replaced with a hydroxyl group. Representative examples of known to those of skill in the art, or a combination thereof. an alkanol group include, but are not limited to. —CH2OH. These resolution methods generally rely on chiral recognition —CHCH-OH, —CHCHCH-OH, and include, for example, chromatography using chiral sta —CHCHCHCH-OH, - CHCHCHCHCH-OH, tionary phases, enantioselective host-guest complexation, CHCH(OH)CH, CHCH(OH)CHCH, CH(OH) resolution or synthesis using chiral auxiliaries, enantioselec CH and —C(CH),CHOH. tive synthesis, enzymatic and nonenzymatic kinetic resolu 0276 Alkylcarboxy' refers to an alkyl group, as defined tion, or spontaneous enantioselective crystallization. Such above, wherein one of the alkyl group’s hydrogenatoms has methods are disclosed generally in Chiral Separation Tech been replaced with a —COOH group. Representative niques: A Practical Approach (2nd Ed.), G. Subramanian examples of an alkylcarboxy group include, but are not lim (ed.), Wiley-VCH, 2000: T. E. Beesley and R. P. W. Scott, ited to, -CHCOOH, CHCHCOOH, Chiral Chromatography, John Wiley & Sons, 1999; and Sat CHCH-CHCOOH, CHCHCH-CHCOOH, inder Ahuja, Chiral Separations by Chromatography, Am. CHCH(COOH)CH, CHCHCHCH-CHCOOH, Chem. Soc., 2000. Furthermore, there are equally well CHCH(COOFOCHCH, CH(COOH)CHCH and known methods for the quantitation of enantiomeric excess or —C(CH) CHCOOH. purity, for example, GC, HPLC, CE, or NMR, and assignment 0277. The term "cycloalkyl as employed herein includes of absolute configuration and conformation, for example, CD saturated and partially unsaturated cyclic hydrocarbon ORD, X-ray crystallography, or NMR. groups having 3 to 12 carbons, 3 to 8 carbons, or 3 to 6 0283 All tautomeric forms and isomeric forms and mix carbons, wherein the cycloalkyl group additionally is option tures, whether individual geometric isomers or stereoisomers ally Substituted. Some cycloalkyl groups include, without or racemic or non-racemic mixtures, of a chemical structure limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopente or Wntire analog is intended, unless the specific stereochem nyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. istry or isomeric form is specifically indicated in the analog (0278. The term “heteroaryl” refers to an aromatic 5-10 name, chemical name or structure. All Such isomeric forms of membered monocyclic, 8-12 membered bicyclic, or 11-14 these compositions are included in the present invention membered tricyclic ring system having 1-3 heteroatoms if unless expressly provided otherwise. In some embodiments, monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if the analogs of this invention are also represented in multiple tricyclic, said heteroatoms selected from O, N, or S (e.g., tautomeric forms, in Such instances, the invention includes all US 2013/0096050 A1 Apr. 18, 2013 36 tautomeric forms of the analogs described herein (e.g., if that range. Thus, for a variable which is inherently discrete, alkylation of a ring system results in alkylation at multiple the variable is equal to any integer value within the numerical sites, the invention includes all such reaction products). All range, including the end-points of the range. Similarly, for a Such isomeric forms of Such analogs are included in the variable which is inherently continuous, the variable is equal present invention unless expressly provided otherwise. All to any real value within the numerical range, including the crystal forms of the analogs described herein are included in end-points of the range. As an example, and without limita the present invention unless expressly provided otherwise. tion, a variable which is described as having values between All deuterated form of the analogs described herein are 0 and 2 takes the values 0, 1 or 2 if the variable is inherently included in the present invention. In some embodiments as discrete, and takes the values 0.0, 0.1, 0.01, 0.001, 10°, least one hydrogen atom of the analog is replace with a 10, 100, 10, 10-, 107,10-,10-, 10 or any other deuterium atom. In some embodiments at least one hydrogen real values 20 and s2 if the variable is inherently continu atom that is involved with a hydrogen-bond is replaced with a OS. deuterium atom. In some embodiments at least one solvent 0286 As used herein, unless specifically indicated other exchangeable hydrogen atom is replaced with a deuterium wise, the word 'or' is used in the inclusive sense of “and/or atom. In some embodiments, the compositions, pharmaceu and not the exclusive sense of “eitherfor.” tical compositions, and analogs contained therein comprise 0287. The term “biological activity” encompasses struc tural and functional properties of a macrocycle of the inven from about 1% to about 100% of their hydrogen replaced with tion. Biological activity is, for example, structural stability, deuterium atoms. In some embodiments, the compositions, alpha-helicity, affinity for a target, resistance to proteolytic pharmaceutical compositions, and analogs contained therein degradation, cell penetrability, intracellular stability, in vivo comprise from about 90% to about 100% of their hydrogen stability, or any combination thereof. replaced with deuterium atoms. In some embodiments, the 0288 The terms “prodrug or “prodrug derivative” mean a compositions, pharmaceutical compositions, and analogs covalently-bonded derivative or carrier of the analog of the contained therein comprise from about 80% to about 90% of claimed invention or active drug Substance which undergoes their hydrogen replaced with deuterium atoms. In some at least Some biotransformation prior to exhibiting its phar embodiments, the compositions, pharmaceutical composi macological effect(s). In general. Such prodrugs have meta tions, and analogs contained therein comprise from about bolically cleavable groups and are rapidly transformed in vivo 70% to about 80% of their hydrogen replaced with deuterium to yield the analog of the claimed invention, for example, by atoms. In some embodiments, the compositions, pharmaceu hydrolysis in blood, and generally include esters and amide tical compositions, and analogs contained therein comprise analogs of the analogs. The prodrug is formulated with the from about 60% to about 70% of their hydrogen replaced with objectives of improved chemical stability, improved patient deuterium atoms. In some embodiments, the compositions, acceptance and compliance, improved bioavailability, pro pharmaceutical compositions, and analogs contained therein longed duration of action, improved organ selectivity, comprise from about 50% to about 60% of their hydrogen improved formulation (e.g., increased hydrosolubility), and/ replaced with deuterium atoms. In some embodiments, the or decreased side effects (e.g., toxicity). In general, prodrugs compositions, pharmaceutical compositions, and analogs themselves have weak or no biological activity and are stable under ordinary conditions. Prodrugs can be readily prepared contained therein comprise from about 40% to about 50% of from the analogs using methods known in the art, such as their hydrogen replaced with deuterium atoms. In some those described in A Textbook of Drug Design and Develop embodiments, the compositions, pharmaceutical composi ment, Krogsgaard-Larsen and H. Bundgaard (eds.), Gordon tions, and analogs contained therein comprise from about & Breach, 1991, particularly Chapter 5: “Design and Appli 30% to about 40% of their hydrogen replaced with deuterium cations of Prodrugs': Design of Prodrugs, H. Bundgaard atoms. In some embodiments, the compositions, pharmaceu (ed.), Elsevier, 1985; Prodrugs: Topical and Ocular Drug tical compositions, and analogs contained therein comprise Delivery, K. B. Sloan (ed.), Marcel Dekker, 1998; Methods in from about 20% to about 30% of their hydrogen replaced with Enzymology, K. Widder et al. (eds.), Vol. 42, Academic Press, deuterium atoms. In some embodiments, the compositions, 1985, particularly pp. 309-396; Burger's Medicinal Chemis pharmaceutical compositions, and analogs contained therein try and Drug Discovery, 5th Ed., M. Wolff (ed.), John Wiley comprise from about 10% to about 20% of their hydrogen & Sons, 1995, particularly Vol. 1 and pp. 172-178 and pp. replaced with deuterium atoms. In some embodiments, the 949-982; Pro-Drugs as Novel Delivery Systems, T. Higuchi compositions, pharmaceutical compositions, and analogs and V. Stella (eds.), Am. Chem. Soc., 1975; and Bioreversible contained therein comprise from about 5% to about 10% of Carriers in Drug Design, E. 13. Roche (ed.), Elsevier, 1987, their hydrogen replaced with deuterium atoms. If the analog each of which is incorporated herein by reference in their of the claimed invention includes a methyl group, a deutrated entireties. In some embodiments, the analog may be a pro analog may have one, two, or three of the hydrogens replaced drug that, when administered to the Subject becomes biologi by deuterium atoms. In some embodiments, the analog may cally active. contain one or more radioisotopes. In some embodiments, as 0289. In some embodiments, the invention relates to a least one hydrogenatom of the analog is replace with a tritium composition or pharmaceutical composition comprising a atom. In some embodiments, the compositions, pharmaceu pharmaceutically acceptable prodrug that, when adminis tical compositions, and analogs contained therein comprise tered to the subject becomes biologically active. The term from about 1% to about 5% of their hydrogens are replaced “pharmaceutically acceptable prodrug as used herein means with tritium atoms. a prodrug of a compound of the invention which is, within the 0284 As used herein, the terms “increase' and “decrease' Scope of sound medical judgment, Suitable for use in contact mean, respectively, to cause a statistically significantly (i.e., with the tissues of humans and lower animals without undue p-0.15) increase or decrease of at least 1%, 2%, or 5%. toxicity, irritation, allergic response, and the like, commen 0285. As used herein, the recitation of a numerical range Surate with a reasonable benefit/risk ratio, and effective for for a variable is intended to convey that the invention may be their intended use, as well as the Zwitterionic forms, where practiced with the variable equal to any of the values within possible. US 2013/0096050 A1 Apr. 18, 2013 37

0290. In some embodiments, the analog of the claimed capable of isolation, for example, when one or more solvent invention is a pharmaceutically-acceptable acid addition salt. molecules are incorporated in the crystal lattice of the crys The term “pharmaceutically-acceptable acid addition salt talline solid. In general, the solvents selected do not interfere means those salts which retain the biological effectiveness with the biological activity of the solute. Solvates encom and properties of the free bases and which are not biologically passes both solution-phase and isolatable Solvates. Represen or otherwise undesirable, formed with inorganic acids such as tative Solvates include hydrates, ethanolates, and methano hydrochloric acid, hydrobromic acid, hydrolodic acid, sulfu lates. ric acid, Sulfamic acid, nitric acid, phosphoric acid, and the 0292. The invention relates to compositions comprising like, and organic acids Such as acetic acid, trichloroacetic an analog of a naturally occurring polypeptide sequence. In acid, trifluoroacetic acid, adipic acid, alginic acid, ascorbic Some embodiments the invention relates to a composition acid, aspartic acid, benzenesulfonic acid, benzoic acid, 2-ac comprising an analog of a naturally occurring polypeptide etoxybenzoic acid, butyric acid, camphoric acid, camphor sequence wherein the analog is from about 80% to 99% Sulfonic acid, cinnamic acid, citric acid, digluconic acid, homologous to a naturally occurring polypeptide sequence. ethanesulfonic acid, glutamic acid, glycolic acid, glycero In some embodiments the invention relates to a composition phosphoric acid, hemisulfic acid, heptanoic acid, hexanoic comprising an analog of a naturally occurring polypeptide acid, formic acid, fumaric acid, 2-hydroxyethanesulfonic sequence wherein the analog is from about 80% to 85% acid (isethionic acid), lactic acid, maleic acid, hydroxymaleic homologous to a naturally occurring polypeptide sequence. acid, malic acid, malonic acid, mandelic acid, mesitylene In some embodiments the invention relates to a composition Sulfonic acid, methanesulfonic acid, naphthalenesulfonic comprising an analog of a naturally occurring polypeptide acid, nicotinic acid, 2-naphthalenesulfonic acid, oxalic acid, sequence wherein the analog is from about 85% to 90% pamoic acid, pectinic acid, phenylacetic acid, 3-phenylpro homologous to a naturally occurring polypeptide sequence. pionic acid, picric acid, pivalic acid, propionic acid, pyruvic In some embodiments the invention relates to a composition acid, pyruvic acid, salicylic acid, Stearic acid, Succinic acid, comprising an analog of a naturally occurring polypeptide Sulfanilic acid, tartaric acid, p-toluenesulfonic acid, unde sequence wherein the analog is from about 90% to 95% canoic acid, and the like. In some embodiments, the analog of homologous to a naturally occurring polypeptide sequence. the claimed invention is a pharmaceutically-acceptable base In some embodiments the invention relates to a composition addition salt. The term “pharmaceutically-acceptable base comprising an analog of a naturally occurring polypeptide addition salt' means those salts which retain the biological sequence wherein the analog is from about 95% to 99% effectiveness and properties of the free acids and which are homologous to a naturally occurring polypeptide sequence. not biologically or otherwise undesirable, formed with inor In some embodiments the invention relates to a composition ganic bases Such as ammonia or hydroxide, carbonate, or comprising an analog of a naturally occurring polypeptide bicarbonate of ammonium or a metal cation Such as Sodium, sequence wherein the analog is about 95%, 96%, 97%, 98%, potassium, lithium, calcium, magnesium, iron, Zinc, copper, or 99% homologous to a naturally occurring polypeptide manganese, aluminum, and the like. Suitable salts include the sequence. In some embodiments the analog is derived from ammonium, potassium, Sodium, calcium, and magnesium the naturally occurring polypeptide of the Secretin family. In salts. Salts derived from pharmaceutically-acceptable Some embodiments, the analog is derived from the naturally organic nontoxic bases include salts of primary, secondary, occurring polypeptide of the secretin family and has at least and tertiary amines, quaternary amine compounds, Substi one B-amino acid residue and/or at least one modified amino tuted amines including naturally occurring Substituted acid residue comprising APC or ACPC. Table 1 below illus amines, cyclic amines and basic ion-exchange resins, such as trates the known wild-type sequences of each naturally occur methylamine, dimethylamine, trimethylamine, ethylamine, ring human secretin family members: diethylamine, triethylamine, isopropylamine, tripropy lamine, tributylamine, ethanolamine, diethanolamine, 2-dim TABLE 1. ethylaminoethanol, 2-diethylaminoethanol, dicyclohexy Amino Acid Sequences for Peptides of the lamine, lysine, arginine, histidine, caffeine, hydrabamine, Secretin Family choline, betaine, ethylenediamine, glucosamine, methylglu camine, theobromine, purines, piperazine, piperidine, N-eth GHRF YADAIFTNSYRKVLGOLSARKLLODIMSRQOGESNOERG ylpiperidine, tetramethylammonium compounds, tetraethy lammonium compounds, pyridine, N,N-dimethylaniline, ARARL N-methylpiperidine, N-methylmorpholine, dicyclohexy GIP YAEGTFISDYSIAMDKIHOODFVNWLLAOKGKKNDWKHNITO lamine, dibenzylamine, N,N-dibenzylphenethylamine, 1-ephenamine, N,N'-dibenzylethylenediamine, polyamine GLP-1 HDEFERHAEGTFTSDWSSYLEGOAAOGFIAWLVKGRG resins, and the like. In some embodiments, the composition of Glucagon HSQGTFTSDYSKYLDSRRAQDFVQWLMNT the claimed invention comprises at least one organic nontoxic bases chosen from isopropylamine, diethylamine, ethanola PACAP-27 HSDGIFTDSYSRYRKOMAVKKYLAAVL mine, trimethylamine, dicyclohexylamine, choline, and caf PACAP-38 HSDGIFTDSYSRYRKOMAVKKYLAAVLGKRYKORVKNK feine. 0291. The term “solvate” means a physical association of PHM HADGVFTSDFSKLLGOLSAKKYLESLM a compound with one or more solvent molecules or a complex PP DVAHGILNEAYRKVLGOLSAGKHLOSLVA of variable stoichiometry formed by a solute (the analog of the claimed invention) and a solvent, for example, water, Secretin HSDGTFTSELSRLREGARLQRLLQGLV ethanol, or acetic acid. This physical association may involve WIP HSDAVFTDNYTRLRKOMAWKKYLNSILN varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances, the Solvate will be

US 2013/0096050 A1 Apr. 18, 2013

TABLE 3 - continued Amino Acid Sequences for Anti-inflammatory Neuropeptides appetite-regulating hormone isoform 5 preproprotein Homo sapiens >gi2O186O285 refNP OO1128418. 1|appetite-regulating hormone isoform 5 preproprotein {Homo sapiens MFTCWWSYLRSTLAAVPGEASRVOFNAPFDVGIKLSGVOYOOHSOALGKFLODILW EEAKEAPADK ghrelin Homo sapiens} >gi53794O41|gb|AAU93 610.11ghrelin Homo sapiens} MPSPGTWCSLLLLGMLWLDLAMAGSSFLSPEHORVO Active form: Ghrelin GSSFLSPEHORWOORKESKKPPAKLPQR-NH2 (Expert Opin. Biol. Ther. (2007) 7 (4) : 461 - 478

0293. In some embodiments, the composition comprises a analog is from about 95% to about 99% homologous to the VIP analog. In some embodiments, the composition com human sequence of apolipoprotein A-1. In some embodi prises a Secretin analog. In some embodiments, the compo ments the apoA-1 analog is about 95%, 96%, 97%, 98%, or sition comprises a PrP analog. In some embodiments, the 99% homologous to the human sequence of apolipoprotein composition comprises a PrPanalog. In some embodiments, A-1. In some embodiments the apoA-1 analog is from about the composition comprises a PHM analog. In some embodi 80% to about 85% homologous to the following of apolipo ments, the composition comprises a PACAP-27 analog. In protein A-1 analog: DWFKAFYDKVAEKFKEAF. some embodiments, the composition comprises a PACAP-38 0295. In some embodiments, the composition comprises a cytokine or interleukin analog. In some embodiments the analog. In some embodiments, the composition comprises a cytokine or interleukin analog is from about 80% to about Glucagon analog. In some embodiments, the composition 99% homologous to the human sequence of cytokine or inter comprises a GLP-1 analog. In some embodiments, the com leukin. In some embodiments the cytokine or interleukin position comprises a GIP analog. In some embodiments, the analog is from about 80% to about 85% homologous to the composition comprises a GHRF analog. In some embodi human sequence of a cytokine or interleukin. In some ments, the composition comprises a secretin family analog embodiments the cytokine or interleukin analog is from about that is derived from mammalian amino acid sequences of 85% to about 90% homologous to the human sequence of a secretin family polypeptides other than humans. In some cytokine or interleukin. In some embodiments the cytokine or embodiments, the secretin family analog may be selective for interleukin analog is from about 90% to about 95% homolo one particular receptor versus another. In some embodiments, gous to the human sequence of a cytokine or interleukin. In the composition comprises a secretin analog wherein the Some embodiments the cytokine or interleukin analog is from secretin analog is selective for, or preferentially binds to, about 95% to about 99% homologous to the human sequence VPAC1, VPAC2, PAC1, VIPR1, or VIPR2. In some embodi of a cytokine or interleukin. In some embodiments the cytok ments, the composition comprises a secretin analog wherein ine or interleukin analog is about 95%, 96%, 97%, 98%, or the secretin analog is selective for, or preferentially binds, 99% homologous to the human sequence of a cytokine or VPAC1. In some embodiments, the composition comprises a interleukin. In some embodiments the cytokine or interleukin secretin analog wherein the secretin analog is selective for, or analog is from about 80% to about 99% homologous to a preferentially binds, VPAC2. In some embodiments, the com cytokine or interleukin chosen from IL-2, IL-4, IL-5, IL-6, position comprises a secretin analog wherein the secretin IL-7, IL-10, IL-12, IL-15, IL-17, IL-18, IL-21, IL-22, IL-23, IL-24, IL-26, IFN-Y, TNF-C., and TNF-B. In some embodi analog is selective for, or preferentially binds, PAC1. In some ments, the cytokine or interleukin analog comprises at least embodiments, the composition comprises a secretin analog one non-natural amino acid within the structure that corre wherein the secretin analog is selective for, or preferentially sponds to helix F in the naturally occurring polypeptide binds, VIPR1. In some embodiments, the composition com sequence upon which the analog is based or derived. In some prises a secretin analog wherein the secretin analog is selec embodiments, the cytokine or interleukin analog comprises at tive for, or preferentially binds, VIPR2. In some embodi least one non-natural amino acid within the structure that ments, the secretin analog is an agonist of at least one of the corresponds to AB loop in the naturally occurring polypep following: VPAC1, VPAC2, PAC1, VIPR1, or VIPR2. In tide sequence upon which the analog is based or derived. Some embodiments, the secretin analog is an antagonist of at 0296. The invention relates to the manufacturing of a syn least one of the following:VPAC1, VPAC2, PAC1, VIPR1, or thetic polypeptide which is an amino acid sequence that cor VIPR2. responds to the sequence of a biologically active polypeptide 0294. In some embodiments, the composition comprises a or fragment thereof. In the synthetic polypeptide, from about apolipoprotein A-1 analog. In some embodiments the apoA-1 14% to about 50% of the C-amino acid residues found in the analog is from about 80% to about 99% homologous to the biologically active polypeptide or fragment are replaced with human sequence of apolipoprotein A-1. In some embodi ments the apoA-1 analog is from about 80% to about 85% B-amino acid residues. In another embodiment of the inven homologous to the human sequence of apolipoprotein A-1. In tion, the C-amino acid residues and the B-amino acid residues some embodiments the apoA-1 analog is from about 85% to are distributed in a repeating pattern. Human cells are then about 90% homologous to the human sequence of apolipo contacted with the synthetic polypeptide to induce the bio protein A-1. In some embodiments the apoA-1 analog is from chemical pathway or biological activity ordinarily induced by about 90% to about 95% homologous to the human sequence the naturally occurring polypeptide upon which the analog is of apolipoprotein A-1. In some embodiments the apoA-1 based. US 2013/0096050 A1 Apr. 18, 2013 42

0297. The compositions of the invention may be prepared the coupling reaction is performed with 2,4,6-trinitroben by the synthetic chemical procedures described herein, as Zene-sulfonic acid (TNBS) (W. S. Hancock and J. E. Bat well as other procedures similar to those which may be used tersby, Anal. Biochem. (1976), 71, 260). In the case of a for making B-amino acid peptides. Such procedures include positive TNBS test (indicating incomplete coupling), the Sus both solution and Solid phase procedures, e.g., using either pension is allowed to react for another three times. This Boc and Fmoc methodologies. The compounds of the inven process is repeated until the desired product has been tion may be synthesized using solid phase synthesis tech achieved. After the removal of the last Fmoc protecting group, niques. Fmoc-N-Protected B-amino acids can be used to Syn the resin is washed with DMF (3x), CHCl (3x) and DMF thesize poly-all-peptides by conventional manual Solid-phase again (3x). The remaining free-amine group is then acety synthesis procedures under standard conditions on any num lated using a cocktail of DIEA:AcO (1:1) for 5 minutes at ber of solid supports, including ortho-chloro-trityl chloride room temperature. Full-length peptides were then cleaved resin. Esterification of Fmoc-B-amino acids with the ortho chloro-trityl resin can be performed according to the method from solid support using TFA:TIS:HO (95:2.5:2.5) for 150 of Barbs et al., Tetrahedron Lett., 1989, 30, 3943. The resin minutes, precipitated in cold ethyl ether and lyophilized. The (150 mg, 1.05 mmol Cl) is swelled in 2 ml CHCl for 10 min. polymer was reconstituted in a 1:1 solution of A:B (A: H.O. A solution of the Fmoc-protected B-amino acid in CHCl, 0.1% TFA) (B: 90:10:0.1 acetonitrile/HO/TFA). and iPr-EtNare then added successively and the suspension is 0299 The compositions described herein may be prepared mixed under argon for 4 h. Subsequently, the resin is filtered by Successive amide bond-forming procedures in which and washed with CHC1/MeOH/iPr-EtN (17:2:1, 3x3 min), amide bonds are formed between the B-amino group of a first CHCl (3x3 min), DMF (2x3 min), CHCl (3x3 min), and B-amino acid residue or a precursor thereof and the C-car MeOH (2x3 min). The substitution of the resin is determined boxyl group of a second B-amino acid residue or CL-amino on a 3 mg sample by measuring the absorbance of the diben acid residue or a precursor thereof. The amide bond-forming Zofulvene adduct at 300 nm. The Fmoc group is removed using 20% piperidine in DMF (4 ml, 2x20 min) under Ar step may be repeated as many times, and with specific bubbling. The resin is then filtered and washed with DMF C.-amino acid residues and/or B-amino acid residues and/or (6x3 min). For each coupling step, a solution of the B-amino precursors thereof, as required to give the desired C/B- acid (3 equiv.), BOP (3 equiv.) and HOBT (3 equiv.) in DMF polypeptide. Also analogs comprising two, three, or more (2 ml) and iPr-EtN (9 eq) are added successively to the resin amino acid residues C.- or B-) may be joined together to yield and the suspension is mixed for 1 h under Ar. Monitoring of larger analogs comprising any combination of C.-, or B-amino the coupling reaction is performed with 2,4,6-trinitroben acids. Cyclic compounds may be prepared by forming pep Zene-sulfonic acid (TNBS) (W. S. Hancock and J. E. Bat tide bonds between the N-terminal and C-terminal ends of a tersby, Anal. Biochem. (1976), 71, 260). In the case of a previously synthesized linear polypeptide or through the dis positive TNBS test (indicating incomplete coupling), the Sus ulfide crosslinking of Sidechains of non-adjacent residues. pension is allowed to react for a further 1 h. The resin is then f-amino acids may be produced enantioselectively from filtered and washed with DMF (3x3 min) prior to the follow corresponding B-amino acids. For instance, by Arndt-Eisert ing Fmoc deprotection step. After the removal of the last homologation of N-protected C-amino acids. Homologation Fmoc protecting group, the resin is washed with DMF (6x3 may be followed by coupling of the reactive diazoketone min), CHCl (3x3 min), EtO (3x3 min) and dried under intermediate of the Wolff rearrangement with a B-amino acid vacuum for 3 h. Finally the peptides are cleaved from the resin residue. using 2% TFA in CHCl (2 ml, 5x15 min) under Ar. The solvent is removed and the oily residues are triturated in ether 0300. In some embodiments, the analog of the invention to give the crude C-/B-polypeptides. The compounds are fur comprises a repeating pattern of the B-amino acid residues in ther purified by HPLC. alignment on a longitudinal axis of the analog in order to 0298. The compositions of the invention may be prepared constrain the conformation of the analog in an active state or by the synthetic chemical procedures described herein, as to avoid disruption of the active site. That is, in the folded well as other procedures similar to those which may be used structure adopted by the analogs of the present invention, the for making B-amino acid peptides. Such procedures include repeating pattern of C- or B-amino acids residues disposes the both solution and Solid phase procedures, e.g., using either synthetic non-natural amino acid residues in alignment along Boc or Fmoc methodologies. The compounds of the invention one longitudinal axis of the folded molecular structure from may be synthesized using Solid phase synthesis techniques. N-terminus to C-terminus when the unnatural polypeptides Fmoc-N-Protected f-amino acids can be used to synthesize adopt a helical conformation. In some embodiments, the ana poly-C/B-peptides by conventional manual Solid-phase Syn log of the invention comprises the following alignment of thesis procedures under standard conditions on any number B-amino acids or ACPC or APC along a longitudinal axis of of solid Supports, including ortho-chloro-trityl chloride resin, the folded molecular structure from N-terminus to C-termi Wang resin (NovaBiochem 0.75 mmol substitution) and Rink nus when the polypeptide adopts a helical conformation cho amid resin (NovaBiochem 0.55 mmol substitution). Resin is sen from the following: typically swelled in 100% DMF for 30 minutes then depro tected using 20% piperidine in DMF for 2 minutes at 80° (3x). Fmoc protected amino acids (natural or non-natural) can then be coupled to the resin using a cocktail of AA:HATU:DIEA: Resin (3:2.5:4:1, LiCL 0.8M final concentration) in DMF for 2 minutes at 70° (3x). The resin is then washed (3x) with DMF, DCM (dichloromethane) (3x) and again with DMF (3x) between deprotection and coupling steps. Monitoring of US 2013/0096050 A1 Apr. 18, 2013 43

-continued istration of VIP analogs, wherein the VIP analog is an agonist or antagonist of at least one receptor chosen from: VPAC1, VPAC2, and PAC1. In some embodiments, the composition comprises an analog, wherein the analog wherein the analog comprises a repetitive pattern of sequential B-amino acids from the amino-terminus to the carboxy-terminus chosen from the following: C.C.C.C.C.C.B., C.C.C.C.C. BC, C.C.C.C. BC.C. wherein the residue positions in a solid dot represent non C.C.C. BC.C.C., C.C. BC.C.C.C. C. BC.C.C.C.C., BC.C.C.C.C.C., C.C.C.C.C.Bf3, natural amino acid residues. In some embodiments, the ana C.C.C.C.f3 BC, C.C.C. BBC.C., C.O.Bf3C.C.C., C.Bf3C.C.C.C., BBC.C.C.C.C. log of the invention comprises the following alignment along BC.C.C.C.C.B., BC.C.C.C. BC, BC.C.C. BC.C., BC.O.BC.C.C., BC.BC.C.C.C. a longitudinal axis of the folded molecular structure from CBC.C.C.C.B., C.B.C.C.C.f3C, CfBC.C.B.C.C., C.BC.BC.C.O., C.O.BC.C.C.B. N-terminus to C-terminus when the polypeptide adopts a C.C. foCBC, C.C. BC. BC.C., C.C.C. BC.C.B., C.C.O.?o?ol, and C.C.C.C.- helical conformation chosen from the following: BC. B. In some embodiments, the composition comprises an analog, wherein the analog comprises a repetitive pattern of sequential B-amino acids from the amino-terminus to the carboxy-terminus chosen from the following: BC.C. BC.C.C.- BC.C. BC.C.C. BC.C.C., BC.C.C.C.C. BC.C.B.C.C.C. BBC.C., BC.C. BC.C.C.- BC.C. BC.C.C.B.Bf3C, and BC.C. BC.C.C.B.C.C. BC.C.C. BBf33. In some embodiments, the composition comprises an analog, wherein the analog comprises a repetitive pattern of sequential B-amino acids from the amino-terminus to the carboxy-ter . minus chosen from the following: wherein the positions with solid dots represent f8-amino acid BBC.C.C.C.C.C.C.C.C.C.C.; BCBBC.C.C.C.C.C.C.C.C.C.; residues. In some embodiments, the analog of the invention comprises the following alignment along a longitudinal axis BC.C.C.C.C.C.C.C.C.C.C.; B.C.C.C.C.C.C.C.C.C.C.C.; of the folded molecular structure from N-terminus to C-ter BC.C.C.C.BBC.C.C.C.C.C.C.; B.C.C.C.C.C.C.C.C.C.C.C.; minus when the polypeptide adopts a helical conformation chosen from the following: BC.C.B.C.C.CBCBBC.C.C.B.C.C.B.; B.C.C.B.C.C.C.B.C.C.BBC.C.B.C.C.B.; BC.C.C.C.C.C.C.C.C.C.C.; B.C.C.C.C.C.C.C.C.C.C.C.; BC.C.C.C.C.C.C.C.C.C.BBC; and BC.C.C.C.C.C.C.C.C.C.C. In some embodiments, the composition comprises an analog, wherein the analog comprises a repetitive pattern of sequen tial B-amino acids from the amino-terminus to the carboxy . terminus chosen from the following: wherein the positions with Solid dots represent 3-amino acid BBC.C.C.C.C.C.C.C.C.C.C.C.; B.C.C.C.C.C.C.C.C.C.C.C.C.; residues. The repeating pattern off-amino acid residues and C-amino BC.C.C.C.C.C.C.C.C.C.C.C.; B.C.C.C.BBC.C.C.C.C.C.C.C.C.; acid residues may be a pattern of from about two to about BC.C.C.C.BBC.C.C.C.C.C.C.C.; B.C.C.C.C.C.C.C.C.C.C.C.C.; seven residues in length, Such as (BC.C.C.C.C.C.), (BC.C.C. BC.C.), (C.C.C.C.C.O.f3), (C.C.C.C.f3), (C.C.O.B), (C.O.B), (C.O.BC.C.O.B), (C.C.- BC.C.C.C.C.C.C.C.C.C.C.C.; B.C.C.C.C.C.C.C.C.C.C.C.C.; BC. BC.f3), and (CB). All unique patterns of C- or 3-amino acids residues from about two to about fourteen residues in length BC.C.C.C.C.C.C.C.C.C.C.C.; B.C.C.C.C.C.C.C.C.C.C.C.C.; are explicitly within the scope of the invention. All unique BC.C.C.C.C.C.C.C.C.C.BBC.C.; BC.C.C.C.C.C.C.C.C.C.C.C.; patterns of C- or B-amino acids residues from about two to and about seven residues in length are explicitly within the scope of the invention. In some embodiments, the composition BC.C.C.C.C.C.C.C.C.C.C.C.B. comprises an analog, wherein the analog wherein the analog 0301 In some embodiments, the composition comprises comprises a repetitive pattern of sequential B-amino acids an analog, wherein the analog comprises a repetitive pattern from the amino-terminus to the carboxy-terminus, and of sequential B-amino acids from the amino-terminus to the wherein the analog is an agonist orantagonist of the receptor carboxy-terminus chosen from the following: BC.C. BC.C.C.- to which it selectively binds or associates. For instance, in BC.C. BC.C.C. BC.C.C., BC.C.C.C.C. BC.C.B.C.C.C. BBC.C., BC.C. BC.C.C.- Some embodiments, the analog is a VIP analog or a functional BC.C. BC.C.C.B.Bf3C, and BCC foCO.BC.O.BC.C.C.BBBB, wherein fragment thereofthat selectivity binds to VPAC1, VPAC2, or any C.-amino acid residue may be a non-natural amino acid. In PAC1 and wherein the VIP analog of functional fragment Some embodiments, the composition comprises an analog, thereof is an agonist or antagonist of at least one receptor wherein the analog comprises a repetitive pattern of sequen chosen from: VPAC1, VPAC2, and PAC1. In some embodi tial B-amino acids from the amino-terminus to the carboxy ments, the methods of treatment or prevention include admin terminus chosen from the following: BC.C. BC.C.C. BC.O.f3C.C.C.- US 2013/0096050 A1 Apr. 18, 2013 44

BC.C.C., BC.C. BC.C.C. BC.C. BC.C.O.f3 BC.C. amino-terminus: BC.C. BC.C.C. BC.C. BC.C.O.?3ffo, and BC.C. BC.C.C. BC.C. BC.C.C.Bf3 Bf3, fiCC232CsC-4Cs faCo.C.734CsCoClio?issC-11C1236, wherein wherein at least one C.-amino acid residue may be a non Bany beta-2 amino acid; C. any alpha amino acid; Cany natural amino acid. In some embodiments, the composition alpha amino acid; f any beta-2 amino acid; C. any alpha comprises an analog, wherein the analog comprises a repeti amino acid; C. any alpha amino acid; Cls any alpha amino tive pattern of sequential B-amino acids from the amino acid; f any beta-2 amino acid; C. any alpha amino acid; terminus to the carboxy-terminus chosen from the following: C., any alpha amino acid; B any beta-2 amino acid; Cls any BC.C. BC.C.C. BC.C. BC.C.O.f3C.C.C., BC.C.BC.C.C. BC.O.BC.C.C. BBC.C. alpha amino acid; Co any alpha amino acid; Co any alpha BC.C. BC.C.C. BC.C. BC.C.O.?3ffo, and BC.C. BC.C.C. BC.C. BC.C.C.Bf3 Bf3, amino acid; fs any beta-2 amino acid; C. any alpha amino wherein from about 1 to about 10 O-amino acid residues may acid; C. any alpha amino acid; B any beta-2 amino acid. be a non-natural amino acid. In any of the above-mentioned 0306 In some embodiments, the composition comprises a patterns one or more of the B-amino acid residues may be VIP analog, wherein the analog comprises the following replaced or modified with cyclic B-amino acid (cyclically repetitive pattern of sequential -amino acids from the constrained beta amino acid), such as APC or ACPC. amino-terminus: 0302) In some embodiments, the composition comprises a fiCC232CsC-4Cs faCo.C.734CsCoClio?issC-11C1236, wherein VIP analog, wherein the analog comprises the following fany cyclic or heterocyclic beta-amino acid; C. any alpha repetitive pattern of sequential -amino acids from the amino acid; Cany alpha amino acid; Bany cyclic or het amino-terminus to the carboxy-terminus: BC.C. BC.C.C.BC.C.- erocyclic beta-amino acid; C. any alpha amino acid; C. any BC.C.C. BC.C. B. In some embodiments, the composition com alpha amino acid; Cls any alpha amino acid; B cyclic or prises a VIP analog, wherein the analog comprises the fol heterocyclic beta-amino acid; Cany alpha amino acid; lowing repetitive pattern of sequential B-amino acids from the C., any alpha amino acid; f. cyclic or heterocyclic beta amino-terminus: amino acid; Cls any alpha amino acid; Co any alpha amino f C. C.2?2C-C-4Cs?BC.C.7?54CsCloCo?sC, C1236, wherein acid; Clo any alpha amino acid; Bs cyclic or heterocyclic Bany beta amino acid; C. any alpha amino acid; Cany beta-amino acid; C. any alpha amino acid; C. any alpha alpha amino acid; B any beta amino acid; Cany alpha amino acid; B cyclic or heterocyclic beta-amino acid amino acid; C. any alpha amino acid; Cls any alpha amino 0307. In some embodiments, the composition comprises a acid; B any beta amino acid; Cany alpha amino acid; VIP analog, wherein the analog comprises the following C., any alpha amino acid; f any beta amino acid; Cls any repetitive pattern of sequential -amino acids from the alpha amino acid; Co any alpha amino acid; Clo any alpha amino-terminus: amino acid; fs any beta amino acid; C. any alpha amino fiCO2Cl2O3C-4Cs faCoC-734CsCloCo?sC-11C1236, wherein acid; C. any alpha amino acid; B any beta amino acid. fany beta-3 amino acid; C. any alpha amino acid; Cany 0303. In some embodiments, the composition comprises a alpha amino acid; B any beta-3 amino acid: C. any alpha VIP analog, wherein the analog comprises the following amino acid; C. any alpha amino acid; Cls any alpha amino repetitive pattern of sequential B-amino acids, from the acid; B any beta-3 amino acid; C. any alpha amino acid; amino-terminus: C., any alpha amino acid; B any beta-3 amino acid; Cls any f1CC-232CsC-4Cs?issCo.C.734CsClo Co?sC-11C1236, wherein alpha amino acid; Co any alpha amino acid; Co any alpha Bany beta-3, beta-2, cyclic or heterocyclic beta-amino acid; amino acid; Bs a beta-3 alanine; Cany alpha amino acid; C. any alpha amino acid; Cany alpha amino acid; f any C. any alpha amino acid; f any beta-3 amino acid. beta-3, beta-2, cyclic or heterocyclic beta-amino acid; 0308. In some embodiments, the composition comprises a C any alpha amino acid; C. any alpha amino acid; Cls any VIP analog, wherein the analog comprises the following alpha amino acid; B any beta-3, beta-2, cyclic or heterocy repetitive pattern of sequential -amino acids from the clic beta-amino acid; Cany alpha amino acid; C., any alpha amino-terminus: amino acid; f any beta-3, beta-2, cyclic or heterocyclic fiCC232CsC-4Cs? CC-734CsCo.ClofssC, C1236, wherein beta-amino acid; Cls any alpha amino acid; Co any alpha Bany beta-3 amino acid; C. any alpha amino acid; Cany amino acid; Clo any alpha amino acid; Bs any beta-3, beta alpha amino acid; B any beta-3 amino acid; C. any alpha 2, cyclic or heterocyclic beta-amino acid; Cany alpha amino acid; C. any alpha amino acid; Cls an alpha leucine; amino acid; Cany alpha amino acid; 3 any beta-3, beta B any beta-3 amino acid; Cany alpha amino acid; C., any 2, cyclic or heterocyclic beta-amino acid. alpha amino acid; f any beta-3 amino acid; Cls any alpha 0304. In some embodiments, the composition comprises a amino acid; Co any alpha amino acid; Co any alpha amino VIP analog, wherein the analog comprises the following acid; fsa beta-3 alanine; C. any alpha amino acid; repetitive pattern of sequential -amino acids from the Cany alpha amino acid; B any beta-3 amino acid. amino-terminus: 0309. In some embodiments, the composition comprises a f C. C.2?2C-C-4Cs?BC.C.7?54CsCloCo?sC, C1236, wherein VIP analog, wherein the analog comprises the following Bany beta-3 amino acid; Cany alpha amino acid; Cany repetitive pattern of sequential -amino acids from the alpha amino acid; f any beta-3 amino acid; C. any alpha amino-terminus: amino acid; C. any alpha amino acid; Cls any alpha amino fiCC232CsC-4Cs faCo.C.734CsCoClio?issC-11C1236, wherein acid; f any beta-3 amino acid, Cany alpha amino acid; Bany beta-3 amino acid; C. any alpha amino acid; Cany C., any alpha amino acid; B any beta-3 amino acid; Cls any alpha amino acid; f any beta-3 amino acid; C. any alpha alpha amino acid; Co any alpha amino acid; Co any alpha amino acid; C. any alpha amino acid; Cls an alpha leucine; amino acid; fs any beta-3 amino acid; C. any alpha amino f any beta-3 amino acid; C. any alpha amino acid; C., any acid; C. any alpha amino acid; B any beta-3 amino acid. alpha amino acid; B any beta-3 amino acid; Cls any alpha 0305. In some embodiments, the composition comprises a amino acid; Co any alpha amino acid; Co any alpha amino VIP analog, wherein the analog comprises the following acid; Bs a beta-3 amino acid; C. any alpha amino acid; repetitive pattern of sequential -amino acids from the Cany alpha amino acid; B any beta-3 amino acid. US 2013/0096050 A1 Apr. 18, 2013

0310. In some embodiments, the composition comprises a 0315. In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following VIP analog, wherein the analog comprises the following repetitive pattern of sequential -amino acids from the repetitive pattern of sequential -amino acids from the amino-terminus: amino-terminus: f1CC-232CsC-4Cs?issCo.C.734CsClo Co?sC-11C1236, wherein B, C, Clf.C.C.C.s (BCC-B4CsCl Clo?sC'Cliefs, wherein f a beta 3-threonine, C. any alpha amino acid; Cany C. abeta-3 threonine or ACPC; C. an alpha arginine: C an alpha amino acid; Babeta-3 arginine; Cany alpha amino alpha leucine; B, a beta-3 arginine or APC: C. an alpha acid; C. any alpha amino acid; Cls any alpha amino acid; lysine; C. an alpha glutamine; Cls an alpha-leucine; B, a f a beta-3 alanine; C any alpha amino acid; C., any alpha beta-3 alanine or ACPC; Clan alpha valine: C, an alpha amino acid; B, a beta-3 lysine; Cls any alpha amino acid; lysine; B, a beta-3 lysine or APC; Cls an alpha tyrosine; Co any alpha amino acid; Clo any alpha amino acid; fs a Co an alpha leucine; Clo an alpha asparagine; fs a beta-3 beta-3 alanine; Cany alpha amino acid; C. any alpha alanine or ACPC; Clan alpha isoleucine; C. an alpha amino acid; f, a beta-3 asparagine. leucine; f, a beta-3 asparagine. 0311. In some embodiments, the composition comprises a 0316. In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following VIP analog, wherein the analog comprises the following repetitive pattern of sequential -amino acids from the repetitive pattern of sequential -amino acids from the amino-terminus: amino-terminus: f1CC-232CsC-4Cs?issCo.C.734CsClo Co?sC-11C1236, wherein fiCC2Cl3?2C-4Cs faCoC-7Cs? 4CsClio?issCiCl2Cl3, wherein Ba beta 3-threonine; Cany alpha amino acid; Cany Bany beta amino acid; Cany alpha amino acid; Cany alpha amino acid; Babeta-3 arginine; Cany alpha amino alpha amino acid; C. any alpha amino acid; B any beta acid; C. any alpha amino acid; Cls an alpha leucine; B, a amino acid; C. any alpha amino acid; Cls any alpha amino beta-3 alanine; Cany alpha amino acid; C., any alpha acid; B any beta amino acid; Cany alpha amino acid; amino acid; B, a beta-3 lysine; Cls any alpha amino acid; C., any alpha amino acid; Cls any alpha amino acid; f any Co any alpha amino acid; Clo any alpha amino acid; fs a beta amino acid; Co any alpha amino acid; Co any alpha beta-3 alanine; Cany alpha amino acid; C. any alpha amino acid; 3s any beta amino acid; C. any alpha amino amino acid; Be a beta-3 asparagine. acid; Cany alpha amino acid; Cany alpha amino acid. 0317. In some embodiments, the composition comprises a 0312. In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following VIP analog, wherein the analog comprises the following repetitive pattern of sequential B-amino acids from the repetitive pattern of sequential B-amino acids from the amino-terminus: amino-terminus: C.C.C.s 62C-4Cs? CC-7Cs?B4C. ClofssCaCl2Cl3, wherein f1CC-232CsC-4Cs?issCo.C.734CsClo Co?sC-11C1236, wherein Bany beta-3, beta-2, cyclic or heterocyclic beta-amino acid; Bany beta amino acid; C.-an alpha arginine; Clan alpha C. any alpha amino acid; Cany alpha amino acid; C. any leucine; f any beta amino acid; C. an alpha lysine; C an alpha amino acid; Bany beta-3, beta-2, cyclic or heterocy alpha glutamine; Cls an alpha-leucine; B any beta amino clic beta-amino acid; C. any alpha amino acid; Cls any alpha acid; C. an alpha valine; C., an alpha lysine; f any beta amino acid; B any beta-3, beta-2, cyclic or heterocyclic amino acid; Cls an alpha tyrosine; Co an alpha leucine; beta-amino acid; Cany alpha amino acid; C., any alpha Co an alpha asparagine; Bs a beta-3 alanine; Clan alpha amino acid; Cls any alpha amino acid; f any beta-3, beta-2, isoleucine; Clan alpha leucine; B any beta amino acid. cyclic or heterocyclic beta-amino acid; Co any alpha amino 0313. In some embodiments, the composition comprises a acid; Clo any alpha amino acid; fs any beta-3, beta-2, cyclic VIP analog, wherein the analog comprises the following or heterocyclic beta-amino acid; C. any alpha amino acid; repetitive pattern of sequential -amino acids from the Cl2=any alpha amino acid; C.1s any alpha amino acid. amino-terminus: 0318. In some embodiments, the composition comprises a f1CC-232CsC-4Cs?issCo.C.734CsClo Co?sC-11C1236, wherein VIP analog, wherein the analog comprises the following fany beta-3 amino acid; C. an alpha arginine; Canalpha repetitive pattern of sequential -amino acids from the leucine; B any beta-3 amino acid; C. an alpha lysine; amino-terminus: C. an alpha glutamine; Cls an alpha leucine; f any beta-3 fiCC2Cl3?2C-4Cs faCoC-7Cs? 4CsClio?issCiCl2Cl3, wherein amino acid; C. an alpha valine; C, an alpha lysine; B any fany beta-3 amino acid; C.-any alpha amino acid; Cany beta-3 amino acid; Cls an alpha tyrosine; Co an alpha leu alpha amino acid; C. any alpha amino acid; B any beta-3 cine; Co an alpha asparagine; Bs any beta-3 amino acid; amino acid; C. any alpha amino acid; Cls any alpha amino C. an alpha isoleucine; C. an alpha leucine; B any beta acid; B any beta-3 amino acid; C. any alpha amino acid; amino acid. C., any alpha amino acid; Cls any alpha amino acid; B any 0314. In some embodiments, the composition comprises a beta-3 amino acid; Co any alpha amino acid; Clo any alpha VIP analog, wherein the analog comprises the following amino acid; Bs any beta-3 amino acid; Cany alpha amino repetitive pattern of sequential -amino acids from the acid; Cany alpha amino acid; Cany alpha amino acid. amino-terminus: 0319. In some embodiments, the composition comprises a f1CC-232CsC-4Cs?issCo.C.734CsClo Co?sC-11C1236, wherein VIP analog, wherein the analog comprises the following f a beta-2 threonine: C, an alpha arginine: C, an alpha repetitive pattern of sequential -amino acids from the leucine; B, a beta-2 arginine; Cls an alpha lysine; C an amino-terminus: alpha glutamine; Cls an alpha leucine; f, a beta-2 alanine: C.C.C.s 62C-4Cs? CC-7Cs?B4C. ClofssCiCl2Cl3, wherein C. an alpha Valine; C, an alpha lysine; B, a beta-2 lysine; Bany beta-2 amino acid; C. any alpha amino acid; Cany Cls an alpha tyrosine; Co an alpha leucine; Co an alpha alpha amino acid; C. any alpha amino acid; B any beta-2 asparagine; Bs a beta-2 alanine; Clan alpha isoleucine; amino acid; C. any alpha amino acid; Cls any alpha amino C. an alpha leucine; Be a beta-2 asparagine. acid; B any beta-2 amino acid; C. any alpha amino acid; US 2013/0096050 A1 Apr. 18, 2013 46

C., any alpha amino acid; Cls any alpha amino acid; B any leucine; Cls an alpha arginine; B any beta-2 amino acid; beta-2 amino acid; Co any alpha amino acid; Co any alpha C. an alpha glutamine; Cls an alpha leucine; B any beta-2 amino acid; Bs any beta-2 amino acid; Cany alpha amino amino acid; C. an alpha Valine acid; C., an alpha lysine; acid; Cany alpha amino acid; Cany alpha amino acid. Cls an alpha lysine; f any beta-2 amino acid; Co an alpha 0320 In some embodiments, the composition comprises a leucine; Co an alpha asparagine; Bs any beta-2 amino acid; VIP analog, wherein the analog comprises the following C-an alpha isoleucine, Can alpha leucine; Clan alpha repetitive pattern of sequential -amino acids from the asparagine. amino-terminus: 0325 In some embodiments, the composition comprises a fiCC2Cs2C-4Cs?BC-C-7Cs?B4C.oOo?sC, C12Otis, wherein VIP analog, wherein the analog comprises the following Bany cyclic or heterocyclic beta-amino acid; C. any alpha repetitive pattern of sequential -amino acids from the amino acid; Cany alpha amino acid; C. any alpha amino amino-terminus: acid; 3 any cyclic or heterocyclic beta-amino acid; C. any fiCC2Cl3?2C-4Cs faCoC-7Cs?issCoClio?issC-11C12O is: wherein alpha amino acid; Cls any alpha amino acid; B any cyclic or Bany cyclic and heterocyclic beta amino acid; C. an alpha heterocyclic beta-amino acid; C any alpha amino acid; arginine; Clan alpha leucine; Clan alpha arginine; fany C., any alpha amino acid; Cls any alpha amino acid; B any cyclic and heterocyclic beta amino acid; C. an alpha cyclic or heterocyclic beta-amino acid; Co any alpha amino glutamine; Cls an alpha leucine; f any cyclic and heterocy acid; Co any alpha amino acid; Bs any cyclic or heterocy clic beta amino acid; C. an alpha Valine acid; C., an alpha clic beta-amino acid; Cany alpha amino acid; C. any lysine; Cls an alpha lysine; B any cyclic and heterocyclic alpha amino acid; C. any alpha amino acid. beta amino acid; Co an alpha leucine; Co an alpha aspar 0321. In some embodiments, the composition comprises a agine; B5 any cyclic and heterocyclic beta amino acid; VIP analog, wherein the analog comprises the following C. an alpha isoleucine; C. an alpha leucine: C, an alpha repetitive pattern of sequential -amino acids from the asparagine. amino-terminus: 0326 In some embodiments, the composition comprises a fiCC2Cs?-C-4Cs?issCC-7Cs? 4CsCl lo?s C-11C12O13, wherein VIP analog, wherein the analog comprises the following Ba beta-3 threonine; Cany alpha amino acid; Cany repetitive pattern of sequential -amino acids from the alpha amino acid; C. any alpha amino acid; f. a beta-3 amino-terminus: lysine; Cany alpha amino acid; Cls any alpha amino acid; C.C. iCl2Cl3?2C-4Cs faCoC-7Cs? 4CsCl lo?s C-11C12O13, wherein f a beta-3 alanine; C any alpha amino acid; C., any alpha B=a beta-3 threonine or an ACPC; C.—an alpha arginine: amino acid; Cls any alpha amino acid; Baa beta-3 tyrosine; Can alpha leucine; Clan alpha arginine; f, a beta-3 Co any alpha amino acid; Co any alpha amino acid; Bs a lysine or APC: C. an alpha glutamine, C.s an alpha leucine; beta-3 alanine; Cany alpha amino acid; C. any alpha fabeta-3 alanine or ACPC; Clan alpha valine acid; C., an amino acid; C. any alpha amino acid. alpha lysine; Cls an alpha lysine; B, a beta-3 tyrosine or; 0322. In some embodiments, the composition comprises a Co an alpha leucine; Clo an alpha asparagine; fs a beta-3 VIP analog, wherein the analog comprises the following alanine or ACPC; Clan alpha isoleucine; C. an alpha repetitive pattern of sequential -amino acids from the leucine; Cls an alpha asparagine. amino-terminus: 0327. In some embodiments, the composition comprises a fiCl2Os32C-4Cs faCoC-7Cs?B4C.oOo?sCiCl2O3: wherein VIP analog, wherein the analog comprises the following fany beta amino acid; C. an alpha arginine: C, an alpha repetitive pattern of sequential -amino acids from the leucine; Cls an alpha arginine; B any beta amino acid; amino-terminus: C. an alpha glutamine; Cls an alpha leucine; f any beta fiCC2Cl3?2C-4Cs faCoC-7Cs? 4CsClio?issC-11C12O is: wherein amino acid; C. an alpha valine acid; C., an alpha lysine; fany beta amino acid; C. any alpha amino acid; Cany Cls an alpha lysine; B any beta amino acid; Co an alpha alpha amino acid; C. an alpha amino acid; B any beta leucine; Clo an alpha asparagine; fs any beta amino acid; amino acid; C. an alpha alpha amino acid; Cls any alpha Canalpha isoleucine; C. an alpha leucine; C. an alpha amino acid; B any beta amino acid; C. any alpha amino asparagine. acid; C., any alpha amino acid; Cls any alpha amino acid, 0323. In some embodiments, the composition comprises a B any beta amino acid; Co any alpha amino acid; Co any VIP analog, wherein the analog comprises the following alpha amino acid; B5 any beta amino acid; Cany alpha repetitive pattern of sequential -amino acids from the amino acid; Cany alpha amino acid; C. any alpha amino amino-terminus: acid; and B any beta amino acid. fiCC2Cs2C-4Cs?BC-C-7Cs?B4C.oOo?sC, C12O is: wherein 0328. In some embodiments, the composition comprises a Bany beta-3 amino acid; Canalpha arginine; Canalpha VIP analog, wherein the analog comprises the following leucine; Cls an alpha arginine; B any beta-3 amino acid; repetitive pattern of sequential -amino acids from the C. an alpha glutamine; Cls an alpha leucine; f any beta-3 amino-terminus: amino acid; C. an alpha valine acid; C., an alpha lysine; fiCC2Cl3?2C-4Cs faCoC-7Cs? 4CsClio?issCiCl2Cla?s: Cls an alpha lysine; f any beta-3 amino acid; Co an alpha wherein B=any beta-3, beta-2, cyclic or heterocyclic beta leucine; Co an alpha asparagine; Bs any beta-3 amino acid; amino acid; Cany alpha amino acid; Cany alpha amino C. an alpha isoleucine; C. an alpha leucine; C, an alpha acid; C. an alpha amino acid; B any beta-3, beta-2, cyclic asparagine. or heterocyclic beta-amino acid; C. an alpha alpha amino 0324. In some embodiments, the composition comprises a acid; Cls any alpha amino acid; B any beta-3, beta-2, cyclic VIP analog, wherein the analog comprises the following or heterocyclic beta-amino acid; C. any alpha amino acid; repetitive pattern of sequential -amino acids from the C., any alpha amino acid; Cls any alpha amino acid; B any amino-terminus: beta-3, beta-2, cyclic or heterocyclic beta-amino acid; fiCC2Cs?-C-4Cs?issCC-7Cs? 4CsCl lo?s C-11C12O is: wherein Co any alpha amino acid; Co any alpha amino acid; Bs any Bany beta-2amino acid; Canalpha arginine; Canalpha beta-3, beta-2, cyclic or heterocyclic beta-amino acid; US 2013/0096050 A1 Apr. 18, 2013 47

Cany alpha amino acid; Cany alpha amino acid; amino-terminus: C. any alpha amino acid; and B any beta-3, beta-2, cyclic fiCC2Cl3?2C-4Cs faCoC-7Cs? 4CloCoO1C12O3C-6, wherein or heterocyclic beta-amino acid. Babeta-3 tyrosine; Cany alpha amino acid; Cany alpha 0329. In some embodiments, the composition comprises a amino acid; C. an alpha amino acid; ?a beta-3 arginine: VIP analog, wherein the analog comprises the following C. an alpha alpha amino acid; Cls any alpha amino acid; repetitive pattern of sequential -amino acids from the f a beta-3 leucine; any alpha amino acid; C., any alpha amino-terminus: amino acid; Cls any alpha amino acid; B, a beta-3 lysine; fiCC2Cs?-C-4Cs?issCC-7Cs? 4CsCl lo?s C-11C12O is ?o: Co any alpha amino acid; Co any alpha amino acid; Bs a wherein C. any beta-3 amino acid; C. any alpha amino acid; beta-3 asparagine; C. any alpha amino acid; C. any alpha Cany alpha amino acid; C. an alpha amino acid; B any amino acid; C. any alpha amino acid; and Be a beta-3 beta-3 amino acid; C. an alpha alpha amino acid; Cls any asparagine. alpha amino acid; B any beta-3 amino acid; Cany alpha 0334. In some embodiments, the composition comprises a amino acid; C., any alpha amino acid; Cls any alpha amino VIP analog, wherein the analog comprises the following acid; f any beta-3 amino acid; Co any alpha amino acid; repetitive pattern of sequential -amino acids from the Co any alpha amino acid; B5 any beta-3 amino acid; amino-terminus: Cany alpha amino acid; Cany alpha amino acid: fiCC2Cl3?2C-4Cs faCoC-7Cs? 4CsClio?issCiCl2Cla?s: C. any alpha amino acid; and B any beta-3 amino acid. wherein f any beta amino acid; C. an alpha threonine: 0330. In some embodiments, the composition comprises a Can alpha arginine; Cls an alpha leucine; B any beta VIP analog, wherein the analog comprises the following amino acid; C. an alpha lysine; Bs an alpha glutamine; repetitive pattern of sequential -amino acids from the B any beta amino acid; C. an alpha alanine: C, an alpha amino-terminus: Valine; Cls an alpha lysine; B any beta amino acid; Co an fiCC2Cs?-C-4Cs?issCC-7Cs? 4CsCl lo?s C-11C12O is ?o: alpha tyrosine; Clo an alpha leucine; fs any beta amino whereinf any beta-2 amino acid; C. any alpha amino acid; acid; Clan alpha alanine: C.12 an alpha isoleucine; Clan Cany alpha amino acid; C. an alpha amino acid; B any alpha leucine; and f any beta amino acid. beta-2 amino acid; C. an alpha alpha amino acid; Cls any alpha amino acid; f any beta-2 amino acid; C any alpha 0335. In some embodiments, the composition comprises a amino acid; C., any alpha amino acid; Cls any alpha amino VIP analog, wherein the analog comprises the following acid; f any beta-2 amino acid; Co any alpha amino acid; repetitive pattern of sequential -amino acids from the Co any alpha amino acid; Bs any beta-2 amino acid; amino-terminus: Cany alpha amino acid; Cl2=any alpha amino acid: BC. Cl2Olaf2C-4Cs faCC-7Cs B4C. Clo?s C-11C-12C is Bo: C. any alpha amino acid; and B any beta-2 amino acid. wherein Bany beta-3 amino acid; C. an alpha threonine; 0331. In some embodiments, the composition comprises a Can alpha arginine; Cls an alpha leucine; B any beta-3 VIP analog, wherein the analog comprises the following amino acid; C. an alpha lysine; Cls an alpha glutamine; repetitive pattern of sequential -amino acids from the f any beta-3 amino acid; C. an alpha alanine; C., an alpha amino-terminus: Valine; Cls an alpha lysine; B any beta-3 amino acid; Co an fiCC2Cs?-C-4Cs?issCC-7Cs? 4CsCl lo?s C-11C12O is ?o: alpha tyrosine; Clo an alpha leucine; Bs any beta-3 amino wherein Bany cyclic or heterocyclic beta-amino acid; acid; Clan alpha alanine: C.12 an alpha isoleucine; Clan C. any alpha amino acid; Cany alpha amino acid; C. an alpha leucine; and B any beta-3 amino acid. alpha amino acid; B any cyclic or heterocyclic beta-amino 0336. In some embodiments, the composition comprises a acid; C. an alpha alpha amino acid; Cls any alpha amino VIP analog, wherein the analog comprises the following acid; 3 any cyclic or heterocyclic beta-amino acid; Cany repetitive pattern of sequential -amino acids from the alpha amino acid; C, any alpha amino acid; Cls any alpha amino-terminus: amino acid; f any cyclic or heterocyclic beta-amino acid; fiCC2Cl3?2C-4Cs faCoC-7Cs? 4CsClio?issCiCl2Cla?s: Co any alpha amino acid; Co any alpha amino acid; Bs any wherein Bany beta-2 amino acid; C. an alpha threonine; cyclic or heterocyclic beta-amino acid; C. any alpha amino C. an alpha arginine, C. an alpha leucine; f any beta-2 acid; C.12 any alpha amino acid; Cany alpha amino acid: amino acid; C. an alpha lysine; Cls an alpha glutamine; and B any cyclic or heterocyclic beta-amino acid. f any beta-2 amino acid; C. an alpha alanine; C., an alpha 0332. In some embodiments, the composition comprises a Valine; Cls an alpha lysine; B any beta-2 amino acid; Co an VIP analog, wherein the analog comprises the following alpha tyrosine; Clo an alpha leucine; Bs any beta-2 amino repetitive pattern of sequential -amino acids from the acid; Clan alpha alanine: C.12 an alpha isoleucine; Clan amino-terminus: alpha leucine; and B any beta-2 amino acid. fiCC2Cs?-C-4Cs?issCC-7Cs? 4CsCl lo?s C-11C12O is ?o: 0337. In some embodiments, the composition comprises a wherein f3, a beta-2 tyrosine: C. any alpha amino acid; VIP analog, wherein the analog comprises the following Cany alpha amino acid; C. an alpha amino acid; B a repetitive pattern of sequential -amino acids from the beta-2 arginine: C. an alpha alpha amino acid; Cls any alpha amino-terminus: amino acid; Babeta-2 leucine; Cany alpha amino acid; fiCC2Cl3?2C-4Cs faCoC-7Cs? 4CsClio?issCiCl2Cla?s: C., any alpha amino acid; Cls any alpha amino acid; Cls a wherein Bany cyclic or heterocyclic beta amino acid; beta-2 lysine; Co any alpha amino acid; Co any alpha C. an alpha threonine: C, an alpha arginine; C. an alpha amino acid; Bs a beta-2 asparagine; Cany alpha amino leucine; B any cyclic or heterocyclic beta amino acid; acid; Cany alpha amino acid; Cany alpha amino acid: C. an alpha lysine; Cls an alpha glutamine f any cyclic or and Clea beta-2 asparagine. heterocyclic beta amino acid; C. an alpha alanine: C, an 0333. In some embodiments, the composition comprises a alpha valine; Cls an alpha lysine; B any cyclic or heterocy VIP analog, wherein the analog comprises the following clic beta amino acid; Co an alpha tyrosine; Co an alpha repetitive pattern of sequential -amino acids from the leucine; B5 any cyclic or heterocyclic beta amino acid; US 2013/0096050 A1 Apr. 18, 2013 48

C. an alpha alanine; C.12 an alpha isoleucine; Cls an alpha repetitive pattern of sequential -amino acids from the leucine; and B any cyclic or heterocyclic beta amino acid. amino-terminus selected from the following: 0338. In some embodiments, the composition comprises a 0349 fiCC2Csf2C-4Cs?BCC-7Csf4C.C. of sGC2Cs. VIP analog, wherein the analog comprises the following wherein f3, any beta amino acid; C. any alpha amino acid; repetitive pattern of sequential -amino acids from the Cany alpha amino acid; C. any alpha amino acid; B any amino-terminus: beta amino acid; C. any alpha amino acid; Cls any alpha fiCC2Cs?-C-4Cs?issCC-7Cs? 4CsCl lo?s C-11C12O is ?o: amino acid; B any beta amino acid; C. any alpha amino wherein Bany beta amino acid; C. an alpha threonine; acid; C., any alpha amino acid; Cls any alpha amino acid; C. an alpha arginine: C. an alpha leucine; f, a beta-2 argi f any beta amino acid; Co any alpha amino acid; Co any nine or APC: C. an alpha lysine; Cls an alpha glutamine; alpha amino acid; B5 any beta amino acid; Cany alpha f any beta-2 amino acid; C. an alpha alanine: C, an alpha amino acid; Cany alpha amino acid; C. any alpha amino Valine; Cls an alpha lysine; B any beta-2 amino acid; Co an acid; alpha tyrosine; Co an alpha leucine; Bs any beta-2 amino 0350 fiC. C.2fBC af2O.C.s?a CC-734CsCloCo?sC. C.12B6, acid; Clan alpha alanine: C.12 an alpha isoleucine; Clan wherein f3, any beta amino acid; C. any alpha amino acid; alpha leucine; and B any beta-2 amino acid. Cany alpha amino acid; Bany beta amino acid; C. any 0339. In some embodiments, the composition comprises a alpha amino acid; C. any alpha amino acid; Cls any alpha VIP analog, wherein the analog comprises the following amino acid; B any beta amino acid; C. any alpha amino repetitive pattern of sequential -amino acids from the acid; C., any alpha amino acid; B any beta amino acid; amino-terminus: Cls any alpha amino acid; Co any alpha amino acid; Co-any fiCC2Cs?-C-4Cs?issCC-7Cs? 4CsCl lo?s C-11C12O is ?o: alpha amino acid; B5 any beta amino acid; Cany alpha wherein Babeta-3 tyrosine; C. an alpha threonine; Clan amino acid; C. any alpha amino acid; f any beta amino alpha arginine; Cls an alpha leucine; Babeta-3 arginine or acid; and APC: C. an alpha lysine; Cls an alpha glutamine; f, a 0351 beta-3 leucine or ACPC; Clan alpha alanine: C, an alpha f1C. Cl2Os32C-4Cs?issCoC-7Cs? 4C-9C lo?s C11C-12C isfs: Valine; Cls an alphalysine; Babeta-3 lysine or APC; Co an wherein Bany beta amino acid; Cany alpha amino acid; alpha tyrosine; Co an alpha leucine; Babeta-3 asparagine C any alpha amino acid; C. an alpha amino acid; f any or ACPC; Clan alpha alanine; C. an alpha isoleucine; beta amino acid; C. an alpha alpha amino acid; Cls any alpha C. an alpha leucine; and f a beta-3 asparagine. amino acid; f any beta amino acid; C. any alpha amino 0340. In some embodiments, the composition comprises a acid; C., any alpha amino acid; Cls any alpha amino acid; VIP analog, wherein the analog comprises the following f any beta amino acid; Co any alpha amino acid; Co any repetitive pattern of sequential -amino acids from the alpha amino acid; B5 any beta amino acid; Cany alpha amino-terminus selected from the following: amino acid; C.12 any alpha amino acid; C.1s any alpha amino 0341 fiCC23Csfs2C-4Cs? Co.C. 734CsCloCo?sC.C. 1266. acid; and f any beta amino acid; and wherein Bany beta amino acid; C. any alpha amino acid; 0352 wherein the repetitive pattern is, optionally, pre C any alpha amino acid; f any beta amino acid; C. any ceded by: alpha amino acid; C. any alpha amino acid; Cls any alpha 0353 HSDAVFTDNY if the composition comprises amino acid; B any beta amino acid; Cany alpha amino fiCC2Cl3?2C-4Cs faCoC-7Cs? 4CsClio?issC-11C12O is O acid; C., any alpha amino acid; B any beta amino acid; BC, CBC's B2C-4Cs BCC-734CsCoCo BSC-11C-1266: O Cls any alpha amino acid; Co any alpha amino acid; Co-any HSDAVFTDN if the composition comprises alpha amino acid; fs any beta amino acid; C. any alpha BCC2Cs (2C-4Cs BCC-7Cs B4C. Co?sC-11C-12C is Ba; and amino acid; Cany alpha amino acid; Be any beta amino 0354 wherein the C-terminus is optionally amidated; and acid; and 0355 wherein the N-terminus is optionally acylated; 0342 0356 or functional fragments thereof. fiC-C2Cla?s 2C-4Cs faCoC-7Cs? 4CsClofssC-11C-12C-1356: 0357. In some embodiments, the composition comprises a wherein f any beta amino acid; C. any alpha amino acid; VIP analog, wherein the analog comprises the following Cany alpha amino acid; C. an alpha amino acid; B any repetitive pattern of sequential -amino acids from the beta amino acid; C. an alpha alpha amino acid; Cls any alpha amino-terminus selected from the following: amino acid; B any beta amino acid; Cany alpha amino 0358 fiCC2Cs2C-4Cs?BC.C.7Cs? CoCo?sCiCl2O is: acid; C., any alpha amino acid; Cls any alpha amino acid; wherein Bany beta amino acid; Cany alpha amino acid; B any beta amino acid; Co any alpha amino acid; Co any Cany alpha amino acid; C. any alpha amino acid; B any alpha amino acid; B5 any beta amino acid; C. any alpha beta amino acid; C. any alpha amino acid; Cls any alpha amino acid; Cany alpha amino acid; Cany alpha amino amino acid; B any beta amino acid; C. any alpha amino acid; and B any beta amino acid; and acid; C., any alpha amino acid; Cls any alpha amino acid; 0343 wherein the repetitive pattern is, optionally, pre B any beta amino acid; Co any alpha amino acid; Co any ceded by: alpha amino acid; fs any beta amino acid; C. any alpha (0344). HSDAVFTDNY if the composition comprises amino acid; C.12 any alpha amino acid; C.1s any alpha amino BC, C-232CsC-4Cs BC-607B4C's CoCo BSC-11C1236; or acid; HSDAVFTDN if the composition comprises 0359 f C. Cl2Cl2C-4Cs faCC 7? CsCoCo BSC, C12O?36. wherein Bany beta amino acid; Cany alpha amino acid; 0345 wherein the C-terminus is optionally amidated; and C any alpha amino acid; f any beta amino acid; C. any 0346 wherein the N-terminus is optionally acylated; alpha amino acid; C. any alpha amino acid; Cls an alpha 0347 or functional fragments thereof. leucine; B any beta amino acid; Cany alpha amino acid; 0348. In some embodiments, the composition comprises a C., any alpha amino acid; B any beta amino acid; Cls any VIP analog, wherein the analog comprises the following alpha amino acid; Co any alpha amino acid; Co any alpha US 2013/0096050 A1 Apr. 18, 2013 49 amino acid; Bs a beta-3 alanine or an ACPC; Cany alpha fiCC2Cl3?2C-4Cs faCoC-7Cs? 4CsClio?issCiCl2Cla?s; or a amino acid; Cany alpha amino acid; Be any beta amino fragment thereof; and wherein at least one or more of the acid; and amino acids HSDAVFTDNY or HSDVFTDN is Substituted 0360 with a non-natural amino acid. fiC-C2Cla?s 2C-4Cs faCoC-7Cs? 4CsClofssC-11C-12C-1356: 0372. In some embodiments, the composition comprises a wherein Bany beta amino acid; C. any alpha amino acid; VIP analog, wherein the analog comprises the following Cany alpha amino acid; C. an alpha amino acid; B any repetitive pattern of sequential -amino acids from the beta amino acid; C. an alpha alpha amino acid; Cls any alpha amino-terminus selected from the following: amino acid; f any beta amino acid; C. any alpha amino 0373 f6, CC2Cs2C-4Cs?BCC-7Csf4C.C. of sGC2Cs. acid; C., any alpha amino acid; Cls any alpha amino acid; wherein f3, any beta amino acid; C. any alpha amino acid; f any beta amino acid; Co any alpha amino acid; Co any Cany alpha amino acid; C. any alpha amino acid; B any alpha amino acid; B5 any beta amino acid; C. any alpha beta amino acid; C. any alpha amino acid; Cls any alpha amino acid; C.12 any alpha amino acid; Cany alpha amino amino acid; B any beta amino acid; C. any alpha amino acid; and B any beta amino acid; and acid; C., any alpha amino acid; Cls any alpha amino acid; 0361 wherein the repetitive pattern is, optionally, pre f any beta amino acid; Co any alpha amino acid; Co any ceded by: alpha amino acid; B5 any beta amino acid; Cany alpha 0362 HSDAVFTDNY if the composition comprises amino acid; Cany alpha amino acid; C. any alpha amino fiCC2Cs?-C-4Cs?issCC-7Cs? 4CsCl lo?s C-11C12O is O acid; fiCC2Cs?-C-4Cs?issCo.C.734CsClo Co?sC-11C12O?36: O 0374 fl C. C.2fBC af2O.C.s?a CC-734CsCloCo?sC. C.12B6, HSDAVFTDN if the composition comprises wherein f3, any beta amino acid; C. any alpha amino acid; BCC2Cs (2C-4Cs BCC-7Cs B4C.9C lo?s C-11C-12C is Ba; and Cany alpha amino acid; Bany beta amino acid; C. any 0363 wherein the C-terminus is optionally amidated; and alpha amino acid; C. any alpha amino acid; Cls an alpha 0364 wherein the N-terminus is optionally acylated; leucine; B any beta amino acid; Cany alpha amino acid; 0365 or functional fragments thereof. C., any alpha amino acid; B any beta amino acid; Cls any 0366. In some embodiments, the composition comprises a alpha amino acid; Co any alpha amino acid; Clo any alpha VIP analog, wherein the analog comprises the following amino acid; Bs a beta-3 alanine or an ACPC; Cany alpha repetitive pattern of sequential -amino acids from the amino acid; C. any alpha amino acid; f any beta amino amino-terminus selected from the following: acid; and 0367 f.C.C.C.sf.C.O.sf.C.C.-7Cs?BC.oOo?sC. Cl2Cls. 0375 wherein Bany beta amino acid; C. any alpha amino acid; f1C. Cl2Os32C-4Cs?issCoC-7Cs? 4C-9C lo?s C11C-12C isfs: C any alpha amino acid; C. any alpha amino acid; f any wherein Bany beta amino acid; Cany alpha amino acid; beta amino acid; C. any alpha amino acid; Cls any alpha Cany alpha amino acid; C. an alpha amino acid; B any amino acid; B any beta amino acid; Cany alpha amino beta amino acid; C. an alpha alpha amino acid; Cls any alpha acid; C., any alpha amino acid; Cls any alpha amino acid; amino acid; B any beta amino acid; C. any alpha amino B any beta amino acid; Co any alpha amino acid; Co any acid; C., any alpha amino acid; Cls any alpha amino acid; alpha amino acid; fs any beta amino acid; C. any alpha B any beta amino acid; Co any alpha amino acid; Co any amino acid; C.12 any alpha amino acid; Cany alpha amino alpha amino acid; B5 any beta amino acid; Cany alpha acid; amino acid; C.12 any alpha amino acid; C.1s any alpha amino 0368 f CO2fBC af2C-4Cs faC.C.734CsCloCo?sC. C.12B6, wherein Bany beta amino acid; C. any alpha amino acid; acid; and B any beta amino acid; C any alpha amino acid; f any beta amino acid; C. any 0376 wherein the repetitive pattern is, optionally, pre alpha amino acid; C. any alpha amino acid; Cls an alpha ceded by: leucine; f any beta amino acid; C any alpha amino acid; 0377 HSDAVFTDNY if the composition comprises C., any alpha amino acid; B any beta amino acid; Cls any fiCC2Cl3?2C-4Cs faCoC-7Cs? 4CsClio?issC-11C12O is O alpha amino acid; Co any alpha amino acid; Co any alpha BC, CBC's B2C-4Cs BCC-734CsCoCo BSC-11C-1266: O amino acid; 3s any beta amino acid; C. any alpha amino HSDAVFTDN f the composition comprises acid; C. any alpha amino acid; B any beta amino acid; and BCC2Cs (2C-4Cs BCC-7Cs B4C. Co?sC-11C-12C is Ba: or a 0369 fragment thereof; and wherein at least one or more of the fiC-C2Cla?s 2C-4Cs faCoC-7Cs? 4CsClofssC-11C-12C-1356: amino acids HSDAVFTDNY or HSDVFTDN is Substituted wherein Bany beta amino acid; C. any alpha amino acid; with a non-natural amino acid. Cany alpha amino acid; C. an alpha amino acid; B any 0378. In some embodiments, the composition comprises a beta amino acid; C. an alpha alpha amino acid; Cls any alpha VIP analog, wherein the analog comprises the following amino acid; f any beta amino acid; C. any alpha amino repetitive pattern of sequential -amino acids from the acid; C., any alpha amino acid; Cls any alpha amino acid; amino-terminus selected from the following: f any beta amino acid; Co any alpha amino acid; Co any 0379 fiCC2Csf2C-4Cs?BCC-7Csf4C.C. of sGC2Cs. alpha amino acid; B5 any beta amino acid; C. any alpha wherein Bany beta amino acid; Cany alpha amino acid; amino acid; C.12 any alpha amino acid; Cany alpha amino Cany alpha amino acid; C. any alpha amino acid; B any acid; and B any beta amino acid; beta amino acid; C. any alpha amino acid; Cls any alpha 0370 wherein the repetitive pattern is, optionally, pre amino acid; B any beta amino acid; C. any alpha amino ceded by: acid; C., any alpha amino acid; Cls any alpha amino acid; 0371 HSDAVFTDNY if the composition comprises B any beta amino acid; Co any alpha amino acid; Co any fiCC2Cs?-C-4Cs?issCC-7Cs? 4CsCl lo?s C-11C12O is O alpha amino acid; B5 any beta amino acid; Cany alpha f1CC-2fBC-af2C-4Cs faCC-734CsCloCo?sC.C. 1266: O amino acid; C.12 any alpha amino acid; C.1s any alpha amino HSDAVFTDN if the composition comprises acid; US 2013/0096050 A1 Apr. 18, 2013 50

0380 fiC. C.2fBC af2C-4Cs faC.C.734CsCloCo?sC. C.12Bs: amino acid; C.12 any alpha amino acid; C.1s any alpha amino wherein Bany beta amino acid; C. any alpha amino acid; acid; and B any beta amino acid; Cany alpha amino acid; Bany beta amino acid; C. any 0388 wherein the repetitive pattern is, optionally, pre alpha amino acid; C. any alpha amino acid; Cls an alpha ceded by: leucine; B any beta amino acid; Cany alpha amino acid; (0389. HSDAVFTDNY if the composition comprises C., any alpha amino acid; f any beta amino acid; Cls any fiCC2Cl3?2C-4Cs faCoC-7Cs? 4CsClio?issC-11C12O is O alpha amino acid; Co any alpha amino acid; Co any alpha BC, CBC's B2C-4Cs BCC-734CsCoCo BSC-11C-1266: O amino acid; 3s any beta amino acid; C. any alpha amino HSDAVFTDN if the composition comprises acid; C. any alpha amino acid; B any beta amino acid; and BCC2Cs (2C-4Cs BCC-7Cs B4C. Co?sC-11C-12C is Bo: and 0381 wherein at least one or more of the amino acids fiC-C2Cla?s 2C-4Cs faCoC-7Cs? 4CsClofssC-11C-12C-1356: HSDAVFTDNY or HSDVFTDN is Substituted with a beta wherein f any beta amino acid; C. any alpha amino acid; amino acid selected from the group chosen from: APC, Cany alpha amino acid; C. an alpha amino acid; B any ACPC, a beta-2 homolog of a wild-type amino acid, or a beta amino acid; C. an alpha alpha amino acid; Cls any alpha beta-3 homolog of a wild-type amino acid. amino acid; B any beta amino acid; Cany alpha amino 0390. In some embodiments, the composition comprises a acid; C., any alpha amino acid; Cls any alpha amino acid; VIP analog, wherein the analog comprises the following B any beta amino acid; Co any alpha amino acid; Co any repetitive pattern of sequential -amino acids from the alpha amino acid; B5 any beta amino acid; C. any alpha amino-terminus selected from the following: amino acid; C. any alpha amino acid; C. any alpha amino 0391 fiCC2Cs2C-4Cs?BC.C.7Cs? CoCo?sCiCl2O is: acid; and B any beta amino acid; wherein Bany beta amino acid; Cany alpha amino acid; 0382 wherein the repetitive pattern is, optionally, pre C any alpha amino acid; C. any alpha amino acid; f any ceded by: beta amino acid; C. any alpha amino acid; Cls any alpha 0383 HSDAVFTDNY if the composition comprises amino acid; B any beta amino acid; C. any alpha amino fiCC2Cs?-C-4Cs?issCC-7Cs? 4CsCl lo?s C-11C12O is O acid; C., any alpha amino acid; Cls any alpha amino acid; BCC2 fos?2C-4Cs BCC-734CsCoCo BSC-11C1266: O B any beta amino acid; Co any alpha amino acid; Co any HSDAVFTDN if the composition comprises alpha amino acid; fs any beta amino acid; C. any alpha BCC2Cs (2C-4Cs BCC-7Cs B4C.9C lo?s C-11C-12C is Bo: and amino acid; C.12 any alpha amino acid; C.1s any alpha amino wherein at least one or more of the amino acids acid; HSDAVFTDNY Or HSDVFTDN is Substituted With a beta 0392 (31 CO2 fos?2C-4Cs fisco C.7?54CsCoOo?sCiCl2(36. amino acid selected from the group chosen from: a beta-3 wherein Bany beta amino acid; Cany alpha amino acid; homolog of the wild-type amino acid sequence. C any alpha amino acid; f any beta amino acid; C. any alpha amino acid; C. any alpha amino acid; Cls any alpha 0384. In some embodiments, the composition comprises a amino acid; f any beta amino acid; C. any alpha amino VIP analog, wherein the analog comprises the following acid; C., any alpha amino acid; B any beta amino acid; repetitive pattern of sequential -amino acids from the Cls any alpha amino acid; Co any alpha amino acid; Co-any amino-terminus selected from the following: alpha amino acid; B5 any beta amino acid; Cany alpha 0385 fiCC2Cs2C-4Cs?-CoC-7Cs54C.oOo?sCiCl2O is: amino acid; Cany alpha amino acid; Be any beta amino wherein Bany beta amino acid; C. any alpha amino acid; acid; and Cany alpha amino acid; Cany alpha amino acid; B any 0393 beta amino acid; C. any alpha amino acid; Cls any alpha BC.C.C.s 62C-4Cs BCC-7Cs B4C. ClofssC-11C-12C is Bo: amino acid; B any beta amino acid; Cany alpha amino wherein Bany beta amino acid; Cany alpha amino acid; acid; C., any alpha amino acid; Cls any alpha amino acid; Cany alpha amino acid; C. an alpha amino acid; B any B any beta amino acid; Co any alpha amino acid; Co any beta amino acid; C. an alpha alpha amino acid; Cls any alpha alpha amino acid; fs any beta amino acid; C. any alpha amino acid; B any beta amino acid; C. any alpha amino amino acid; C.12 any alpha amino acid; Cany alpha amino acid; C., any alpha amino acid; Cls any alpha amino acid; acid; B any beta amino acid; Co any alpha amino acid; Co any 0386 fiC. C.2fBC af2C-4Cs faC.C.734CsCloCo?sC. C.12B6, alpha amino acid; B5 any beta amino acid; Cany alpha wherein Bany beta amino acid; C. any alpha amino acid; amino acid; C.12 any alpha amino acid; C.1s any alpha amino Cany alpha amino acid; Bany beta amino acid; C. any acid; and B any beta amino acid; alpha amino acid; C. any alpha amino acid; Cls an alpha 0394 wherein the repetitive pattern is, optionally, pre leucine; B any beta amino acid; Cany alpha amino acid; ceded by: C., any alpha amino acid; f any beta amino acid; Cls any 0395 HSDAVFTDNY if the composition comprises alpha amino acid; Co any alpha amino acid; Co any alpha BCC2Cs (2C-4Cs BCC-7Cs B4C. Co?sC-11C-12C is O amino acid; 3s any beta amino acid; C. any alpha amino fiC. C.2fBC-af2C-4Cs?BCC-734CsCloCo?sC-11C1236: O acid; C. any alpha amino acid; B any beta amino acid; and HSDAVFTDN if the composition comprises 0387 fiCC2Cl3?2C-4Cs faCoC-7Cs? 4CsClio?issCiCl2Cla?s: and fiC-C2Cla?s 2C-4Cs faCoC-7Cs? 4CsClofssC-11C-12C-1356: wherein at least one or more of the amino acids wherein f any beta amino acid; C. any alpha amino acid; HSDAVFTDNY or HSDVFTDN is Substituted with a beta Cany alpha amino acid; C. an alpha amino acid; B any amino acid selected from the group chosen from: a beta-3 beta amino acid; C. an alpha alpha amino acid; Cls any alpha homolog of the wild-type amino acid sequence, a beta-2 amino acid; B any beta amino acid; Cany alpha amino homolog of the wild-type amino acid sequence, ACPC, or acid; C., any alpha amino acid; Cls any alpha amino acid; APC. B any beta amino acid; Co any alpha amino acid; Co any 0396. In some embodiments, the composition comprises a alpha amino acid; B5 any beta amino acid; C. any alpha VIP analog, wherein the analog comprises the following US 2013/0096050 A1 Apr. 18, 2013

repetitive pattern of sequential -amino acids from the acid; C., any alpha amino acid; B any beta amino acid; amino-terminus selected from the following: Cls any alpha amino acid; Co any alpha amino acid; Co-any 0397 f, C. Cl2Os32C-4Cs?BCC-7Cs?a CoCo BSC. C.12Cs. alpha amino acid; B5 any beta amino acid; Cany alpha wherein f any beta amino acid; C. any alpha amino acid; amino acid; C. any alpha amino acid; f any beta amino Cany alpha amino acid; Cany alpha amino acid; B any acid; and beta amino acid; C. any alpha amino acid; Cls any alpha 0405 amino acid; B any beta amino acid; Cany alpha amino acid; C., any alpha amino acid; Cls any alpha amino acid; wherein Bany beta amino acid; C. any alpha amino f any beta amino acid; Co any alpha amino acid; Co any acid; Cany alpha amino acid; C. an alpha amino acid; alpha amino acid; B5 any beta amino acid; C. any alpha Bany beta amino acid; C. an alpha alpha amino acid; amino acid; Cany alpha amino acid; Cany alpha amino Cls any alpha amino acid; B any beta amino acid; Cany acid; alpha amino acid; C., any alpha amino acid; Cls any alpha 0398 fiCC2Csf2O.C.s (BCC-7Cs?a CoCo BSC. Cl2O?36. amino acid; B any beta amino acid; Co any alpha amino wherein f any beta amino acid; C. any alpha amino acid; acid; Co any alpha amino acid; fs any beta amino acid; Cany alpha amino acid; Bany beta amino acid; C. any Cany alpha amino acid; Cany alpha amino acid: alpha amino acid; C. any alpha amino acid; Cls an alpha C. any alpha amino acid; and B any beta amino acid; amino acid; B any beta amino acid; Cany alpha amino 0406 wherein the repetitive pattern is, optionally, pre acid; C., any alpha amino acid; B any beta amino acid; ceded by: fs any alpha amino acid; Co any alpha amino acid; Co-any (0407 HSDAVFTDNY if the composition comprises alpha amino acid; B5 any beta amino acid; C. any alpha BCC2Cs (2C-4Cs BCC-7Cs B4C. Co?sC-11C-12C is O amino acid; C. any alpha amino acid; f any beta amino fiC. C.2fBC-af2C-4Cs?BCC-734CsCloCo?sC-11C1236: O acid; and HSDAVFTDN if the composition comprises 0399 fiC-C2Cla?s 2C-4Cs faCoC-7Cs? 4CsClofssC-11C-12C-1356: fiCC2Cl3?2C-4Cs faCoC-7Cs? 4CsClio?issCiCl2Cla?s: and wherein Bany beta amino acid; C. any alpha amino acid; wherein the Tat position 7 of HSDAVFTDNY is substituted C any alpha amino acid; C. an alpha amino acid; f any with a beta amino acid selected from the group chosen from: beta amino acid; C. an alpha alpha amino acid; Cls any alpha a beta-3 homolog of the wild-type amino acid sequence, a amino acid; f any beta amino acid; C. any alpha amino beta-2 homolog of the wild-type amino acid sequence, ACPC, acid; C., any alpha amino acid; Cls any alpha amino acid; or APC. f any beta amino acid; Co any alpha amino acid; Co any 0408. In some embodiments, the composition comprises a alpha amino acid; B5 any beta amino acid; C. any alpha VIP analog, wherein the analog comprises the following amino acid; C.12 any alpha amino acid; Cany alpha amino repetitive pattern of sequential -amino acids from the acid; and f any beta amino acid; amino-terminus selected from the following: 04.00 wherein the repetitive pattern is, optionally, pre 04.09 fiCC2Csf2C-4Cs?BCC-7Csf4C.C. of sGC2Cs. ceded by: wherein f3, any beta amino acid; C. any alpha amino acid; 0401 HSDAVFTDNY if the composition comprises Cany alpha amino acid; C. any alpha amino acid; B any fiCC2Cs?-C-4Cs?issCC-7Cs? 4CsCl lo?s C-11C12O is O beta amino acid; C. any alpha amino acid; Cls any alpha BCC2 fos?2C-4Cs BCC-734CsCoCo BSC-11C1266: O amino acid; B any beta amino acid; C. any alpha amino HSDAVFTDN if the composition comprises acid; C., any alpha amino acid; Cls any alpha amino acid; BCC2Cs (2C-4Cs BCC-7Cs B4C.9C lo?s C-11C-12C is Bo: and B any beta amino acid; Co any alpha amino acid; Co any wherein the Dat position 8 of HSDAVFTDNY is substituted alpha amino acid; B5 any beta amino acid; Cany alpha with a beta amino acid selected from the group chosen from: amino acid; Cany alpha amino acid; C. any alpha amino a beta-3 homolog of the wild-type amino acid sequence, a acid; beta-2 homolog of the wild-type amino acid sequence, ACPC, 0410 fiC. C.2fBC af2O.C.s?a CC-734CsCloCo?sC. C.12B6, or APC. wherein f3, any beta amino acid; C. any alpha amino acid; 0402. In some embodiments, the composition comprises a Cany alpha amino acid; Bany beta amino acid; C. any VIP analog, wherein the analog comprises the following alpha amino acid; C. any alpha amino acid; Cls an alpha repetitive pattern of sequential -amino acids from the amino acid; B any beta amino acid; C. any alpha amino amino-terminus selected from the following: acid; C., any alpha amino acid; B any beta amino acid; 0403 f6, CC2Csf2O.C.s (BCC-7Cs?a CoCo BSC. C.12Cs. Cls any alpha amino acid; Co any alpha amino acid; Co-any wherein Bany beta amino acid; C. any alpha amino acid; alpha amino acid; B5 any beta amino acid; Cany alpha Cany alpha amino acid; Cany alpha amino acid; B any amino acid; C. any alpha amino acid; f any beta amino beta amino acid; C. any alpha amino acid; Cls any alpha acid; and amino acid; B any beta amino acid; Co-any alpha amino 0411 acid; C., any alpha amino acid; Cls any alpha amino acid; f1C. Cl2Os32C-4Cs?issCoC-7Cs? 4C-9C lo?s C11C-12C isfs: B any beta amino acid; Co any alpha amino acid; Co any wherein Bany beta amino acid; Cany alpha amino acid; alpha amino acid; B5 any beta amino acid; C. any alpha Cany alpha amino acid; C. an alpha amino acid; B any amino acid; C.12 any alpha amino acid; Cany alpha amino beta amino acid; C. an alpha alpha amino acid; Cls any alpha acid; amino acid; B any beta amino acid; C. any alpha amino 0404 f51CC-BCE.C.O.sf.C.C.734CsCoCo?sC. C.12B6, acid; C., any alpha amino acid; Cls any alpha amino acid; wherein Bany beta amino acid; C. any alpha amino acid; B any beta amino acid; Co any alpha amino acid; Co any Cany alpha amino acid; Bany beta amino acid; C. any alpha amino acid; B5 any beta amino acid; Cany alpha alpha amino acid; C. any alpha amino acid; Cls an alpha amino acid; C.12 any alpha amino acid; C.1s any alpha amino amino acid; B any beta amino acid; Cany alpha amino acid; and B any beta amino acid; US 2013/0096050 A1 Apr. 18, 2013 52

0412 wherein the repetitive pattern is, optionally, pre amino-terminus to the carboxy-terminus: BC.C. BC.C.C.BC.C.- ceded by: BC.C.C. BC.C.B. In some embodiments, the composition com 0413 HSDAVFTDNY if the composition comprises prises a VIP analog, wherein the analog comprises the fol BCC2Cs (2C-4Cs BCC-7Cs B4C.9C lo?s C-11C-12C is O lowing repetitive pattern of sequential B-amino acids from the f1CC-2fBC-af2C-4Cs faCC-734CsCloCo?sC.C. 1266: O amino-terminus: HSDAVFTDN if the composition comprises fiCC232CsC-4Cs? CC-734CsCo.ClofssC, C1236, wherein fiCC2Cs?-C-4Cs?issCC-7Cs? 4CsCl lo?s C-11C12O is ?o: and Bany beta amino acid; Cany alpha amino acid; Cany wherein the Dat position 8 of HSDAVFTDNY and, option alpha amino acid; B any beta amino acid; Cany alpha ally, the Tat position 7 of HSDAVFTDNY is substituted with amino acid: C. any alpha amino acid; Cls any alpha amino a beta amino acid selected from the group chosen from: a acid; B any beta amino acid; Cany alpha amino acid; beta-3 homolog of the wild-type amino acid sequence, a C., any alpha amino acid; f any beta amino acid; Cls any beta-2 homolog of the wild-type amino acid sequence, ACPC, alpha amino acid; Co any alpha amino acid; Co any alpha or APC. amino acid; fs any beta amino acid; C. any alpha amino 0414. In some embodiments, the composition comprises a acid; C. any alpha amino acid; Be any beta amino acid; VIP analog, wherein the analog comprises the following wherein the repetitive pattern is, optionally, preceded by: repetitive pattern of sequential -amino acids from the HSDAVFTDNY if the composition comprises; and amino-terminus selected from the following: 0421 wherein the C-terminus is, optionally, amidated; 0415 fiCC2Csf2O.C.s (BCC-7Cs?a CoCo BSC. C.12Cs. and wherein Bany beta amino acid; C. any alpha amino acid; 0422 wherein the N-terminus is, optionally, acylated: Cany alpha amino acid; Cany alpha amino acid; B any 0423 or functional fragments thereof. beta amino acid; C. any alpha amino acid; Cls any alpha 0424. In some embodiments, the composition comprises a amino acid; B any beta amino acid; Cany alpha amino VIP analog, wherein the analog comprises the following acid; C., any alpha amino acid; Cls any alpha amino acid; repetitive pattern of sequential -amino acids from the B any beta amino acid; Co any alpha amino acid; Co any amino-terminus: alpha amino acid; B5 any beta amino acid; C. any alpha fiC. C.2fBC-af2C-4Cs?BCC-734CsCloCo?sC-11C1236. Wherein amino acid; Cany alpha amino acid; Cany alpha amino f a beta 3-threonine, C. any alpha amino acid; Cany acid; alpha amino acid; Babeta-3 arginine; Cany alpha amino 0416) f. C. C.2fBCsf2C-4Cs? Co.C. 734CsCloCo?sC.C. 1266. acid; C. any alpha amino acid; Cls any alpha amino acid; wherein f any beta amino acid; C. any alpha amino acid; Babeta-3 alanine; Co any alpha amino acid; C., any alpha Cany alpha amino acid; Bany beta amino acid; C. any amino acid; B, a beta-3 lysine; Cls any alpha amino acid; alpha amino acid; C. any alpha amino acid; Cls an alpha Co any alpha amino acid; Co any alpha amino acid; Bs a amino acid; B any beta amino acid; Cany alpha amino beta-3 asparagine; Cany alpha amino acid; C. any alpha acid; C., any alpha amino acid; f any beta amino acid; amino acid; f any beta amino acid; wherein the repetitive Cls any alpha amino acid; Co any alpha amino acid; Co-any pattern is, optionally, preceded by: HSDAVFTDNY if the alpha amino acid; fs any beta amino acid; C. any alpha composition comprises; and amino acid; Cany alpha amino acid; Be any beta amino 0425 wherein the C-terminus is, optionally, amidated; acid; and and 0417 0426 wherein the N-terminus is, optionally, acylated: fiC-C2Cla?s 2C-4Cs faCoC-7Cs? 4CsClofssC-11C-12C-1356: 0427 or functional fragments thereof. wherein f any beta amino acid; C. any alpha amino acid; 0428. In some embodiments, the composition comprises a Cany alpha amino acid; C. an alpha amino acid; B any VIP analog, wherein the analog comprises the following beta amino acid; C. an alpha alpha amino acid; Cls any alpha repetitive pattern of sequential -amino acids from the amino acid; f any beta amino acid; C. any alpha amino amino-terminus: acid; C., any alpha amino acid; Cls any alpha amino acid; fiC. C.2fBC-af2C-4Cs?BCC-734CsCloCo?sC-11C1236. Wherein f any beta amino acid; Co any alpha amino acid; Co any Ba beta 3-threonine; Cany alpha amino acid; Cany alpha amino acid; B5 any beta amino acid; C. any alpha alpha amino acid; Babeta-3 arginine; Cany alpha amino amino acid: C.12 any alpha amino acid; Cany alpha amino acid; C. any alpha amino acid; Cls any alpha amino acid; acid; and B any beta amino acid; f a beta-3 alanine; C any alpha amino acid; C., any alpha 0418 wherein the repetitive pattern is, optionally, pre amino acid; B, a beta-3 lysine; Cls any alpha amino acid; ceded by: Co any alpha amino acid; Clo any alpha amino acid; fs a 0419. HSDAVFTDNY if the composition comprises beta-3 alanine; Cany alpha amino acid; C. any alpha fiCC2Cs?-C-4Cs?issCC-7Cs? 4CsCl lo?s C-11C12O is O amino acid; Be a beta-3 asparagine; wherein the repetitive BCC2 fos?2C-4Cs BCC-734CsCoCo BSC-11C1266: O pattern is, optionally, preceded by: HSDAVFTDNY if the HSDAVFTDN if the composition comprises composition comprises; and BCC2Cs (2C-4Cs BCC-7Cs B4C.9C lo?s C-11C-12C is Bo: and 0429 wherein the C-terminus is, optionally, amidated; wherein the Tat position 7 of HSDAVFTDNY and, option and ally, the Dat position 8 of HSDAVFTDNY is substituted with 0430 wherein the N-terminus is, optionally, acylated: a beta amino acid selected from the group chosen from: a 0431 or functional fragments thereof. beta-3 homolog of the wild-type amino acid sequence, a 0432. In some embodiments, the composition comprises a beta-2 homolog of the wild-type amino acid sequence ACPC, VIP analog, wherein the analog comprises the following or APC. repetitive pattern of sequential -amino acids from the 0420. In some embodiments, the composition comprises a amino-terminus: VIP analog, wherein the analog comprises the following fiC. C.2fBC-af2C-4Cs?BCC-734CsCloCo?sC-11C1236. Wherein repetitive pattern of sequential -amino acids from the Ba beta 3-threonine; Cany alpha amino acid; Cany US 2013/0096050 A1 Apr. 18, 2013 alpha amino acid; Babeta-3 arginine; Cany alpha amino leucine; B, a beta-3 asparagine; wherein the repetitive pat acid; C. any alpha amino acid; Cls an alpha leucine; B, a tern is, optionally, preceded by: HSDAVFTDNY if the com beta-3 alanine; Cany alpha amino acid; C., any alpha position comprises; and amino acid; f. a beta-3 lysine; Cls any alpha amino acid; 0445 wherein the C-terminus is, optionally, amidated; Co any alpha amino acid; Co any alpha amino acid; Bs a and beta-3 alanine: C. any alpha amino acid; C. any alpha 0446 wherein the N-terminus is, optionally, acylated: amino acid; Be a beta-3 asparagine; wherein the repetitive 0447 or functional fragments thereof. pattern is, optionally, preceded by: HSDAVFTDNY if the 0448. In some embodiments, the composition comprises a composition comprises; and VIP analog, wherein the analog comprises the following 0433 wherein the C-terminus is, optionally, amidated; repetitive pattern of sequential -amino acids from the and amino-terminus: 0434 wherein the N-terminus is, optionally, acylated: fiCC2Cl3?2C-4Cs faCoC-7Cs? 4CsClio?issCiCl2Cl3, wherein 0435 or functional fragments thereof. Bany beta amino acid; Cany alpha amino acid; Cany 0436. In some embodiments, the composition comprises a alpha amino acid; C. any alpha amino acid; B any beta VIP analog, wherein the analog comprises the following amino acid; C. any alpha amino acid; Cls any alpha amino repetitive pattern of sequential -amino acids from the acid; B any beta amino acid; Cany alpha amino acid; amino-terminus: C., any alpha amino acid; Cls any alpha amino acid; f any f1CC-2fBC-af2C-4Cs faCC-734CsCloCo?sC-11C1236. Wherein beta amino acid; Co any alpha amino acid; Co any alpha fany beta amino acid; C. any alpha amino acid; Cany amino acid; 3s any beta amino acid; C. any alpha amino alpha amino acid; B any beta amino acid; Cany alpha acid; C.12 any alpha amino acid; Cany alpha amino acid: amino acid; C. any alpha amino acid; Cls any alpha amino wherein the repetitive pattern is, optionally, preceded by: acid; B any beta amino acid; Cany alpha amino acid; HSDAVFTDNY if the composition comprises; and C., any alpha amino acid; f any beta amino acid; Cls any 0449 wherein the C-terminus is, optionally, amidated; alpha amino acid; Co any alpha amino acid; Co any alpha and amino acid; Bs a beta-3 alanine; Cany alpha amino acid; 0450 wherein the N-terminus is, optionally, acylated: C. any alpha amino acid; f, a beta-3 asparagine; wherein 0451 or functional fragments thereof. the repetitive pattern is, optionally, preceded by: 0452. In some embodiments, the composition comprises a HSDAVFTDNY if the composition comprises; and VIP analog, wherein the analog comprises the following 0437 wherein the C-terminus is, optionally, amidated; repetitive pattern of sequential B-amino acids from the and amino-terminus: fiCC2Cl3?2C-4Cs faCoC-7Cs? 4CsClio?issCiCl2Cl3, wherein 0438 wherein the N-terminus is, optionally, acylated: Ba beta-3 threonine; Cany alpha amino acid; Cany 0439 or functional fragments thereof. alpha amino acid; C. any alpha amino acid; f. a beta-3 0440. In some embodiments, the composition comprises a lysine; Cany alpha amino acid; Cls any alpha amino acid; VIP analog, wherein the analog comprises the following f a beta-3 alanine; C any alpha amino acid; C., any alpha repetitive pattern of sequential -amino acids from the amino acid; Cls any alpha amino acid; Babeta-3 tyrosine; amino-terminus: Co any alpha amino acid; Co any alpha amino acid; Bs a f1CC-2fBC-af2C-4Cs faCC-734CsCloCo?sC-11C1236. Wherein beta-3 alanine; Cany alpha amino acid; C. any alpha fany beta amino acid; C. an alpha arginine: C, an alpha amino acid; C. any alpha amino acid; wherein the repetitive leucine; B any beta amino acid; C. an alpha lysine; C an pattern is, optionally, preceded by: HSDAVFTDNY if the alpha glutamine; Cls an alpha leucine; B any beta amino composition comprises; and acid; C. an alpha Valine: C, an alpha lysine; B any beta 0453 wherein the C-terminus is, optionally, amidated; amino acid; Cls an alpha tyrosine; Co an alpha leucine; and Coan alpha asparagine; fs=any beta amino acid; Clan 0454 wherein the N-terminus is, optionally, acylated: alpha isoleucine; Clan alpha leucine, B any beta amino acid; wherein the repetitive pattern is, optionally, preceded 0455 or functional fragments thereof. 0456. In some embodiments, the composition comprises a by: HSDAVFTDNY if the composition comprises; and VIP analog, wherein the analog comprises the following 0441 wherein the C-terminus is, optionally, amidated; repetitive pattern of sequential -amino acids from the and amino-terminus: 0442 wherein the N-terminus is, optionally, acylated: fiCC2Cl3?2C-4Cs faCoC-7Cs? 4CsClio?issC-11C12O is: wherein 0443) or functional fragments thereof. fany beta amino acid; C. an alpha arginine: C, an alpha 0444. In some embodiments, the composition comprises a leucine; Cls an alpha arginine; B any beta amino acid; VIP analog, wherein the analog comprises the following C. an alpha glutamine; Cls an alpha leucine; f any beta repetitive pattern of sequential -amino acids from the amino acid; C. an alpha Valine acid; C., an alpha lysine; amino-terminus: Cls an alpha lysine; B any beta amino acid; Co an alpha f1CC-2fBC-af2C-4Cs faCC-734CsCloCo?sC-11C1236. Wherein leucine; Co an alpha asparagine; Bs any beta amino acid; fabeta-3 threonine or ACPC; C, an alpha arginine; Clan C. an alpha isoleucine; C. an alpha leucine; C. an alpha alpha leucine; B, a beta-3 arginine or APC: C. an alpha asparagine; wherein the repetitive pattern is, optionally, pre lysine: C. an alpha glutamine; Cls an alpha leucine; f, a ceded by: HSDAVFTDNY if the composition comprises; and beta-3 alanine or ACPC; Clan alpha valine: C, an alpha 0457 wherein the C-terminus is, optionally, amidated; lysine; B, a beta-3 lysine or APC; Cls an alpha tyrosine; and Co an alpha leucine; Co an alpha asparagine; Bs a beta-3 0458 wherein the N-terminus is, optionally, acylated: alanine or ACPC; Clan alpha isoleucine; C. an alpha 0459 or functional fragments thereof. US 2013/0096050 A1 Apr. 18, 2013 54

0460. In some embodiments, the composition comprises a APC: C. an alpha lysine; Cls an alpha glutamine; B, a VIP analog, wherein the analog comprises the following beta-3 leucine or ACPC; Clan alpha alanine: C, an alpha repetitive pattern of sequential -amino acids from the Valine; Cls an alphalysine; Babeta-3 lysine or APC; Co an amino-terminus: alpha tyrosine; Clo an alpha leucine; fs a beta-3 asparagine fiCC2Cs?-C-4Cs?issCC-7Cs? 4CsCl lo?s C-11C12O13, wherein or ACPC; Clan alpha alanine; C. an alpha isoleucine; f—a beta-3 threonine or an ACPC; C.—an alpha arginine: C. an alpha leucine; and Be a beta-3 asparagine; wherein Can alpha leucine; Cls an alpha arginine; B, a beta-3 the repetitive pattern is, optionally, preceded by: lysine or APC: C. an alpha glutamine; Cls an alpha leucine; HSDAVFTDN; and fabeta-3 alanine or ACPC; Clan alpha valine acid; C., an 0473 wherein the C-terminus is, optionally, amidated; alpha lysine; Cls an alpha lysine; B, a beta-3 tyrosine or; and Cls an alpha leucine; Co an alpha asparagine; fs a beta-3 0474 wherein the N-terminus is, optionally, acylated: alanine or ACPC; Clan alpha isoleucine; C. an alpha 0475 or functional fragments thereof. leucine, C. an alpha asparagine; wherein the repetitive pat 0476. In some embodiments, the composition comprises a tern is, optionally, preceded by: HSDAVFTDNY if the com VIP analog, wherein the analog comprises the following position comprises; and repetitive pattern of sequential -amino acids from the 0461 wherein the C-terminus is, optionally, amidated; amino-terminus: and fiCC2Cl3?2C-4Cs faCoC-7Cs? 4CsClio?issCiCl2Cla?s: 0462 wherein the N-terminus is, optionally, acylated: wherein Babeta-3 tyrosine; C. an alpha threonine; Clan 0463 or functional fragments thereof. alpha arginine: C. an alpha leucine; f, a beta-3 arginine or 0464. In some embodiments, the composition comprises a APC: C. an alpha lysine; Cls an alpha glutamine; B, a VIP analog, wherein the analog comprises the following beta-3 leucine or ACPC; Clan alpha alanine: C, an alpha repetitive pattern of sequential -amino acids from the Valine; Cls an alphalysine; Babeta-3 lysine or APC; Co an amino-terminus: alpha tyrosine; Co an alpha leucine; Babeta-3 asparagine fiCC2Cs?-C-4Cs?issCC-7Cs? 4CsCl lo?s C-11C12O is ?o: or ACPC; Clan alpha alanine; C. an alpha isoleucine; wherein Bany beta amino acid; C. any alpha amino acid; C. an alpha leucine; and Be a beta-3 asparagine; wherein C any alpha amino acid; C. an alpha amino acid; f any the repetitive pattern is, optionally, preceded by: beta amino acid; C. an alpha alpha amino acid; Cls any alpha HSDAVFTDN; and amino acid; f any beta amino acid; C. any alpha amino 0477 wherein the C-terminus is, optionally, amidated; acid; C., any alpha amino acid; Cls any alpha amino acid; and B any beta amino acid; Co any alpha amino acid; Co any 0478 wherein the N-terminus is, optionally, acylated: alpha amino acid; B5 any beta amino acid; C. any alpha 0479 or functional fragments thereof. amino acid; C.12 any alpha amino acid; Cany alpha amino 0480. In some embodiments, the composition comprises acid; and f any beta amino acid; wherein the repetitive HSDAVFTDN or HSDAVFTDNY, wherein at least one of the pattern is, optionally, preceded by: HSDAVFTDN and amino acids from HSDAVFTDN or HSDAVFTDNY are non 0465 wherein the C-terminus is, optionally, amidated; natural or beta amino acids. In some embodiments, the com and position comprises HSDAVFTDN or HSDAVFTDNY, 0466 wherein the N-terminus is, optionally, acylated: wherein at leastone of the amino acids from HSDAVFTDN or 0467 or functional fragments thereof. HSDAVFTDNY is a beta-3, beta-2, cyclic, or heterocyclic 0468. In some embodiments, the composition comprises a beta amino acids. In some embodiments, the C-terminus is VIP analog, wherein the analog comprises the following not amidated. In some embodiments, the N-terminus is not repetitive pattern of sequential -amino acids from the acylated. In some embodiments, the composition comprises amino-terminus: HSDAVFTDN or HSDAVFTDNY, wherein the amino acids BCC2Cs (2C-4Cs BCC-7Cs B4C.9C lo?s C-11C-12C is Bo: from HSDAVFTDN or HSDAVFTDNY are alpha amino wherein Ba beta-3 tyrosine; Cany alpha amino acid; acids. In some embodiments, the composition comprises Cany alpha amino acid; C. an alpha amino acid; B a HSDAVFTDN or HSDAVFTDNY, wherein the amino acids beta-3 arginine; C. an alpha alpha amino acid; Cls any alpha from HSDAVFTDN or HSDAVFTDNY are not alpha amino amino acid; Babeta-3 leucine; Cany alpha amino acid; acids. In some embodiments, the composition comprises C., any alpha amino acid; Cls any alpha amino acid; f a HSDAVFTDN or HSDAVFTDNY, wherein none of the beta-3 lysine; Co any alpha amino acid; Co any alpha amino acids from HSDAVFTDN or HSDAVFTDNY are amino acid; fis a beta-3 asparagine; Cany alpha amino beta-3 amino acids. In some embodiments, the composition acid; C.12 any alpha amino acid; Cany alpha amino acid: comprises HSDAVFTDN or HSDAVFTDNY, wherein none and Be a beta-3 asparagine; wherein the repetitive pattern is, of the amino acids from HSDAVFTDN or HSDAVFTDNY optionally, preceded by: HSDAVFTDN; and are beta-2 amino acids. In some embodiments, the composi 0469 wherein the C-terminus is, optionally, amidated; tion comprises HSDAVFTDN or HSDAVFTDNY, wherein and none of the amino acids from HSDAVFTDN or 0470 wherein the N-terminus is, optionally, acylated: HSDAVFTDNY are ACPC or APC. In some embodiments, 0471 or functional fragments thereof. the composition comprises HSDAVFTDN or 0472. In some embodiments, the composition comprises a HSDAVFTDNY, wherein none of the amino acids from VIP analog, wherein the analog comprises the following HSDAVFTDN or HSDAVFTDNY are cyclic. In some repetitive pattern of sequential -amino acids from the embodiments, the composition comprises HSDAVFTDN or amino-terminus: HSDAVFTDNY, wherein none of the amino acids from fiCC2Cs?-C-4Cs?issCC-7Cs? 4CsCl lo?s C-11C12O is ?o: HSDAVFTDN or HSDAVFTDNY are heterocyclic. wherein Babeta-3 tyrosine; Clan alpha threonine; Clan 0481) “Selective” or “Selectivity” means that the analog of alpha arginine; Cls an alpha leucine; Babeta-3 arginine or the present invention has a binding preference for one protein US 2013/0096050 A1 Apr. 18, 2013 as compared to another protein. In some embodiments, the due designated f(position 2) is D-Phe, and wherein the analog binding preference may be measured as an affinity for a interferes with the VPAC1 receptor signaling pathway. In protein in terms of half maximal inhibitory concentration Some embodiments, the invention relates to compositions or (IC50). In some embodiments, the binding preference may be pharmaceutical compositions comprising a VIP analog, measured as an affinity for a protein in terms of half maximal wherein the analog comprises an O-amino acid and at least effective concentration (EC50). For example, an analog one B-amino acid, and wherein the analog is between 75% selective to VPAC2 receptor with a selectivity to VPAC2 and 99% homologous to HflDAVFTNSYRKVLKRL means that the analog may bind to VPAC1 receptor but has a SARKLLODIL, where residue designated f (position 2) is higher binding affinity for a domain of the VPAC2 receptor if D-Phe, and wherein the analog is an antagonist of the VPAC1 the analog is exposed to both VPAC1 and VPAC2 at similar or receptor. In some embodiments, the composition comprises a equivalent concentrations. As used herein, an analog that VIP analog is from about 80% to about 99% homologous to selectively binds to VPAC2 refers to an analog with increased HfDAVFTNSYRKVLKRLSARKLLODIL, where residue selectivity for the VPAC2 receptor compared to other known designated f(position 2) is D-Phe. In some embodiments the receptors or proteins to which the peptide may bind. In some VIP analog is from about 80% to about 85% homologous to embodiments, the analog selective for VPAC2 may be an HfDAVFTNSYRKVLKRLSARKLLODIL, where residue agonist of the VPAC2 receptor peptide. In some embodi designated f(position 2) is D-Phe. In some embodiments the ments, the analog selective for VPAC2 may be an antagonist VIP analog is from about 85% to about 90% homologous to of VPAC2 receptor. In some embodiments, an analog selec HfDAVFTNSYRKVLKRLSARKLLODIL, where residue tive to VPAC2 receptor means that the analog may bind to designated f(position 2) is D-Phe. In some embodiments the VPAC1 receptor but has a higher binding affinity for a domain VIP analog is from about 90% to about 95% homologous to of the VPAC2 receptor if the analog is exposed to PAC1, HfDAVFTNSYRKVLKRLSARKLLODIL, where residue VPAC1 receptor and VPAC2 receptors at similar or equiva designated f(position 2) is D-Phe. In some embodiments the lent concentrations. In some embodiments, an analog selec VIP analog is from about 95% to about 99% homologous to tive to VPAC1 receptor means that the analog may bind to a HfDAVFTNSYRKVLKRLSARKLLODIL, where residue domain of VPAC2 or PAC1 receptor but has a higher binding designated f(position 2) is D-Phe. In some embodiments the affinity for a domain of the VPAC1 receptor if the analog is VIP analog is about 95%, 96%, 97%, 98%, or 99% homolo exposed to PAC1, VPAC1 receptor and VPAC2 receptors at gous to HflDAVFTNSYRKVLKRLSARKLLODIL, where similar or equivalent concentrations. As used herein, an ana residue designated f(position 2) is D-Phe. In some embodi log that selectively binds to VPAC1 refers to an analog with ments, the composition or pharmaceutical compositions increased selectivity for the VPAC1 receptor compared to comprise a VIP analog, wherein the analog is either: (a) an other known receptors or proteins to which the peptide may antagonist of VPAC1 receptor; or (b) interferes with VPAC1 bind. In some embodiments, the analog selective for VPAC1 receptor signaling pathway and comprises the following may be an agonist of the VPAC1 receptor peptide. In some repetitive pattern of sequential -amino acids from the embodiments, the analog selective for VPAC1 may be an amino-terminus: f1CC-232CsC-4Cs?issCo.C.734CsClo Clo?s. antagonist of VPAC1 receptor. In some embodiments, an wherein Bany beta amino acid; Cany alpha amino acid; analog selective to VPAC1 receptor means that the analog Cany alpha amino acid; Bany beta amino acid; C. any may bind to VPAC2 receptor but has a higher binding affinity alpha amino acid; C. any alpha amino acid; Cls any alpha for a domain of the VPAC1 receptor if the analog is exposed amino acid; B any beta amino acid; C. any alpha amino to both VPAC1 receptor and VPAC2 receptor at similar or acid; C., any alpha amino acid; f any beta amino acid; equivalent concentrations. As used herein, an analog that Cls any alpha amino acid; Co any alpha amino acid; Co-any selectively binds to PAC1 refers to an analog with increased alpha amino acid; Bs any beta amino acid; wherein the selectivity for the PAC1 receptor as compared to other known repetitive patternis, optionally, preceded by: HfDAV FTNSY. receptors or proteins to which the peptide may bind. In some and embodiments, the analog selective for PAC1 may be an ago 0483 wherein residue designated f(position 2) is D-Phe nist of the PAC1 receptor peptide. In some embodiments, the analog selective for PAC1 may be an antagonist of PAC1 0484 wherein the C-terminus is, optionally, amidated; receptor. In some embodiments, an analog selective to PAC1 and receptor means that the analog may bind to VPAC2 or VPAC1 0485 wherein the N-terminus is, optionally, acylated: receptors but has a higher binding affinity for a domain of the 0486 or functional fragments thereof. PAC1 receptor if the analog is exposed to PAC1, VPAC1 receptor and VPAC2 receptors at similar or equivalent con In some embodiments, the composition or pharmaceutical centrations. The degree of selectivity may be determined by a compositions comprise a VIP analog, wherein the analog is ratio of VPAC2 receptor binding affinity to VPAC1 receptor either: (a) an antagonist of VPAC1 receptor; or (b) interferes binding affinity or by a ratio of VPAC2 receptor binding with VPAC1 receptor signaling pathway and comprises the affinity to PAC1 receptor binding affinity. Binding affinity is following repetitive pattern of sequential -amino acids from the amino-terminus: BC. C.2fB2C-C-4Cs?-C.C.734CsCoCo Bs, determined as described below in Example 1. whereinf any beta 3 amino acid; Cany alpha amino acid; 0482 In any of the embodiments described below wherein Cany alpha amino acid; Bany beta 3 amino acid; C. any the polypeptide comprises a residue designated f, the residue alpha amino acid; C. any alpha amino acid; Cls any alpha designated f is D-Phe or L-Phe or S. In some embodiments, amino acid; B any beta 3 amino acid; Cany alpha amino the invention relates to compositions or pharmaceutical com acid; C., any alpha amino acid; f any beta 3 amino acid; positions comprising a VIP analog, wherein the analog com Cls any alpha amino acid; Co any alpha amino acid; Co-any prises an O-amino acid and at least one 3-amino acid, and alpha amino acid; Bs any beta 3 amino acid; wherein the wherein the analog is between 75% and 99% homologous to repetitive patternis, optionally, preceded by: HfDAV FTNSY. 1-1 HflDAVFTNSYRKVLKRLSARKLLODIL; where resi and US 2013/0096050 A1 Apr. 18, 2013 56

0487 wherein residue designated f(position 2) is D-Phe 0495. In some embodiments, the composition comprises a 0488 wherein the C-terminus is, optionally, amidated; VIP analog, wherein the analog comprises the following and repetitive pattern of sequential -amino acids from the amino-terminus: fiCC2Cl3?2C-4Cs faCoC-7Cs? 4CsClio?is: 0489 wherein the N-terminus is, optionally, acylated: wherein Bany beta amino acid; Cany alpha amino acid; 0490 or functional fragments thereof. Cany alpha amino acid; C. an alpha amino acid; B any In some embodiments, the composition or pharmaceutical beta amino acid; C. an alpha alpha amino acid; Cls any alpha compositions comprise a VIP analog, wherein the analog is amino acid; B any beta amino acid; C. any alpha amino either: (a) an antagonist of VPAC1 receptor; or (b) interferes acid; C., any alpha amino acid; Cls any alpha amino acid; with VPAC1 receptor signaling pathway and comprises the B any beta amino acid; Co any alpha amino acid; Co any following repetitive pattern of sequential B-amino acids from alpha amino acid; Bs any beta amino acid; wherein the the amino-terminus: BC, CBC.C.O.sf.C.C.7?, OsCoCo Bs, repetitive patternis, optionally, preceded by: HflDAV FTNSY wherein Ba beta-3 arginine; Cany alpha amino acid; or Hf DAV FTNS and C any alpha amino acid; ?a beta-3 leucine; C any alpha 0496 wherein the C-terminus is, optionally, amidated; amino acid; C. any alpha amino acid; Cls any alpha amino and acid; Babeta-3 serine; Cany alpha amino acid; C., any 0497 wherein the N-terminus is, optionally, acylated: 0498 or functional fragments thereof; and wherein resi alpha amino acid; Baa beta-3 lysine; Cls any alpha amino due designated f(position 2) is D-Phe. acid; Co any alpha amino acid; Co any alpha amino acid; 0499. In some embodiments, the composition comprises a fis a beta-3 aspartic acid; wherein the repetitive pattern is, VIP analog, wherein the analog comprises the following optionally, preceded by: HflDAV FTNSY; and repetitive pattern of sequential -amino acids from the 0491 wherein residue designated f(position 2) is D-Phe amino-terminus: fiCC2Cl3?2C-4Cs faCoC-7Cs? 4CsClio?is: 0492 wherein the C-terminus is, optionally, amidated; wherein Ba beta-3 arginine or beta-3 tyrosine; Cany and alpha amino acid; Cany alpha amino acid; C. an alpha amino acid; Babeta-3 lysine or beta-3 leucine; C. an alpha 0493 wherein the N-terminus is, optionally, acylated: alpha amino acid; Cls any alpha amino acid; B. a beta-3 0494 or functional fragments thereof. serine or a beta-3 leucine; C any alpha amino acid; C., any In some embodiments, the composition comprises alpha amino acid; Cls any alpha amino acid; Baa beta-3 HfIDAVFTDN or Hf)AVFTDNY, wherein at least one of the leucine or beta-3 lysine; Co any alpha amino acid; Clo any amino acids from Hf DAVFTDN or HfDAVFTDNY are non alpha amino acid; Bs a beta-3 aspartic acid or beta-3 natural or beta amino acids, wherein residue designated f glutamine; wherein the repetitive pattern is, optionally, pre (position 2) is D-Phe. In some embodiments, the composition ceded by: HflDAV FTNSY or HflDAV FTNS, and comprises HflDAVFTDN or HflDAVFTDNY, wherein at least 0500 wherein the C-terminus is, optionally, amidated; one of the amino acids from HfDAVFTDN or and HflDAVFTDNY is a beta-3, beta-2, cyclic, or heterocyclic 0501 wherein the N-terminus is, optionally, acylated: 0502 or functional fragments thereof, and wherein resi beta amino acids, and wherein residue designated f(position due designated f(position 2) is D-Phe. 2) is D-Phe. In some embodiments, the C-terminus is not 0503. In some embodiments, the composition comprises a amidated. In some embodiments, the N-terminus is not acy VIP analog, wherein the analog comprises the following lated. In some embodiments, the composition comprises repetitive pattern of sequential -amino acids from the HfDAVFTDN or Hf)AVFTDNY, wherein the amino acids amino-terminus: BCC2Cs (2C-4Cs BCC-7Cs B4C. Clofs: from HflDAVFTDN or HflDAVFTDNY are alpha amino wherein B=a beta-3 arginine, beta-3 tyrosine, or APC: acids, and wherein residue designated f(position 2) is D-Phe. C. any alpha amino acid; Cany alpha amino acid; C. an In some embodiments, the composition comprises alpha amino acid; BACPC or APC: C. an alpha alpha HfDAVFTDN or Hf)AVFTDNY, wherein the amino acids amino acid; Cls any alpha amino acid; BACPC or a beta-3 from Hfl)AVFTDN or HflDAVFTDNY are not alpha amino leucine; Cany alpha amino acid; C., any alpha amino acid; acids, and wherein residue designated f(position 2) is D-Phe. Cls any alpha amino acid; B, a beta-3 leucine, beta-3 lysine, In some embodiments, the composition comprises or APC: Co any alpha amino acid; Co any alpha amino acid; HfDAVFTDN or Hf)AVFTDNY, wherein none of the amino ?s=a beta-3 aspartic acid or ACPC; wherein the repetitive acids from Hf DAVFTDN or Hf DAVFTDNY are beta-3 pattern is, optionally, preceded by: HflDAV FTNSY or amino acids, and wherein residue designated f(position 2) is Hf)AV FTNS: and D-Phe. In some embodiments, the composition comprises 0504 wherein the C-terminus is, optionally, amidated; HfDAVFTDN or Hf)AVFTDNY, wherein none of the amino and acids from Hf DAVFTDN or Hf DAVFTDNY are beta-2 0505 wherein the N-terminus is, optionally, acylated: amino acids, and wherein residue designated f(position 2) is 0506 or functional fragments thereat, and wherein residue D-Phe. In some embodiments, the composition comprises designated f(position 2) is D-Phe. HfDAVFTDN or Hf)AVFTDNY, wherein none of the amino 0507. In some embodiments, the invention relates to com acids from Hf DAVFTDN or Hf DAVFTDNY are ACPC or positions or pharmaceutical compositions comprising a VIP APC, and wherein residue designated f(position 2) is D-Phe. analog, wherein the analog comprises an O-amino acid and at In some embodiments, the composition comprises least one B-amino acid, and wherein the analog is between HfDAVFTDN or Hf)AVFTDNY, wherein none of the amino 75% and 100% homologous to one or more of the following acids from HflDAVFTDN or HfDAVFTDNY are cyclic, Sequences: wherein residue designated f(position 2) is D-Phe. In some embodiments, the composition comprises Hfl)AVFTDN or HfDAVFIDNY, wherein none of the amino acids from HfDAV FTNSY ZKVXK RLXAR KLLQD IL HflDAVFTDN or HflDAVFTDNY are heterocyclic, and HfDAV FTNSY RKVXK RLXAR ZLLQD IL wherein residue designated f(position 2) is D-Phe. US 2013/0096050 A1 Apr. 18, 2013 57

- Continued - Continued Hf DAV FTNSY RKVXK RLXAR KLLQx IL HSDAV FTDNY tRLRz QLxVK KyLNx ILN Hf DAV FTNSY ZKVXK RLXAR ZLLOX IL Hf DAV FTNSY RKVLz RLXAR KLLQx IL HSDAW FTDNy TRLzK QAVK zYLikA Iln Hf DAV FTNSY ZKVLZ RLXAR KLLOX IL HSDAW FTDNy TRLzK QxAVK kYLikA Iln Hf DAV FTNSY RKVXK RLSAR ZLLXD IL HSDAW FTDNy TRLzK QxAVK zYLikA Iln Hf DAV FTNSY RKVXK RXSAR KLLXD IL wherein each underlined residue is a beta amino acid corre Hf DAV FTNSY RKVXK RXSAR ZLLXD IL sponding to the single code amino acid upon which it is based, wherein X is a ACPC, and wherein Z is APC, or functional wherein residue designated f(position 2) is D-Phe, wherein fragments thereof. each underlined residue is a beta amino acid, wherein X is a 0509. In some embodiments, the invention relates to com ACPC, wherein Z is APC, and wherein the analog interferes positions or pharmaceutical compositions comprising a VIP with the VPAC1 receptor signaling pathway. In some embodi analog, wherein the analog comprises an O-amino acid and at ments, the invention relates to compositions or pharmaceuti least one B-amino acid, and wherein the analog is between cal compositions comprising a VIP analog, wherein the ana 75% and 99% homologous to HSDAVFTDNYTRL log comprises an O-amino acid and at least one B-amino acid, RKOVAAKKYLQSIKNKRY, and wherein the analog stimu and wherein the analog is between 75% and 100% homolo lates the VPAC2 receptor signaling pathway. In some gous to one or more of the following sequences: embodiments, the invention relates to compositions or phar maceutical compositions comprising a VIP analog, wherein the analog comprises an O-amino acid and at least one Hf DAV FTNSY ZKVXK RLXAR KLLQD IL B-amino acid, and wherein the analog is between 75% and Hf DAV FTNSY RKVXK RLXAR ZLLQD IL 99% homologous to HSDAVFTDNYTRLRKQVAAKKY LQSIKNKRY, wherein the analog is an agonist of the VPAC2 Hf DAV FTNSY RKVXK RLXAR KLLOX IL receptor. In some embodiments, the composition comprises a VIP analog is from about 80% to about 99% homologous to Hf DAV FTNSY ZKVXK RLXAR ZLLOX IL HSDAVFTDNYTRLRKQVAAKKYLQSIKNKRY. In some Hf DAV FTNSY RKVLZ RLXAR KLLOX IL embodiments the VIP analog is from about 80% to about 85% homologous to HSDAVFTDNYTRLRKQVAAKKY Hf DAV FTNSY ZKVLZ RLXAR KLLOX IL LQSIKNKRY. In some embodiments the VIP analog is from Hf DAV FTNSY RKVXK RLSAR ZLLXD IL about 85% to about 90% homologous to HSDAVFTDNYTR LRKQVAAKKYLQSIKNKRY. In some embodiments the Hf DAV FTNSY RKVXK RXSAR KLLXD IL VIP analog is from about 90% to about 95% homologous to HSDAVFTDNYTRLRKQVAAKKYLQSIKNKRY. In some Hf DAV FTNSY RKVXK RXSAR ZLLXD IL embodiments the VIP analog is from about 95% to about 99% wherein residue designated f(position 2) is D-Phe, wherein homologous to HSDAVFTDNYTRLRKQVAAKKY each underlined residue is a beta amino acid, wherein X is a LQSIKNKRY. In some embodiments the VIP analog is about ACPC, wherein Z is APC, and wherein the analog is an 95%, 96%, 97%, 98%, or 99% homologous to HSDAVFTD antagonist of the VPAC1 receptor; or functional fragments NYTRLRKQVAAKKYLQSIKNKRY. In some embodi thereof. ments the VIP analog is HSDAVFTDNYTRL RKOVAAKKYLQSIKNKRY. 0508. In some embodiments, the invention relates to com 0510. In some embodiments, the composition or pharma positions or pharmaceutical compositions comprising a VIP ceutical composition comprises a VIP analog, wherein the analog, wherein the analog comprises an O-amino acid and at analog comprises the following repetitive pattern of sequen least one 3-amino acid, and wherein the analog is between tial B-amino acids from the amino-terminus: 75% and 100% homologous to one or more of the following fiCC232CsC-4Cs faCo.C.734CsCoClio?issC-11C1236, wherein Sequences: Bany beta amino acid; Cany alpha amino acid; Cany alpha amino acid; B any beta amino acid; Cany alpha amino acid; C. any alpha amino acid; Cls any alpha amino HSDAV FTDNY TRLRK Q1AVK KYLNa ILN acid; f any beta amino acid; C. any alpha amino acid; C., any alpha amino acid; B any beta amino acid; Cls any HSDAV FTDNY tRLrK QLaVK kYLNa alpha amino acid; Co any alpha amino acid; Clo any alpha HSDAV FTDNY tRLRk QLaVK KyLNa amino acid; 3s any beta amino acid; C. any alpha amino acid; C. any alpha amino acid; B any beta amino acid; and HSDAV FTDNy TRL rK Q1AVK kYLnA wherein the repetitive pattern is, optionally, preceded by: HSDAV FTDNY tRLzK QLxVK kYLNx HSDAV FTDNY or HSDAV FTDN; and wherein the repeti tive pattern is, optionally, succeeded by: K, KR, or KRY HSDAV FTDNY tRLzK QLxVK zYLNx 0511 wherein the C-terminus is, optionally, amidated; and 0512 wherein the N-terminus is unmodified or modified: or functional fragments thereof. US 2013/0096050 A1 Apr. 18, 2013

0513. In some embodiments, the composition or pharma 0523. In some embodiments, the composition comprises a ceutical composition comprises a VIP analog, wherein the VIP analog, wherein the analog comprises the following analog comprises the following repetitive pattern of sequen repetitive pattern of sequential -amino acids from the tial B-amino acids from the amino-terminus: amino-terminus: f1CC-232CsC-4Cs?issCo.C.734CsClo Co?sC-11C1236, wherein fiCC2Cl3?2C-4Cs faCoC-7Cs? 4CsClio?issCiCl2Cla?s: f a beta-3 threonine, C. any alpha amino acid; Cany wherein f3, any beta amino acid; C. any alpha amino acid; alpha amino acid; Babeta-3 arginine; Cany alpha amino Cany alpha amino acid; C. an alpha amino acid; B any acid; C. any alpha amino acid; Cls an alpha leucine; B, a beta amino acid; C. an alpha alpha amino acid; Cls any alpha beta-3 alanine; Cany alpha amino acid; C., any alpha amino acid; f any beta amino acid; C. any alpha amino amino acid; B, a beta-3 lysine; Cls any alpha amino acid; acid; C., any alpha amino acid; Cls any alpha amino acid; Co any alpha amino acid; Clo any alpha amino acid; fs a f any beta amino acid; Co any alpha amino acid; Co any beta-3 serine; Cany alpha amino acid; Cany alpha alpha amino acid; B5 any beta amino acid; Cany alpha amino acid; f, a beta-3 asparagine; and wherein the repeti amino acid; Cany alpha amino acid; C. any alpha amino tive pattern is, optionally, preceded by: HSDAV FTDNY or acid; and B any beta amino acid; and wherein the repetitive HSDAV FTDN, and wherein the repetitive pattern is, option pattern is, optionally, preceded by: HSDAV FTDNY or ally, succeeded by: K, KR, or KRY HSDAV FTDN and wherein the repetitive pattern is, option 0514 wherein the C-terminus is, optionally, amidated; ally, succeeded by: K, KR, or KRY and 0524 wherein the C-terminus is, optionally, amidated; 0515 wherein the N-terminus is unmodified or modified: and or functional fragments thereof, 0525 wherein the N-terminus is unmodified or modified: 0516 wherein the VIP analog or functional fragment or functional fragments thereof. thereof is a VPAC2 agonist. 0526 In some embodiments, the composition comprises a 0517. In some embodiments, the composition or pharma VIP analog, wherein the analog comprises the following ceutical composition comprises a VIP analog, wherein the repetitive pattern of sequential -amino acids from the analog comprises the following repetitive pattern of sequen amino-terminus: tial B-amino acids from the amino-terminus: fiCC2Cl3?2C-4Cs faCoC-7Cs? 4CsClio?issCiCl2Cla?s: f C. C.2?2C-C-4Cs?BC.C.7?54CsCloCo?sC, C1236, wherein wherein B=a beta-3 threonine or a beta-3 tyrosine; C.—any Bany beta amino acid; C. any alpha amino acid; Cany alpha amino acid; Cany alpha amino acid; C. an alpha alpha amino acid; B any beta amino acid; Cls any alpha amino acid; 32 a beta-3 lysine or a beta-3 arginine: C. an amino acid; C. any alpha amino acid; Cls any alpha amino alpha alpha amino acid; Cls any alpha amino acid; f a acid; B any beta amino acid; Cany alpha amino acid; beta-3 alanine or a beta-3 valine; Cany alpha amino acid; C., any alpha amino acid; f any beta amino acid; Cls any C., any alpha amino acid; Cls any alpha amino acid; Baa alpha amino acid; Co any alpha amino acid; Co any alpha beta-3 tyrosine or a beta-3 lysine; Co any alpha amino acid; amino acid; 3s any beta amino acid; C. any alpha amino Co any alpha amino acid; Bs a beta-3 serine or a beta-3 acid; C. any alpha amino acid; B any beta amino acid; and glutamine; Cany alpha amino acid; Cany alpha amino wherein the repetitive pattern is, optionally, preceded by: acid; C. any alpha amino acid; and Be a beta-3 lysine or a HSDAV FTDNY; and wherein the repetitive pattern is, beta-3 asparagine; and wherein the repetitive pattern is, optionally, succeeded by: K, KR, or KRY optionally, preceded by: HSDAV FTDNY or HSDAV 0518 wherein the C-terminus is, optionally, amidated; FTDNY wherein the repetitive pattern is, optionally, suc and ceeded by: K, KR, or KRY 0519 wherein the N-terminus is unmodified or modified: 0527 wherein the C-terminus is, optionally, amidated; or functional fragments thereof, and wherein the analog or and functional fragment thereof is a VPAC2 agonist. 0528 wherein the N-terminus is unmodified or modified: 0520. In some embodiments, the composition or pharma or functional fragments thereof. ceutical composition comprises a VIP analog, wherein the 0529. In some embodiments, the composition comprises a analog comprises the following repetitive pattern of sequen VIP analog, wherein the analog comprises the following tial B-amino acids from the amino-terminus: repetitive pattern of sequential -amino acids from the f C. C.2?2C-C-4Cs?BC.C.7?54CsCloCo?sC, C1236, wherein amino-terminus: B. a beta-3 threonine; Cany alpha amino acid; Cany fiCC2Cl3?2C-4Cs faCoC-7Cs? 4CsClio?issCiCl2Cla?s: alpha amino acid; Babeta-3 arginine; Cany alpha amino wherein B=a beta-3 threonine or a beta-3 tyrosine; C–any acid; C. any alpha amino acid; Cls any alpha amino acid; alpha amino acid; Cany alpha amino acid; C. an alpha Babeta-3 alanine; Cany alpha amino acid; C., any alpha amino acid; ?a beta-3 lysine or a beta-3 arginine; C an amino acid; f. a beta-3 lysine; Cls any alpha amino acid; alpha alpha amino acid; Cls any alpha amino acid; B a Co any alpha amino acid; Co any alpha amino acid; Bs a beta-3 alanine or a beta-3 valine; Cany alpha amino acid; beta-3 serine; Cany alpha amino acid; Cany alpha C., any alpha amino acid; Cls any alpha amino acid; Baa amino acid; Be a beta-3 asparagine; and wherein the repeti beta-3 tyrosine or a beta-3 lysine; Co any alpha amino acid; tive pattern is, optionally, preceded by: HSDAVFTDNY, and Co any alpha amino acid; fsa beta-3 serine or a beta-3 wherein the repetitive pattern is, optionally, succeeded by: K. glutamine; Cany alpha amino acid; Cany alpha amino KR, or KRY acid; C. any alpha amino acid; and f a beta-3 lysine or a 0521 wherein the C-terminus is, optionally, amidated; beta-3 asparagine; and wherein the repetitive pattern is, and optionally, preceded by: HSDAV FTDNY or HSDAV FTDN: 0522 wherein the N-terminus is unmodified or modified: and wherein the repetitive pattern is, optionally, succeeded or functional fragments thereof. by: K, KR, or KRY. US 2013/0096050 A1 Apr. 18, 2013 59

0530 wherein the C-terminus is, optionally, amidated; least one B-amino acid, and wherein the analog is between and 75% and 100% homologous to one or more of the following 0531 wherein the N-terminus is unmodified or modified: Sequences: or functional fragments thereof. 0532 and wherein the analog or functional fragment thereof is a VPAC2 agonist. 0533. In some embodiments, the invention relates to com positions or pharmaceutical compositions comprising a VIP analog, wherein the analog comprises an O-amino acid and at least one 3-amino acid, and wherein the analog is between 75% and 100% homologous to one or more of the following Sequences:

HSDAVFTDNYTRLZKQXSAKKYLXSIKNKRY HSDAVFTDNYTRLZKQXSAKZYLXSIKNKRY wherein each underlined residue is a beta amino acid corre sponding to the single code amino acid upon which it is based, wherein X is a ACPC, and wherein Z is APC, or functional fragments thereof, wherein the C-terminus is, optionally, amidated; wherein the N-terminus is, optionally, modified; and wherein the VIP analog or functional fragment thereof is HSDAVFTDNYTRLZKQXSAKKYLXSIKNKRY a VPAC2 agonist. HSDAVFTDNYTRLZKQXSAKZYLXSIKNKRY 0536. In some embodiments, the invention relates to com wherein each underlined residue is a beta amino acid corre positions or pharmaceutical compositions comprising a VIP sponding to the single code amino acid upon which it is based, analog, wherein the analog comprises an O-amino acid and at wherein X is a ACPC, and wherein Z is APC, or functional least one B-amino acid, and wherein the analog is between fragments thereof, wherein the C-terminus is, optionally, 75% and 100% homologous to one or more of the following amidated; and wherein the N-terminus is unmodified. Sequences: 0534. In some embodiments, the invention relates to com positions or pharmaceutical compositions comprising a VIP analog, wherein the analog comprises an O-amino acid and at HSDAW FTDNY T R LRK QVAAK KYLQs IKNKR Y least one 3-amino acid, and wherein the analog is between HSDAW FTDNY T R LRK QVAAK KYLOS IKNKR Y 75% and 100% homologous to one or more of the following Sequences: HSDAV FTDNY TRLRK QVAAK KYLQS IKNKR Y HSDAW FTDNY LZK QVXAK KYLOS IKNKR Y HSDAW FTDNY T R HSDAW FTDNY T R LZK QVXAK KYLOX IKNKR Y

HSDAW FTDNY

HSDAW FTDNY T R LRZ QVXAK KYLOX IKNKR Y HSDAV FTDNY XRLRz QVXAK KYLQx IKNKR Y HSDAV FTDNY TRLZK QVAAK ZYLXS IKNKR Y HSDAV FTDNY TRLZK QXAAK KYLXS IKNKR Y HSDAVFTDNYTRLZKQXSAKKYLXSIKNKRY HSDAV FTDNY TRLZK QXAAK ZYLXS IKNKR Y HSDAVFTDNYTRLZKQXSAKZYLXSIKNKRY wherein each underlined residue is an unnatural amino acid wherein each underlined residue is a beta amino acid corre corresponding to the single code amino acid upon which it is sponding to the single code amino acid upon which it is based, based, wherein X is a ACPC, and wherein Z is APC; or wherein X is a ACPC, and wherein Z is APC, or functional functional fragments thereof, wherein the C-terminus is, fragments thereof, wherein the C-terminus is, optionally, optionally, amidated; wherein the N-terminus is, optionally, amidated; and wherein the N-terminus is, optionally, modi modified; and wherein the VIP analog or functional fragment fied. thereof is a VPAC1 agonist. 0535 In some embodiments, the invention relates to com 0537. In some embodiments, the invention relates to com positions or pharmaceutical compositions comprising a VIP positions or pharmaceutical compositions comprising a VIP analog, wherein the analog comprises an O-amino acid and at analog, wherein the analog comprises an O-amino acid and at US 2013/0096050 A1 Apr. 18, 2013 60 least one 3-amino acid, and wherein the analog is between 0539. In some embodiments, the invention relates to com 75% and 100% homologous to one or more of the following positions or pharmaceutical compositions comprising a VIP Sequences: analog, wherein the analog comprises an O-amino acid and at least one B-amino acid, and wherein the analog comprises an amino acid sequence that is between 75% and 100% homolo HSDAW FTDNY T R LRK QVAAK KYLOS IKNKR Y gous to one or more of the following sequences: HSDAW FTDNY T R LRK QVAAK KYLQs IKNKR Y HSDAV FTDNY TRLRK QVAAK KYLQS IKNKR Y HSDAW FTDNY T R LRK QVAAK KYLOS IKNKR Y HSDAW FTDNY LZK QVXAK KYLOS IKNKR Y HSDAW FTDNY T R LRK QVAAK KYLQs IKNKR Y HSDAW FTDNY T R LZK QVXAK ZYLOS IKNKR Y HSDAV FTDNY TRLRK QVAAK KYLQS IKNKR Y HSDAW FTDNY T R LZK QVXAK KYLOX IKNKR Y HSDAV FTDNY XRLZK QVXAK KYLQs IKNKR Y HSDAW FTDNY LZK QVXAK ZYLOX IKXKR Y HSDAV FTDNY TRLZK QVXAK ZYLOS IKNKR Y HSDAV FTDNY TRLRZ QVXAK KYLOX IKNKR Y HSDAV FTDNY TRLZK QVXAK KYLQx IKNKR Y HSDAV FTDNY XRLRZ QVXAK KYLOX IKNKR Y HSDAW FTDNY LZK QVXAK ZYLOX IKXKR Y HSDAV FTDNY TRLZK QVAAK ZYLXS IKNKR Y HSDAW FTDNY T R HSDAV FTDNY TRLZK QXAAK KYLXS IKNKR Y HSDAV FTDNY XRLRZ QVXAK KYLOX IKNKR Y HSDAV FTDNY TRLZK QXAAK ZYLXS IKNKR Y HSDAV FTDNY TRLZK QVAAK ZYLXS IKNKR Y wherein each underlined residue is a beta amino acid corre HSDAV FTDNY TRLZK QXAAK KYLXS IKNKR Y sponding to the single code amino acid upon which it is based, wherein X is a ACPC, and wherein Z is APC, or functional HSDAV FTDNY TRLZK QXAAK ZYLXS IKNKR Y fragments thereof, wherein the C-terminus is, optionally, wherein each underlined residue is any unnatural amino acid; amidated; wherein the N-terminus is, optionally, modified; any beta-2 amino acid; any beta-3 amino acid; or a beta-3 and wherein the VIP analog or functional fragment thereof is homoamino acid corresponding to the single code amino acid a VPAC1 agonist. upon which it is based; wherein X is a ACPC, and wherein Z 0538. In some embodiments, the invention relates to com is APC; or functional fragments thereof; wherein the C-ter positions or pharmaceutical compositions comprising a VIP minus is, optionally, amidated; wherein the N-terminus is, analog, wherein the analog comprises an O-amino acid and at optionally, modified; and wherein the VIP analog or func least one 3-amino acid, and wherein the analog is between tional fragment thereof is a VPAC1 or VPAC2 agonist. 75% and 100% homologous to one or more of the following 0540. In some embodiments, the invention relates to com Sequences: positions or pharmaceutical compositions comprising a VIP analog, wherein the analog comprises an O-amino acid and at HSDAW FTDNY R least one B-amino acid, and wherein the analog comprises an T LRK QVAAK KYLOS IKNKR Y amino acid sequence that is between 75% and 100% homolo HSDAW FTDNY T R LRK QVAAK KYLOS IKNKR Y gous to: HSDAV FTDNY TRLRK QVAAK KYLQS IKNKR Y HSDAW FTDNY LZK QVXAK KYLOS IKNKR Y HSDAVFTDNYTRLRKOVAAKKYLOSIKNKRY

HSDAW FTDNY R or functional fragments thereof; and wherein the VIP analog T LZK QVXAK ZYLOS IKNKR Y or functional fragment thereof is a VPAC2 agonist. HSDAW FTDNY T R LZK QVXAK KYLOX IKNKR Y 0541. In some embodiments, the invention relates to com positions or pharmaceutical compositions comprising a VIP HSDAW FTDNY LZK QVXAK ZYLOX IKXKR Y analog, wherein the analog comprises an O-amino acid and at HSDAV FTDNY TRLRZ QVXAK KYLOX IKNKR Y least one B-amino acid, and wherein the analog comprises an amino acid sequence that is between 75% and 100% homolo HSDAV FTDNY XRLRz QVXAK KYLQx IKNKR Y gous to any of the amino acid sequence provided in this HSDAV FTDNY TRLZK QVAAK ZYLXS IKNKR Y application. 0542. The invention relates to methods of manufacturing a HSDAV FTDNY TRLZK QXAAK KYLXS IKNKR Y composition comprising an analog, wherein the analog com prises an O-amino acid and at least one B-amino acid. In some HSDAV FTDNY TRLZK QXAAK ZYLXS IKNKR Y embodiments, the invention relates to methods of manufac wherein each underlined residue is a beta-3 homoamino acid turing a composition comprising an analog, wherein the ana corresponding to the single code amino acid upon which it is log comprises an O-amino acid, at least one 3-amino acid, and based, wherein X is a ACPC, and wherein Z is APC; or at least one modified amino acid residue comprising ACPC or functional fragments thereof, wherein the C-terminus is, APC. The invention relates to methods of manufacturing a optionally, amidated; wherein the N-terminus is, optionally, composition comprising a secretin family analog, wherein modified; and wherein the VIP analog or functional fragment the secretin family analog comprises an O-amino acid and at thereof is a VPAC1 agonist. least one B-amino acid. The invention relates to methods of US 2013/0096050 A1 Apr. 18, 2013 manufacturing a composition comprising a VIP analog, moPhe-OH, (S)-2-(trifluoromethyl)-f-Phe-OH, (S)-2-cy wherein the VIP analog comprises an O-amino acid and at ano-B-HomoPhe-OH, (S)-2-methyl-3-Phe-OH, (S)-3,4- least one f-amino acid. The method used to fabricate dimethoxy-B-Phe-OH, (S)-3-(trifluoromethyl)-3-HomoPhe polypeptide compounds may be any means of polypeptide OH, (S)-3-(trifluoromethyl)-f-Phe-OH, (S)-3-cyano-B-Phe synthesis. Using methods of peptide synthesis, polypeptides OH, (S)-3-methoxy-B-Phe-OH, (S)-3-methyl-[3-Phe-OH, fabricated according to the present method are generally less (S)-4-(4-pyridyl)-f-HomoAla-OH, (S)-4-(trifluoromethyl)- than about 100 residues long. In some embodiments, the B-Phe-OH, (S)-4-bromo-?-Phe-OH, (S)-4-chloro-B-Ho invention relates to a method of manufacturing an analog (or moPhe-OH, (S)-4-chloro-B-Phe-OH, (S)-4-cyano-B-Ho fragments herein) comprising non-natural amino acids from moPhe-OH, (S)-4-cyano-B-Phe-OH, (S)-4-fluoro-B-Phe about 5 total residues to about 50 total residues, from about 10 OH, (S)-4-iodo-B-HomoPhe-OH, (S)-4-methyl-3- total residues to about 20 total residues, from about 20 total HomoPhe-OH, (S)-4-methyl-f-Phe-OH, (S)-B-Tyr-OH, (S)- residues to about 30 total residues, from about 30 total resi Y.Y-diphenyl-B-HomoAla-OH, (S)-2-methyl-B-Homophe dues to about 40 total residues, from about 40 total residues to OH, (S)-3,4-difluoro-B-HomoPhe-OH, (S)-3- about 50 total residues, from about 50 to about 60 total resi (trifluoromethyl)-O-HomoPhe-OH, (S)-3-cyano-B- dues, from about 60 to about 70 total residues from about 70 HomoPhe-OH, (S)-3-methyl-f-HomoPhe-OH, (S)-Y.Y- to about 80 total residues, from about 80 to about 90 total diphenyl-?-HomoAla-OH, 3-Amino-3-(3-bromophenyl) residues, and from about 90 to about 100 total residues. propionic acid, and 3-Amino-4,4,4-trifluorobutyric acid. Ranges above and below these stated ranges are within the Scope of the invention. Many commercial services, such as 0543. In some embodiments, the fragment comprises 2, 3, Abgent (San Diego, Calif., USA) offer peptide synthesis ser 4, 5, 6,7,8,9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, vices up to about 100 residues. In some embodiments, the 23, 24, 25, 26, 27, 28, 29, 30, 31, 32,33, 34,35, 36, 37,38, 39, invention relates to a method of manufacturing an analog 30, 31, 32,33, 34,35, 36, 37,38, 39, or 40 amino acids of the comprising no more than 100 non-natural amino acids. In wild type protein sequence. In some embodiments, the frag Some embodiments, the invention relates to a method of ment comprises any of the above-mentioned numbers of manufacturing an analog comprising no more than 90 non amino acids located anywhere within the peptide. Thus, one natural amino acids. In some embodiments, the invention skilled in the art understands that a fragment of any of these relates to a method of manufacturing an analog comprising no lengths can be walked along the length of the peptide, thus more than 80 non-natural amino acids. In some embodiments, providing any fragment of the peptide with the same or simi the invention relates to a method of manufacturing an analog lar function as the native or wild-type amino acid sequence. comprising no more than 70 non-natural amino acids. In some embodiments, the invention relates to a method of manufac 0544 One of ordinary skill in the art would readily appre turing an analog comprising no more than 60 non-natural ciate that the protecting groups would be removed from the amino acids. In some embodiments, the invention relates to a final chemical structure of the analog which becomes admin method of manufacturing an analog comprising no more than istered to a subject. One of ordinary skill would be able to 50 non-natural amino acids. In some embodiments, the inven predict the final chemical structure of the analog by using the tion relates to a method of manufacturing an analog compris protecting groups selectively to create a polypeptide with a ing no more than 40 non-natural amino acids. In some desirable chirality or secondary structure. For instance, if the embodiments, the invention relates to a method of manufac analog of the composition is manufactured using (S)-Fmoc turing an analog comprising no more than 30 non-natural 3-methyl-B-HomoPhe-OH, the final yielded product should amino acids. In some embodiments, the invention relates to a comprise at least one B-amino acid residue of a 3-methyl-3- method of manufacturing an analog comprising no more than homophenylalanine. 20 non-natural amino acids. In some embodiments, the inven tion relates to a method of manufacturing an analog compris 0545. In some embodiments, the method of manufactur ing no more than 10 non-natural amino acids. In some ing the analog comprises synthesizing the analog using at embodiments, the method of manufacturing the analog com least one, and in Some embodiments, a plurality of cyclic prises synthesizing the analog using at least one, and, in some amino acid residues. In some embodiments, the VIP analog of embodiments, a plurality of the following non-naturally the claimed invention comprises the cyclic amino acid resi occurring amino acid residues: (2S,3R)-3-(amino)-2-hy dues. In some embodiments, the VIP analog of the claimed droxy-4-(4-nitrophenyl)butyric acid, (2R,3R)-3-(amino)-2- invention comprises at least one disulfide bridge that forms a hydroxy-4-phenylbutyric acid, (R)-3-(amino)-5-phenylpen cyclic chain of atoms along a side chain of two amino acid tanoic acid, (R)-3-(amino)-4-(2-naphthyl)butyric acid, (R)- residues. 2-methyl-B-Phe-OH, (R)-3,4-dimethoxy-B-Phe-OH, (R)-(3- 0546. In some embodiments, the VIP analog of the pyridyl)-f-Ala-OH, (R)-3-(trifluoromethyl)-3-Phe-OH, (R)- claimed invention comprises the following sequence: 3-cyano-?-Phe-OH, (R)-3-methoxy-B-Phe-OH, (R)-3- methyl-3-Phe-OH, (R)-4-(4-pyridyl)-3-HomoAla-OH, (R)- 4-(trifluoromethyl)-O-HomoPhe-OH, (R)-4- HSDAVFTDNYTRLRKOMAWKKYLNSILN; (trifluoromethyl)-f-Phe-OH, (R)-4-bromo-f-Phe-OH, (R)- 4-chloro-B-HomoPhe-OH, (R)-4-chloro-3-Phe-OH, (R)-4- wherein at least one of the amino acid residues is a B-amino cyano-B-HomoPhe-OH, (R)-4-cyano-B-Phe-OH, (R)-4- acid residue, and at least one of the amino acid residues is an fluoro-f-Phe-OH, (R)-4-methoxy-3-Phe-OH, (R)-4-methyl C.-amino acid residue. In some embodiments, the at least one B-Phe-OH, (R)-3-Tyr-OH, (R)-4-(3-pyridyl)-3-HomoAla C.-amino acid residue is a non-natural amino acid residue. In OH, (R)-4-fluoro-B-HomoPhe-OH, (S)-5-phenylpentanoic Some embodiments, the amino acid residues at positions 1, 3, acid, (S)-5-hexenoic acid, (S)-5-phenyl-pentanoic acid, (S)- 6, 7, 10, and 23 of the VIP analog are not alanine, glycine, or 6-phenyl-5-hexenoic acid, (S)-2-(trifluoromethyl)-B-Ho any Bamino acid residue with a methyl side chain. US 2013/0096050 A1 Apr. 18, 2013 62

0547. In some embodiments, the VIP analog of the wherein any one or more of X1, X2, Xs, X, Xs, X, X7, Xs. claimed invention comprises the following sequence: X, or Xo is a beta-amino acid, and wherein X-T: X-D; X-R or K; XM or L: Xs=A or V: X-R or K; X,R or K: Xs=S or A: X-L or K; and XN or K. In some embodi HSDAVFXXNYTRLR XOXAXXX,YLNXIXX. ments, the VIP analog of the claimed invention comprises the wherein any of X1,X2, Xs, X, Xs, X, X7, Xs, Xo, or Xo may following sequence: be a beta-amino acid. In some embodiments, the VIP analog of the claimed invention comprises the following sequence: HSDAVFXXNYTRLR XCXAXXX,YLNXIXX. wherein any one or more of X1, X2, Xs, X, Xs, X, X7, Xs. HSDAVFXXNYTRLR XOXAXXX,YLNXIXX. Xo, or Xo is a f-amino acid residue. In some embodiments, wherein any of X1,X2, Xs, X, Xs, X, X7, Xs, Xo, or Xo are at least one of the Bi-amino acid residues is substituted with af-amino acid residue. In some embodiments, at least one of a residue chosen from the following: (S,S)-trans-2-aminocy the Bi-amino acid residues is substituted with a residue cho clopentanecarboxylic acid (S,S)-ACPC), (S,R)-trans-2-ami Sen from the following: (S,S)-trans-2-aminocyclopentanecar nocyclopentanecarboxylic acid (S,R)-ACPC), (R.S)-trans boxylic acid (S,S)-ACPC), (S,R)-trans-2-aminocyclopen 2-aminocyclopentanecarboxylic acid ((R.S)-ACPC), or tanecarboxylic acid ((S,R)-ACPC), (R.S)-trans-2- (R,R)-trans-2-aminocyclopentanecarboxylic acid (R,R)- aminocyclopentanecarboxylic acid ((R.S)-ACPC), or (R,R)- ACPC) if the amino acid is non-polar, or pyrrolidine analogue trans-2-aminocyclopentanecarboxylic acid (R,R)-ACPC) if of (S,S)-ACPC, (R.S)-ACPC, (S,R)-ACPC, (R,R)-ACPC), the amino acid is non-polar; or pyrrolidine analogue of (S,S)- which is designated APC, if the amino acid is basic. In some ACPC, (R.S)-ACPC, (S,R)-ACPC, (R,R)-ACPC), which is embodiments, at least one of the f-amino acid residues is designated APC, if the amino acid is basic. In some embodi substituted with a residue chosen from the following: (S,S)- ments, at least one of the f-amino acid residues is substituted trans-2-aminocyclopentanecarboxylic acid (S,S)-ACPC) if with a residue chosen from the following: (S,S)-trans-2-ami the amino acid is non-polar, or pyrrolidine analogue of (S,S)- nocyclopentanecarboxylic acid (S,S)-ACPC) if the amino ACPC if the residue is basic. acid is non-polar; or pyrrolidine analogue of (S,S)-ACPC if 0550. In some embodiments, the VIP analog of the the residue is basic. claimed invention comprises the following sequence: 0548. In some embodiments, the VIP analog of the claimed invention comprises the following sequence: wherein X, X, X7, Xo, and X are beta-amino acid resi HSDAVFXX2NYTRLR XOXAXXX,YLNXIXX. dues derived from the naturally occurring C.-amino acid resi wherein any one or more of X1, X2, Xs, X, Xs, X, X7, Xs. due at that position, and wherein X-T: XD: X-R or K: X, or Xo is a beta-amino acid, and wherein X-T: X-D; X-Mor L: X-A or V: X-R or KX-R or KX-S or A: X-R or K; XM or L: Xs=A or V: X-R or K; X,R or K: X-L or K; and X=N or K. HSDAVFXXNYXRLX Xs=S or A: X-L or K; and XN or K. In some embodi XQXX-XXXYLNXIX-X ments, the VIP analog of the claimed invention comprises the following sequence: wherein X. X. X, X and X are f3-amino acid residues derived from the naturally occurring C-amino acid residue at that position. In some embodiments, at least one of the B-amino acid residues is substituted with a residue chosen HSDAVFXX2NYTRLR XOXAXXX,YLNXIXXo from the following: (S,S)-trans-2-aminocyclopentanecar wherein any one of X1,X2, Xs, X, Xs, X. X7, Xs, Xo, or Xo boxylic acid (S,S)-ACPC), (S,R)-trans-2-aminocyclopen is a f-amino acid residue. In some embodiments, at least one tanecarboxylic acid (S,R)-ACPC), (R.S)-trans-2-aminocy of the Bi-amino acid residues is substituted with a residue clopentanecarboxylic acid ((R.S)-ACPC), or (R,R)-trans-2- chosen from the following: (S,S)-trans-2-aminocyclopentan aminocyclopentanecarboxylic acid ((R,R)-ACPC) if the ecarboxylic acid ((S,S)-ACPC), (S,R)-trans-2-aminocyclo amino acid is non-polar, or pyrrolidine analogue of (S,S)- pentanecarboxylic acid (S,R)-ACPC), (R.S)-trans-2-ami ACPC, (R.S)-ACPC, (S,R)-ACPC, (R,R)-ACPC), which is nocyclopentanecarboxylic acid ((R.S)-ACPC), or (R,R)- designated APC, if the amino acid is basic. In some embodi trans-2-aminocyclopentanecarboxylic acid (R,R)-ACPC) if ments, at least one of the f-amino acid residues is substituted the amino acid is non-polar; or pyrrolidine analogue of (S,S)- with a residue chosen from the following: (S,S)-trans-2-ami ACPC, (R.S)-ACPC, (S,R)-ACPC, (R,R)-ACPC), which is nocyclopentanecarboxylic acid (S,S)-ACPC) if the amino designated APC, if the amino acid is basic. In some embodi acid is non-polar; or pyrrolidine analogue of (S,S)-ACPC if ments, at least one of the f-amino acid residues is substituted the residue is basic. with a residue chosen from the following: (S,S)-trans-2-ami 0551. In some embodiments, the VIP analog of the nocyclopentanecarboxylic acid (S,S)-ACPC) if the amino claimed invention comprises the following sequence: acid is non-polar; or pyrrolidine analogue of (S,S)-ACPC if the residue is basic. 0549. In some embodiments, the VIP analog of the claimed invention comprises the following sequence: wherein at least one of X1, X2, Xs, X, Xs, X. X7, Xs, Xo, Xo, X, X, or X is a beta-amino acid, and wherein X-T: HSDAVFXXNYTRLR XOXAXXX,YLNXIXXo X-D: X-R or K; XM or L: X. A or V: X-R or K: X-R or K; X =S or A: X-L or K; and X=N or K. In US 2013/0096050 A1 Apr. 18, 2013

some embodiments, the VIP analog of the claimed invention trans-2-aminocyclopentanecarboxylic acid (S,S)-ACPC), comprises the following sequence: (S,R)-trans-2-aminocyclopentanecarboxylic acid (S,R)- ACPC), (R.S)-trans-2-aminocyclopentanecarboxylic acid ((R.S)-ACPC), or (R,R)-trans-2-aminocyclopentanecar boxylic acid (R,R)-ACPC) if the amino acid is non-polar; or wherein at least one of X1, X2, Xs, X, Xs, X. X7, Xs, Xo, pyrrolidine analogue of (S,S)-ACPC, (R.S)-ACPC, (S,R)- Xo, X1,X2, or Xis is a f-amino acid residue, and wherein ACPC, (R,R)-ACPC), which is designated APC, if the amino X=TXD;Xs=R or K: X-Mor LXs=A or V:X-R or K: acid is basic. In some embodiments, at least one of the X-R or K; X =S or A: X-L or K; and X=N or K. In Bi-amino acid residues is substituted with a residue chosen Some embodiments, at least one of the f-amino acid residues from the following: (S,S)-trans-2-aminocyclopentanecar is substituted with a residue chosen from the following: (S,S)- boxylic acid (S,S)-ACPC) if the amino acid is non-polar; or trans-2-aminocyclopentanecarboxylic acid (S,S)-ACPC), pyrrolidine analogue of (S,S)-ACPC if the residue is basic. (S,R)-trans-2-aminocyclopentanecarboxylic acid (S,R)- 0554. In some embodiments, the VIP analog of the ACPC), (R.S)-trans-2-aminocyclopentanecarboxylic acid claimed invention comprises at least 17% f-amino acid resi ((R.S)-ACPC), or (R,R)-trans-2-aminocyclopentanecar dues. In some embodiments, the VIP analog of the claimed boxylic acid (R,R)-ACPC) if the amino acid is non-polar; or invention comprises from about 15% to about 30% B-amino pyrrolidine analogue of (S,S)-ACPC, (R.S)-ACPC, (S,R)- acid residues. In some embodiments, the VIP analog of the ACPC, (R,R)-ACPC), which is designated APC, if the amino claimed invention comprises from about 15% to about 30% acid is basic. In some embodiments, at least one of the B-amino acid residues wherein the first ten amino acids of the Bi-amino acid residues is substituted with a residue chosen amino acid sequence are alpha amino acids. In some embodi from the following: (S,S)-trans-2-aminocyclopentanecar ments, the VIP analog of the claimed invention comprises boxylic acid (S,S)-ACPC) if the amino acid is non-polar; or from about 16% to about 29% B-amino acid residues. In some pyrrolidine analogue of (S,S)-ACPC if the residue is basic. embodiments, the VIP analog of the claimed invention com 0552. In some embodiments, the VIP analog of the prises from about 17% to about 29% -amino acid residues. claimed invention comprises the following sequence: In some embodiments, the VIP analog of the claimed inven tion comprises from about 18% to about 29% B-amino acid residues. In some embodiments, the VIP analog of the claimed invention comprises from about 19% to about 29% wherein X1,X2, X, XXs, XX-7,Xs are non-natural amino B-amino acid residues. In some embodiments, the VIP analog acids and wherein the underlined residues are B-amino acid of the claimed invention comprises from about 20% to about residues. In some embodiments, the VIP analog of the 29% -amino acid residues. claimed invention comprises the following sequence: 0555. In some embodiments, the VIP analog of the claimed invention comprises B-amino acid residues at residue positions 11, 14, 18, 21, and 25 of HSDAVFTDNYTRL RKOMAVKKYLNSILN. In some embodiments, the VIP analog of the claimed invention comprises B-amino acid resi wherein X1,X2, Xs, X, Xs, X, X7, Xs are non-natural amino dues at positions 11, 14, 18, 21, and 25 of HSDAVFTDNY acids and wherein the underlined residues are (3-amino acid TRLRKQMAVKKYLNSILN, wherein the position 11 is residues. In some embodiments, at least one of the f-amino f3-homothreonine, position 14 is f-homoarginine, position acid residues is substituted with a residue chosen from the 18 is f-homoalanine, position 21 is f-homolysine, and following: (S,S)-trans-2-aminocyclopentanecarboxylic acid position 25 is f-homoserine. In some embodiments, at least ((S,S)-ACPC), (S,R)-trans-2-aminocyclopentanecarboxylic one of the Bi-amino acid residues is substituted with a residue acid (S,R)-ACPC), (R.S)-trans-2-aminocyclopentanecar chosen from the following: (S,S)-trans-2-aminocyclopentan boxylic acid ((R.S)-ACPC), or (R,R)-trans-2-aminocyclo ecarboxylic acid ((S,S)-ACPC), (S,R)-trans-2-aminocyclo pentanecarboxylic acid (R,R)-ACPC) if the amino acid is pentanecarboxylic acid (S,R)-ACPC), (R.S)-trans-2-ami non-polar; or pyrrolidine analogue of (S,S)-ACPC, (R.S)- nocyclopentanecarboxylic acid (R.S)-ACPC), or (R,R)- ACPC, (S,R)-ACPC, (R,R)-ACPC), which is designated trans-2-aminocyclopentanecarboxylic acid ((R,R)-ACPC) if APC, if the amino acid is basic. In some embodiments, at least the amino acid is non-polar, or pyrrolidine analogue of (S,S)- one of the Bi-amino acid residues is substituted with a residue ACPC, (R.S)-ACPC, (S,R)-ACPC, (R,R)-ACPC), which is chosen from the following: (S,S)-trans-2-aminocyclopentan designated APC, if the amino acid is basic. In some embodi ecarboxylic acid (S,S)-ACPC) if the amino acid is non-polar; ments, at least one of the f-amino acid residues is substituted or pyrrolidine analogue of (S,S)-ACPC if the residue is basic. with a residue chosen from the following: (S,S)-trans-2-ami 0553. In some embodiments, the VIP analog of the nocyclopentanecarboxylic acid (S,S)-ACPC) if the amino claimed invention comprises the following sequence: acid is non-polar; or pyrrolidine analogue of (S,S)-ACPC if the residue is basic. (OMe) TOrnLRAib QLUAAib ornYLOS IOrnOrn. 0556. In some embodiments, the VIP analog of the claimed invention comprises the following sequence: wherein Orn-ornithine, Y(OMe)-O-methylated Tyrosine, Aib-C.-aminoisobutyric acid, U-aminobutyric acid (i.e., side chain ethyl), and wherein each underlined position is a B-amino acid residue. In some embodiments at least one of the f-amino acid residue are (3-amino acid residues. In some wherein X, X2, X, X and Xs are B-amino acid residues and embodiments, at least one of the f-amino acid residues is wherein all other C.-amino residues are naturally-occurring or substituted with a residue chosen from the following: (S,S)- non-naturally occurring amino acid residues. In some US 2013/0096050 A1 Apr. 18, 2013 64 embodiments, the VIP analog of the claimed invention com wherein each underlined residue is: a B-homoamino acid prises the following sequence: residue; or, if a non-polar (e.g., A., V), the underlined residues is/are (S,S)-trans-2-aminocyclopentanecarboxylic acid (S, S)-ACPC); or, if the underlined position is basic, (such as Lys HSDAVFTDNY XRL XKQL XVK XYLN XIXX7 or Arg), the underlined residue is a pyrrolidine analogue of (S,S)-ACPC, which is designated APC. (Note: Ac-acetyl: wherein X, X, X, X, Xs, X, and X, are f3-amino acid N'-norleucine; K*-D* indicates that the side chains of these residues and wherein all other amino acids are C.-amino resi two residues are linked via an amide bond.) In some embodi dues are naturally-occurring or non-naturally occurring ments, the sidechains of Kand Dare not linked via any bond. amino acid residues. In some embodiments, the VIP analog of 0559 a?b-Peptide analogues will be synthesized: the claimed invention comprises the following sequence: Ac-HSDAV FTENY TKLRK QNAVK Ke YLND* LKKGG T HSDAVFTDNY XRL XKQL XVK XYLN XIXX7 Ac-HSDAV FTENY TKLRK QNAVK Krk YLND* LKKGGT wherein X, X2, Xs, X, and Xs are B-amino acid residues; wherein X is a beta amino acid, or an alpha-leucine, and Ac-HSDAV FTENY TKLRK QNAVK Krk YLND+ LKKGG T wherein X7 is an beta amino acid oran alpha-asparagine; and Ac-HSDAV FTENY TKLRK QNAVK KYLND* LKKGG T wherein all other amino acids are C-amino residues are natu rally-occurring or non-naturally occurring amino acid resi Ac-HSDAV FTENY TKLRK QNAVK Krk YLND* LKKGG T dues. Ac-HSDAV FTENY TKLRK QN'AvK KYLND* LKKGG T 0557. In some embodiments, the composition of the claimed invention comprises a VIP analog that is up to 75%, Ac-HSDAV FTENY TKLRK QNAVK Krk YLND* LKKGG T 80%, 85%, 90%. 95%, or 99% homologous to the following Ac-HSDAV FTENY TKLRK RNAAK NYLNN LKKGG T Sequence: Ac-HSDAV FTENY TKLRK RNAAK NYLNN LKKGG T

HSDAVFTDNY XRL XKQL XVK XYLN XIXX7 Ac-HSDAV FTENY TKLRK RNAAK NYLNN LKKGG T wherein X, X, X, X, and Xs are f3-amino acid residues; Ac-HSDAV FTENY TKLRK RNAAK NYLNN LKKGG T wherein X is a beta amino acid, or an alpha-leucine, and wherein X7 is an beta amino acid or an alpha-asparagine Ac-HSDAV FTENY TKLRK RNAAK NYLNN LKKGG T 0558. In some embodiments, the VIP analog comprises a Ac-HSDAV FTENY TKLRK RNAAK NYLNN LKKGG T cyclic amino acid residue covalently bonded to one or more contiguous or non-contiguous amino acid sidechain residues Ac-HSDAV FTENY TKLRK RNAAK NYLNN LKKGG T via a lactam ring. In some embodiments, the VIP analog wherein each underlined residue is: a B-homoamino acid comprises a cyclic amino acid residue covalently bonded to residue; or, if a non-polar (e.g., A.V), the underlined positions one or more contiguous or non-contiguous amino acid will be replaced by (S,S)-trans-2-aminocyclopentanecar boxylic acid ((S,S)-ACPC); or if the underlined residue is sidechain residues via an amide bond. In some embodiments, basic, (such as Lys or Arg), the underlined residue is/are the the VIP analog of the claimed invention comprises one of the pyrrolidine analogue of (S,S)-ACPC, which is designated following sequences: APC; and wherein Ac-acetyl; N'-norleucine; K*-D* indi cates that the side chains of these two residues are linked via an amide bond. In some embodiments, the sidechains of K HSDAV FTDNY ARLRK QMAVK KA NS ILA and Dare not linked via any bond. In some embodiments, the VIP analog comprises a cyclic amino acid residue covalently HSDAV FTDNY ARLRK QMAVK KALNS ILA bonded to one or more contiguous or non-contiguous amino HSDAV FTDNY ARLRK QMAVK LNS ILA acid sidechain residues via the following synthetic linking Structures: HSDAV FTDNY ARLRK QMAVK KA NS ILA HSDAV FTDNY ARLRKQ MAVK KA NS LA.

HSDAV FTDNY ARLRKO MAVK NS LA. / HSDAV FTDNY ARLRKO MAVK KA NS I A. NRN HADAV FTAAY ARLRK QMAAK KA AA IAA HADAV FTAAY ARLRK QMAAK KA a NN HADAW FTAAY ARL R QMAAK KALAA IAA / K NFN HADAV FTAAY ARLRK QMAAK KALAA IAA HADAV FTAAY ARLRKQ MAAK KALAA IAA HADAV FTAAY ARLRKO MAAK KALAA IAA

HADAV FTAAY ARLRKQ MAAK KALAA IAA NRN

US 2013/0096050 A1 Apr. 18, 2013 66

-continued -continued

NRN

US 2013/0096050 A1 Apr. 18, 2013 68

-continued -continued

2 N -> NFN/ N N US 2013/0096050 A1 Apr. 18, 2013 69

-continued -continued

N N

0560. In some embodiments, the analog does not comprise a cyclic Substituent in its side chain. In some embodiments, NRN the cyclic amino acid residues are not covalently bonded to one or more contiguous or non-contiguous amino acid sidechain residues via the following synthetic linking struc- N tures: N NRN

2 7. 2 N Us A. NRN NE a NN --~7. \= NRN

2 / ~x. a NN --7- NRN / NFN

a NNF 4N --- NFN f NRN US 2013/0096050 A1 Apr. 18, 2013 70

-continued -continued US 2013/0096050 A1 Apr. 18, 2013 71

-continued -continued

f NRN

A- \ N NRN

<-f US 2013/0096050 A1 Apr. 18, 2013 72

-continued -continued

frkN N E N Us N N N E N

N

N E N - N I f N E N \r-uk - P N

U N N E N

f Y,N E N

N

N E N US 2013/0096050 A1 Apr. 18, 2013 73

-continued -continued

NRN/ \ 1N V NFN

^- N N a N NRN f NRN

1N / \NRN a N - NRN 2 N / NRN

1N V NRN 1N \ NRN

a NN NRN 4N C. A / NRN 1N \ -K NRN V1N 0561. In some embodiments, the analogs of the present NFN invention comprise at least one or a plurality of the following cyclic amino acid residues, some of which being described US 2013/0096050 A1 Apr. 18, 2013 74 with a protecting group that becomes eliminated from the Some embodiment of the invention the polypeptides or frag analog either during synthesis or when the analog is purified ments thereofmay comprise one or more PEGylated residues after synthesis: in either or both sequences. 0562 L-3-HomohydroxyProline hydrochloride 0590. In some embodiments, the analog or fragment 0563 (1R,2R)-Boc-2-aminocyclohexane carboxylic acid thereof comprises a PEG molecule covalently attached to one {(1R,2R)-ACHC} or all of the n-residue within the analog. In some embodi 0564 (1R,2R)-Fmoc-2-aminocyclohexane carboxylic ments, the analog is at least one PEG molecule covalently acid (1R,2R)-ACHC} attached to a residue in the C-terminal extension of the analog 0565 (1R,2S)-Boc-2-aminocyclohexane carboxylic acid or fragment thereof. In some embodiments, the analog com {(1R,2S)-ACHC} prises more than one PEG molecule, there may be a combi 0566 (1R,2S)-Fmoc-2-aminocyclohexane carboxylic nation of Lys, Cys, K(CO(CH)SH), K(W) and carboxy acid (1R,2S)-ACHC} terminal amino acid PEGylation. For example, if there are 0567 (1S,2R)-Boc-2-aminocyclohexane carboxylic acid two PEG molecules, one may be attached to a Lys residue and {(1S,2R)-ACHC} one may be attached to a Cys residue. In some embodiments, 0568 (1S,2R)-Fmoc-2-aminocyclohexane carboxylic the polypeptide comprises one or more covalently bound acid (1S,2R)-ACHC} PEG molecules, wherein at least one of the PEG molecules is 0569 (1S,2S)-Boc-2-aminocyclohexane carboxylic acid branched. In some embodiments, one or more of the PEG {(1S,2S)-ACHC} molecules are linear. In some embodiments, the composition 0570 (1S,2S)-Fmoc-2-aminocyclohexane carboxylic comprises one or more PEG molecule, wherein the PEG acid (1S,2S)-ACHC} molecule is between about 200 daltons and about 100,000 0571 (1R,2R)-Boc-2-aminocyclopentane carboxylic acid daltons in molecular weight. In some embodiments, the PEG {(1R,2R)-ACPC} molecule is chosen from 10,000, 20,000, 30,000, 40,000, 0572 (1R,2R)-Fmoc-2-aminocyclopentane carboxylic 50,000 and 60,000 daltons. In some embodiments, it is cho acid (1R,2R)-ACPC} sen from 20,000, 30,000, 40,000, or 60,000 daltons. Where 0573 (1S,2S)-Boc-2-aminocyclopentane carboxylic acid there are two PEG molecules covalently attached to the ana {(1S,2S)-ACPC} log or fragment thereof, each is 1,000 to 40,000 daltons and, 0574 (1S,2S)-Fmoc-2-aminocyclopentane carboxylic they have molecular weights of 20,000 and 20,000 daltons, acid (1S,2S)-ACPC 10,000 and 30,000 daltons, 30,000 and 30,000 daltons, or 0575 Boc-cis-2-aminocyclopentane carboxylic acid, cis 20,000 and 40,000 daltons. In some embodiments mini-PEG Acpc sTM are covalently bound to at least one residue or side chain 0576 Fmoc-cis-2-aminocyclopentane carboxylic acid, of an a, or 3-amino acid. In some embodiments, the mini cis-Acpc PEGTM is chosen from the following list of products: 0577 (R)-Boc-(2-carboxymethyl)-piperidine, (R)-(1-pip 8-Amino-3,6-Dioxaoctanoic Acid, 11-Amino-3,6,9-Triox eridin-2-yl)-acetic acid aundecanoic Acid, 8-Amino-3,6-Dioxaoctanoic 0578 (R)-Fmoc-(2-carboxymethyl)-piperidine, (R)-(1- Acid DCHA, 11-Amino-3,6,9-Trioxaundecanoic Fmoc-piperidin-2-yl)-acetic acid Acid DCHA. 0579 (S)-Boc-(2-carboxymethyl)-piperidine (S)-(1-Boc 0591. In some embodiments the method of treatment or piperidin-2-yl)-acetic acid prevention of a human disorder depends upon the analog 0580 (S)-Fmoc-(2-carboxymethyl)-piperidine (S)-(1- being synthesized. For instance: Peptides for triggering Band Fmoc-piperidin-2-yl)-acetic acid T cell activity can be used to treat autoimmune disease, 0581 (R.S)-Boc-2-carboxymorpholine Boc-Cop including uveitis, collagen-induced, adjuvant and rheumatoid 0582 (R.S)-Boc-2-carboxymorpholine Fmoc-Cop arthritis, thyroiditis, myasthenia gravis, multiple Sclerosis 0583 (R.S)-Boc-nipecotic acid Boc-Nip and diabetes. Examples of these peptides are interleukins 0584 (R.S)-Boc-nipecotic acid Fmoc-Nip (referenced in Aulitzky, WE: Schuler,M; Peschel, C.: Huber, 0585 (R)-Fmoc-nipecotic acid (R)-Fmoc-Nip C.; Interleukins. Clinical pharmacology and therapeutic use. 0586 (R)-Fmoc-nipecotic acid (R)-Boc-Nip Drugs. 48(5):667-77, November 1994) and cytokines (refer 0587 (3S)-Boc-1-pyrrolidine-3-carboxylic acid (3S)- enced in Peters, M.: Actions of cytokines on the immune Boc-beta-Pro-OH response and viral interactions: an overview. Hepatology. 0588 (3S)-Fmoc-1-pyrrolidine-3-carboxylic acid (3S)- 23(4):909-16, April 1996). Fmoc-beta-Pro-OH 0592 Enkephlin analogs, agonist analogs and antagonist 0589. In some embodiments, the analogs of the present analogs can be used to treat AIDS, ARC, and cancer, pain invention comprise at least one or a plurality of non-natural modulation, Huntington's, Parkinson's diseases. amino acid residues that can modified by PEGylation. In Some embodiments the analogs or fragments of the polypep 0593 LHRH and analogs, agonists and antagonists can be tides related to this invention comprise PEG molecules which used to treat prostatic tumors and reproductive physiopathol are covalently bound to the side chain of the C, or B amino ogy, including breast cancer, and infertility. acids in the polypeptide. In some embodiments, the polypep 0594 Peptides and peptidomimetics that target crucial tides of this invention comprise the PEGylated cyclic amino enzymes, oncogenes or oncogene products, tumor-suppres acid residues or cyclic amino acid side chains. PEG molecule sor genes and their products, growth factors and their corre (s) may be covalently attached to any Lys, Cys, K(W) or sponding receptors can be used to treat cancer. Examples of K(CO(CH2)SH) residue at any position in the analog or these peptides are described in Unger, C. Current concepts of fragment of analog. In some embodiments, the analog or a treatment in medical oncology: new anticancer drugs. Journal fragment thereof comprises a C-terminal extension may com of Cancer Research & Clinical Oncology. 122(4): 189-98, prise one or more Cys residues which may be PEGylated. In 1996. US 2013/0096050 A1 Apr. 18, 2013

0595 Neuropeptide Y and other pancreatic polypeptides, 0605 Peptide based antivirals can be used to treat viral and analogs, agonists and antagonists can be used to treat diseases. Examples of these peptides are described in Toes, R. stress, anxiety, neurodegernative diseases, depression and E.; Feltkamp, M.C.; Ressing, M. E.; Vierboom, M. P.; Blom, associated vasoconstrictive activities. R. J.; Brandt, R. M.; Hartman, M.: Offringa, R.; Melief, C.J.; 0596) Gluco-incretins, including gastric inhibitory Kast, W. M.: Cellular immunity against DNA tumour viruses: polypeptide, glucose-dependent insulinotropic polypeptide, possibilities for peptide-based vaccines and immune escape. PACAP/Glucagon and glucagon-like polypeptide-1 and 2 Biochemical Society Transactions. 23(3):692-6, 1995. and analogs, agonists and antagonists can be used to treat 0606 Corticotropin releasing factor and peptide analogs, Type II diabetic hyperglycaemia. Atrial natriuretic factor and agonist analogs and antagonist analogs can be used to treat analogs, agonists and antagonists can be used to treat conges disease associated with high CRF, i.e Alzheimer's disease, tive heart failure. anorexia nervosa, depressive disorders, arthritis, and multiple 0597 Integrin and analogs, agonists and antagonists can Sclerosis. be used to treat osteoporosis, Scarformation, bone synthesis, 0607 Peptide agonist analogs and antagonist analogs of inhibition of vascular occlusion, and inhibition of tumor inva platelet-derived wound-healing formula (PDWHF) can be sion and metastasis. used as a therapy for donor tissue limitations and wound 0598. Glucagon, glucagon-like peptide 1, PACAP/Gluca healing constraints in Surgery. Examples of these peptides are gon, and analogs, agonists and antagonists can be used to treat described in Rudkin, G. H.; Miller, T. A.; Growth factors in diabetes cardiovascular emergencies. surgery. Plastic & Reconstructive Surgery. 97(2):469-76, 0599 Antithrombotic peptides and analogs, agonists and 1996. Fibronectin, fibrinopeptide inhibitors and analogs, ago antagonists can be used to treat cardiovascular and cere nists and antagonists can be used to treat metastasis (i.e. brovascular diseases. Examples of these peptides RGD, enzyme inhibition, tumor cell migration, invasion, and D-Phe-Pro-Arg and others named are described in Ojima I.: metastasis). Chakravarty S.; Dong Q. Antithrombotic agents: from ROD 0608 Chemokine (types of cytokine, including interleu to peptide mimetics. Bioorganic & Medicinal Chemistry. kin-8, RANTES, and monocyte chemotactic peptide) ana 3(4):337-60, 1995. logs, agonist analogs and antagonist analogs can be used to 0600 Cytokines/interleukins and analogs, agonists and treat arthritis, hypersensitivity, angiogenesis, renal disease, antagonists can be used to treat inflammatory disease, glomerulonephritis, inflammation, and hematopoiesis. immune response dysfunction, hematopoiesis, mycosis fun 0609 Neutral endopeptidase inhibitors analogs, agonist goides, aplastic anemia, thrombocytopenia, and malignant analogs and antagonist analogs can be used to treat hyperten melanoma. Examples of these peptides are Interleukins, ref sion and inflammation. Examples of these peptides are erenced in Aulitzky et al. and Peters et al., which is herein described in Gregoire, J. R. Sheps, S. G: Newer antihyper incorporated by reference. tensive drugs. Current Opinion in Cardiology. 10(5):445-9. 0601 Endothelin and analogs, agonists and antagonists 1995. can be used to treat arterial hypertension, myocardial infarc 0610 Substance Panalogs, agonistanalogs and antagonist tion, congestive heart failure, atherosclerosis, shock condi analogs can be used to treat immune system dysfunction, pain tions, renal failure, asthma and vasospasm Natriuretic hor transmission/perception and in autonomic reflexes and mones and analogs, agonists and antagonists can be used to behaviors. Alpha-melanocyte-stimulating hormone analogs, treat cardiovascular disease and acute renal failure. Examples agonist analogs and antagonist analogs can be used to treat of these peptides are named and described in Espiner, E. A. AIDS, rheumatoid arthritis, and myocardial infarction. Richards, A. M.; Yandle, T. G.; Nicholls, M. G.; Natriuretic 0611 Bradykinin (BK) analogs, agonist analogs and hormones. Endocrinology & Metabolism Clinics of North antagonist analogs can be used to treat inflammatory diseases America. 24(3):481-509, 1995. (edema, etc), asthma, allergic reactions (rhinitis, etc), anes 0602 Peptides that activate or inhibit tyrosine kinase, or thetic uses, and septic shock. bind to TK-activating or inhibiting peptides and analogs, 0612 Secretin analogs can be used to treat cardiovascular agonists and antagonists can be used to treat chronic myel emergencies. ogenous and acute lymphocytic leukemias, breast and ova 0613 GnRH analogs, agonist analogs and antagonistana rian cancers and other tyrosine kinase associated diseases. logs can be used to treat hormone-dependent breast and pros Examples of these peptides are described in Smithgall, T E.; tate tumors. SH2 and SH3 domains: potential targets for anti-cancer drug 0614 Somatostatin analogs, agonist analogs and antago design. Journal of Pharmacological & Toxicological Meth nist analogs can be used to treat gut neuroendocrine tumors. ods. 34(3):125-32, 1995. 0615 Gastrin, Gastrin Releasing Peptide analogs, agonist 0603 Renin inhibitors analogs, agonists and antagonists analogs and antagonist analogs can be used as an adjuvant to can be used to treat cardiovascular disease, including hyper chemotherapy or Surgery in Small cell lung cancer and other tension and congestive heart failure. Examples of these pep malignancies, or to treat allergic respiratory diseases, asthma tides are described in Rosenberg, S. H.; Renin inhibition. and allergic rhinitis. Cardiovascular Drugs & Therapy.9(5):645-55, 1995. 0616 Laminin analogs, agonist analogs and antagonist 0604 Angiotensin-converting enzyme inhibitors, ana analogs, the Laminin derivative antimetastatic drug YIGSR logs, agonists and antagonists can be used to treat cardiovas analogs, Laminin-derived synthetic peptides analogs, agonist cular disease, including hypertension and congestive heart analogs and antagonist analogs can be used to treat tumor cell failure. Peptides that activate or inhibit tyrosine phosphory growth, angiogenesis, regeneration studies, vascularization lases can be used to treat cardiovascular diseases. Examples of the eye with diabetes, and ischemia. The peptides of this of these peptides are described in Srivastava, A. K.; Protein category can inhibit the tumor growth and metastasis of leu tyrosine phosphorylation in cardiovascular system. Molecu kemic cells and may be useful as a potential therapeutic lar & Cellular Biochemistry. 149-150:87–94, 1995. reagent for leukaemic infiltrations. Peptides containing this US 2013/0096050 A1 Apr. 18, 2013 76 sequence also inhibit experimental metastasis. Exemplary 0627 Peptide immunogens for prevention of HIV-1 and references include McGowan K.A. Marinkovich MP Lami HTLV-I retroviral infections can be used to treat AIDS. nins and human disease. Microscopy Research & Technique. Examples of these peptides are described in Hart, M. K.: 51(3):262-79, Nov. 1, 2000: Yoshida N. Ishii E. Nomizu M. Palker, T. J.; Haynes, B. F. Design of experimental synthetic Yamada Y. Mohri S. Kinukawa N. Matsuzaki A. Oshima K. peptide immunogens for prevention of HIV-1 and HTLV-I Hara T. Miyazaki S. The laminin-derived peptide YIGSR retroviral infections. Pharmaceutical Biotechnology. 6:821 (Tyr-Ile-Gly-Ser-Arg) inhibits human pre-Bleukaemic cell 45, 1995. growth and dissemination to organs in SCID mice. British 0628 Galanin analogs, agonist analogs and antagonist Journal of Cancer. 80(12): 1898-904, 1999. Examples of analogs can be used to treat Alzheimer's disease, depression, these peptides are also described in Kleinman, H. K. Weeks, eating disorders, chronic pain, prevention of ischemic dam B. S.; Schnaper, H. W.; Kibbey, M.C.; Yamamura, K.; Grant, age, and growth hormone modulation. D. S. The laminins: a family of basement membrane glyco 0629 Tachykinins (neurokinin A and neurokinin B) ana proteins important in cell differentiation and tumor logs, agonist analogs and antagonist analogs can be used to metastases. Vitamins & Hormones. 47:161-86, 1993. treat pain transmission/perception and in autonomic reflexes 0.617 Defensins, corticostatins, dermaseptins, mangain and behaviors. ins, and otherantibiotic (antibacterial and antimicrobial) pep 0630 RGD containing peptide analogs can be used to treat tides analogs, agonist analogs and antagonist analogs can be various diseases involved with cell adhesion, antithrombot used to treat infections, tissue inflammation and endocrine ics, and acute renal failure. regulation. 0631 Osteogenic growth peptide analogs, agonist analogs 0618. Vasopressin analogs, agonist analogs and antagonist and antagonist analogs can be used as treatment of systemic analogs can be used to treat neurological disorders, stress and bone loss. Examples of these peptides are described in Bab Diabetes insipidus. IA. Regulatory role of osteogenic growth peptide in prolif 0619. Oxytocin analogs, agonist analogs and antagonist eration, osteogenesis, and hemopoiesis. Clinical Ortho analogs can be used to treat neurological disorders and to paedics & Related Research. (313):64-8, 1995. induce labor. 0632 Parathyroid hormone, parathyroid hormone related 0620 ACTH-related peptides and analogs, agonist ana peptide analogs, agonist analogs and antagonist analogs can logs and antagonist analogs can be used as neurotrophic, be used to treat diseases affecting calcium homeostasis (hy neuroprotective, and peripheral demyelinating neuropathy percalcemia), bone metabolism, vascular disease, and athero agents. Amyloid-beta peptide analogs, agonist analogs and Sclerosis. antagonist analogs can be used to treat Alzheimer's disease. 0633 Kallidin analogs, agonist analogs and antagonist 0621 Epidermal growth factor, receptor analogs, agonist analogs can be used to treat tissue injury or inflammation and analogs and antagonist analogs can be used to treat necrotiz pain signaling pathological conditions of the CNS. ing enterocolitis, Zollinger-Ellison syndrome, gastrointesti 0634 T cell receptor peptide analogs, agonist analogs and nal ulceration, colitis, and congenital microVillus atrophycar antagonist analogs can be used in immunotherapy. Examples cinomas. of these peptides are described in Brostoff, SW; T cell recep 0622 Leukocyte adhesion molecule analogs, agonistana torpeptide vaccines as immunotherapy. Agents & Actions— logs and antagonist analogs can be used to treat atheroscle Supplements. 47:53-8, 1995. rosis, inflammation. Examples of these peptides are described 0635 Platelet-derived growth factor (PDGF) analogs, in Barker, J. N., Adhesion molecules in cutaneous inflamma agonist analogs and antagonist analogs can be used to treat tion. Ciba Foundation Symposium. 189:91-101. non-neoplastic hyperproliferative disorders, therapy for 0623 Major histocompatibility complex (MUG) analogs, donor tissue limitations and wound-healing constraints in agonist analogs and antagonist analogs can be used to treat Surgery. autoimmune, immunodysfunctional, immuno modulatory 0636 Amylin, calcitonin gene related peptides (CGRP) diseases and as well as used for their corresponding therapies. analogs, agonist analogs and antagonist analogs can be used Examples of these peptides are described in Appella, E.; to treat insulin-dependent diabetes. Padlan, E. A.; Hunt, D. F.; Analysis of the structure of natu 0637 VIP analogs, agonist analogs and antagonist ana rally processed peptides bound by class I and class II major logs can be used to treat allergic respiratory diseases, asthma histocompatibility complex molecules. EXS. 73:105-19. and allergic rhinitis, and nervous control of reproductive 1995. functions. 0624 Corticotropin releasing factor analogs can be used 0638 Growth hormone-releasing hormone (GHRH) ana to treat neurological disorders. logs, agonist analogs and antagonist analogs can be used to 0625 Neurotrophins (including brain-derived neu treat growth hormone deficiency and immunomodulation. rotrophic factor (BDNF), nerve growth factor, and neurotro 0639 HIV protease inhibiting peptide analogs, agonist phin 3) analogs, agonist analogs and antagonist analogs can analogs and antagonist analogs can be used to treat AIDS. be used to treat neurological disorders. Examples of these peptides are described in Bugelski, P. J.; 0626 Cytotoxic T-cell activating peptide analogs, agonist Kirsh, R.; Hart, T.K; HIV protease inhibitors: effects on viral analogs and antagonist analogs can be used to treat infectious maturation and physiologic function in macrophages. Journal diseases and cancer. Examples of these peptides are described of Leukocyte Biology. 56(3):374-80, 1994. in: Chesnut R. W.; Sette, A.: Cells, E.; Wentworth, P.; Kubo, 0640 Thymopoietin active fragment peptides analogs, R. T.; Alexander, J.; Ishioka, G.; Vitiello, A.; Grey, H. M: agonist analogs and antagonist analogs can be used to treat Design and testing of peptide-based cytotoxic T-cell-medi rheumatoid arthritis and virus infections. ated immunotherapeutics to treat infectious diseases and can 0641 Cecropins analogs, agonist analogs and antagonist cer. Pharmaceutical Biotechnology. 6:847-74, 1995. analogs can be used as antibacterials. US 2013/0096050 A1 Apr. 18, 2013 77

0642 Thyroid releasing hormone (TRH) analogs, agonist 0658 Bestatin analogs, agonist analogs and antagonist analogs and antagonist analogs can be used to treat spinal analogs can be used to treat muscular dystrophy, anticancer, cord injury and shock. antileukemia, immune response modulator, and acute non 0643) Erythropoietin (EPO) analogs, agonist analogs and lymphocytic leukemia. antagonist analogs can be used to treat anemia. 0659 Leupeptin analogs, agonist analogs and antagonist 0644 Fibroblast growth factor (FGF), receptor analogs, analogs can be used as a protease inhibitor, exact role in agonist analogs and antagonist analogs can be as stimulation diseases not determined yet. of bone formation, as well as used as a treatment for Kaposi's 0660 Luteinizing hormone and releasing hormone ana sarcoma, neuron regeneration, prostate growth, tumor growth logs, agonist analogs and antagonist analogs can be used as a inhibition, and angiogenesis. infertility male contraceptive. 0.645 Stem cell factor analogs, agonist analogs and 0661 Neurotensin analogs, agonist analogs and antago antagonist analogs can be used to treat anemias. GP120, nist analogs can be used, e.g., as antipsychotic, analgesic, GP160, CD4 fragment peptides analogs, agonist analogs and anti-cancer, and/or neuroprotective agents, e.g., for treating antagonist analogs can be used to treat HIV and AIDS. stroke victims, e.g., by inducing hypothermia So as to provide 0646. Insulin-like growth factor (IGF) analogs, agonist neuroprotection. analogs and antagonist analogs, and IGF receptor analogs, 0662 Motilin analogs, agonist analogs and antagonist agonist analogs and antagonist analogs can be used to treat analogs can be used for the control of gastric emptying. breast and other cancers, noninsulin-dependent diabetest 0663 Insulin analogs, agonist analogs and antagonistana mellitus, cell proliferation, apoptosis, hematopoiesis, HIV, logs can be used to treat diabetes. AIDS, growth disorders, osteoporosis, and insulin resistance. 0664 Transforming growth factor (TGF) analogs, agonist 0647 Colony stimulating factors (granulocyte-macroph analogs and antagonist analogs can be used for cell prolifera age colony-stimulating factor (GMCSF), granulocyte tion and differentiation, cancer treatment, immunoregulation, colony-stimulating factor (GCSF), and macrophage colony therapy for donor tissue limitations, and wound-healing con stimulating factor (MCSF) analogs, agonist analogs and straints in Surgery. antagonist analogs can be used to treat anemias. 0665 Bone morphogenetic proteins (BMPs) analogs, ago 0648 Kentsin analogs, agonist analogs and antagonist nist analogs and antagonist analogs can be used as therapy for analogs can be used for immunomodulation. donor tissue limitations, osteogenesis, and wound-healing 0649 Lymphocyte activating peptide (LAP) analogs, ago constraints in Surgery. nist analogs and antagonist analogs can be used for immuno 0666 Bombesin and Enterostatin analogs, agonistanalogs modulation. Examples of these peptides are described in and antagonist analogs can be used to prevent the prolifera Loleit, M.: Deres, K.; Wiesmuller, K. H.; Jung, G.; Eckert, tion of tumor cells, modulation of feeding, and neuroendo M.; Bessler, W. G. Biological activity of the Escherichia coli crine functions. These peptides fall within a Supercategory of lipoprotein: detection of novel lymphocyte activating peptide the neuromedins described above. These peptides are segments of the molecule and their conformational charac described in such exemplary references as Yamada K. Wada terization. Biological Chemistry Hoppe-Seyler. 375(6):407 E. Wada K. 12, June 1994. 0667 Bombesin-like peptides: studies on food intake and 0650 Tuftsin analogs, agonist analogs and antagonistana Social behaviour with receptor knock-out mice. Annals of logs can be used for immunomodulation. Medicine. 32(8):519-29, November 2000; Ohki-Hamazaki 0651 Prolactin analogs, agonist analogs and antagonist H. Neuromedin B. Progress in Neurobiology. 62(3):297-312, analogs can be used to treat rheumatic diseases, systemic October 2000; Still CD. Future trends in weight management. lupus erythematosus, and hyperprolactemia. Journal of the American Osteopathic Association.99(10 SuPt 0652 Angiotensin II analogs, agonist analogs and antago 2):S18-9, 1999; MartinezV. Tachey. Bombesin and the brain nist analogs and Angiotensin II receptor(s) analogs, agonist gut axis. Peptides. 21 (11):1617-25, 2000; Afferent signals analogs and antagonist analogs can be used to treat hyperten regulating food intake. Proceedings of the Nutrition Society. Sion, hemodynamic regulation, neurological disorders, dia 59(3):373-84, 2000; Takenaka Y. Nakamura F. Jinsmaa Y. betic nephropathies, aortoarterities induced RVH., hyperal Lipkowski A. W. Yoshikawa M. Enterostatin (VPDPR) has dosteronism, heavy metal induced cardiovascular effects, anti-analgesic and anti-amnesic activities. BioScience Bio diabetes mellitus and thyroid dysfunction. technology & Biochemistry. 65(1):236-8, 2001 J. 0653 Dynorphin analogs, agonist analogs and antagonist 0668 Glucagon, glucagon-like peptide 1 analogs, agonist analogs can be used to treat neurological disorders, pain analogs and antagonist analogs can be used to treat diabetes management, algesia, spinal cord injury and epilepsy. cardiovascular emergencies. 0654 Calcitonin analogs, agonist analogs and antagonist 0669 Pancreastatin, chromogranins A, B and Canalogs, analogs can be used to treat neurological disorders, immune agonist analogs and antagonist analogs—conditions associ system dysfunction, calcium homeostasis, and osteoporosis. ated with inhibition of insulin secretion, exocrine pancreatic 0655 Pituitary adenylate cyclase activating polypeptide secretion and gastric acid secretion, and stimulation of secre analogs, agonist analogs and antagonist analogs may modu tion. late growth, signal transduction vasoactivity roles. 0670) Endorphins analogs, agonist analogs and antagonist 0656 Cholecystokinin analogs, agonist analogs and analogs can be used to treat neurological disorders, alleviat antagonist analogs can be used to treat feeding disorders, ing pain, treatment of opioid abuse, obesity, and diabetes. panic disorders, and anti-opioid properties. Examples of these peptides are named and described in 0657 Pepstatin analogs, agonist analogs and antagonist Dalayeun, J. F.; Nores, J. M.; Bergal, S.; Physiology of beta analogs can be used as pepsin and HIV protease inhibitors endorphins. A close-up view and a review of the literature. (AIDS). Biomedicine & Pharmacotherapy. 47(8):311-20, 1993. US 2013/0096050 A1 Apr. 18, 2013

0671 Miscellaneous opioid peptides analogs, agonistana tin, Orexin, Receptor activity modulating protein, Urotensin) logs and antagonist analogs, including (but not limited to) can be used to treat obesity, weight problems, neuropathy, adrenal peptide E analogs, alpha casein fragment analogs, sleep deprivation, sleep disorder including insomnia, and beta casomorphin analogs, dermorphin analogs, kyotorphin lung cell repair. These orphan receptor ligands are described analogs, metophamide neuropeptide FF (NPFF) analogs, in such references as In DS. Orphan G protein-coupled recep melanocyte inhibiting factor analogs, agonist analogs and tors and beyond. Japanese Journal of Pharmacology. 90(2): antagonistanalogs can be used to treat neurological disorders, 101-6, 2002; Maguire J.J. Discovering orphan receptor func alleviating pain, as well as for the treatment of opioid abuse. tion using human in vitro pharmacology. Current Opinion in 0672 Vasotocin analogs, agonist analogs and antagonist Pharmacology. 3(2): Bs-9, 2003; Szekeres P. G. Functional analogs can be used for sleep disorders including but not assays for identifying ligands at orphan G protein-coupled limited to insomnia. 0673 Protein kinase C and inhibitors analogs, agonist receptors. Receptors & Channels. 8(5-6):297-308, 2002: analogs and antagonist analogs can be used to treat cancer, Shiau A. K. Coward P. Schwarz, M. Lehmann J. M. Orphan apoptosis, Smooth muscle function, and Alzheimer's disease. nuclear receptors: from new ligand discovery technologies to Examples of these peptides are named and described in novel signaling pathways. Current Opinion in Drug Discov Philip, P. A.; Harris, A. L.; Potential for protein kinase C ery & Development. 4(5):575-90, 2001: Civelli 0. Nothacker inhibitors in cancer therapy. Cancer Treatment & Research. H P. Saito Y. Wang Z. Lin S H. Reinscheid R. K. Novel 78:3-27, 1995. neurotransmitters as natural ligands of orphan G-protein 0674 Amyloid, amyloid fibrin, analogs, agonist analogs coupled receptor S. Trends in Neurosciences. 24(4): 230-7. and antagonist analogs can be used to treat neurodegenerative 2001; Darland T. Heinricher M. M. Grandy DK. Orphan in F diseases and diabetes. Q/nociceptin: a role in pain and analgesia, but so much more. 0675 Calpain and other calmodulin-inhibitory protein Trends in Neurosciences. 21 (5):215-21, 1998, the disclosures analogs, agonist analogs and antagonist analogs can be used of which are incorporated herein by reference. to treat neurodegenerative disorders, cerebral ischaemia, 0682 Another embodiment of the invention includes ana cataracts, myocardial ischaemia, muscular dystrophy and logs of Glycoprotein IIb/IIIa inhibitors. The central role of platelet aggregation. platelet-rich thrombus in the pathogenesis of acute coronary 0676 Charybdotoxin and Apamin analogs, agonist ana syndromes (ACSs) is well-known. Glycoprotein IIb/IIIa (Gp logs and antagonist analogs can be used for treatment of IIb/IIIa) receptor analogs, agonist analogs and antagonist neurodegenerative diseases and pain and cerebral ischemia. analogs can be used as potent modulators of platelet function 0677 Phospholipase A2 analogs, agonist analogs and that may be expected to affect favorably the natural history of antagonistanalogs and Phospholipase A2 receptor inhibiting/ ACSs. Exemplary references for this category include Bhatt activating peptides analogs, agonist analogs and antagonist DL. Topol E. J. Current role of platelet glycoprotein IIb/IIIa analogs can be used to treat acute pancreatitis, pancreatic inhibitors in acute coronary syndromes. JAMA. cancer, abdominal trauma, and inflammation, e.g., sepsis, 284(12): 1549-58, 2000; Kereiakes DJ. Oral blockade of the infections, acute pancreatitis, various forms of arthritis, can platelet glycoprotein IIb/IIIa receptor: fact or fancy'?. Ameri cer, complications of pregnancy, and postoperative states. can Heart Journal. 138(1 Pt 2):S39-46, 1999: Bassand J. P. 0678 Potassium channel activating and inhibiting ana Low-molecular-weight heparin and other antithrombotic logs, agonist analogs and antagonist analogs can be used to agents in the setting of a fast-track revascularization in treat various diseases. Examples of these peptides are unstable coronary artery disease. Haemostasis. 30 Suppl described in Edwards, G.; Weston, A.1-1; Pharmacology of 2:114-21; discussion 106-7, 2000. the potassium channel openers. Cardiovascular Drugs & 0683 Apo-lipoprotein A-I analogs, agonist analogs and Therapy. 9 Suppl 2:185-93, March 1995. antagonist analogs may increase the HDL levels of Subjects 0679 IgG activators, inhibitors analogs, agonist analogs upon administration. Analogs of the present invention that are and antagonist analogs can be used to treat autoimmune dis homolgous to Apo-lipoprotein A-I may be useful to treat or eases and immune dysfunctions. Examples of these peptides prevent liver disease and inflammatory diseases including but are described in Mouthon, L.; Kaveri, S. V.; Spalter, S. H.; not limited to artherosclerosis. Analogs of the present inven Lacroix-Desmazes, S.; Lefranc, C. Desai, R.; KaZatchkine, tion that are homolgous to Apo-lipoprotein A-I may be useful M. D: Mechanisms of action of intravenous immune globulin to increase the amount of formation of pre-131 HDL in in immune-mediated diseases. Clinical & Experimental human plasma. Immunology. 104 Suppl 1:3-9, 1996. 0680 Endotoxin and inhibitor analogs, agonist analogs 0684. The cytokine analogs of the present invention may and antagonist analogs can be used for decreasing cardiac treat or prevent autoimmune disease, inflammatory disease, output, systemic hypotension, decreased blood flow and O. and dysfunctional growth or differentiation of cells such as delivery to tissues, intense pulmonary vasoconstriction and cellular proliferative disorders, the development of neoplasia, hypertension, bronchoconstriction, increased permeability, tumors, and cancer. pulmonary oedema, Ventilation-to-perfusion inequalities, 0685. The present invention provides for the use of an hypoxaemia, and haemoconcentration. Examples of these antibody or binding composition which specifically binds to peptides are named and described in Burrell, R: Human a specified analog. in some embodiments the antibody spe responses to bacterial endotoxin. Circulatory Shock. 43(3): cifically binds the analog derived from a mammalian 137-53, July 1994. polypeptide, e.g., a polypeptide derived from a primate, 0681. Orphan receptor ligand analogs, agonist analogs human, cat, dog, rat, or mouse. Antibodies can be raised to and antagonist analogs (including but not limited to ADNF, various analogs, including individual, polymorphic, allelic, Adrenomedullin, Apelin, Ghrelin, Mastoparan (MCD pep strain, or species variants, and fragments thereof both in their tides), Melanin concentrating hormone, Nociceptin/Nocista naturally occurring (full-length) forms or in their synthetic US 2013/0096050 A1 Apr. 18, 2013 79 forms. Additionally, antibodies can be raised to the analogs in bind with at least a K, of about 1 mM, usually at least about their inactive state or active state. Anti-idiotypic antibodies 300 LM, typically at least about 10 LM, at least about 30 uM, may also be used. at least about 10 uM, and at least about 3 uM or more. These 0686. A number of immunogens may be selected to pro antibodies can be screened for binding to the naturally occur duce antibodies specifically reactive with ligand or receptor ring polypeptides upon which the analogs are derived. proteins. Synthetic analogs may serve as an immunogen for 0690. In some instances, it is desirable to prepare mono the production of monoclonal or polyclonal antibodies. Such clonal antibodies (mAbs) from various mammalian hosts, antibodies may be used as antagonists or agonists for their Such as mice, rodents, primates, humans, etc. Description of targets modulating the disease state associated with the natu techniques for preparing Such monoclonal antibodies may be rally accruing proteins and analogs listed above. Synthetic found in, e.g., Stites, et al. (eds.) Basic and Clinical Immu polypeptides of the claimed invention may also be used either nology, 4th ed., Lange Medical Publications, Los Altos, in pure or impure form. Synthetic peptides, made using the Calif., and references cited therein; Harlow and Lane (1988) appropriate protein sequences, may also be used as an immu Antibodies: A Laboratory Manual CSH Press; Goding (1986) nogen for the production of antibodies. Naturally folded or Monoclonal Antibodies: Principles and Practice, 2nd ed., denatured material can be used, as appropriate, for producing Academic Press, New York, N.Y.; and particularly in Kohler antibodies. Either monoclonal or polyclonal antibodies may and Milstein (1975) Nature 256:495-497, which discusses be generated, e.g., for Subsequent use in immunoassays to one method of generating monoclonal antibodies. Summa measure the protein, or for immunopurification methods. rized briefly, this method involves injecting an animal with an Methods of producing polyclonal antibodies are well known analog described herein. The animal is then sacrificed and to those of skill in the art. cells taken from its spleen, which are then fused with 0687 Typically, an immunogen, Such as a purified analog myeloma cells. The result is a hybrid cell or “hybridoma' that of the invention, is mixed with an adjuvant and animals are is capable of reproducing in vitro. The population of hybri immunized with the mixture. The animal’s immune response domas is then screened to isolate individual clones, each of to the immunogen preparation is monitored by taking test which secrete a single antibody species to the analog. In this bleeds and determining the titer of reactivity to the protein of manner, the individual antibody species obtained are the interest. For example, when appropriately high titers of anti products of immortalized and cloned single B cells from the body to the immunogen are obtained, usually after repeated immune animal generated in response to a specific site rec immunizations, blood is collected from the animal and anti ognized on the immunogenic Substance. sera are prepared. Further fractionation of the antisera to (0691. Other suitable techniques involve selection of enrich for antibodies reactive to the protein can be performed libraries of antibodies in phage or similar vectors. See, e.g., if desired. See, e.g., Harlow and Lane; or Coligan. Immuni Huse, et al. (1989) Science 246:1275-1281; and Ward, et al. Zation can also be performed through other methods, e.g., (1989) Nature 341:544-546. The polypeptides and antibodies DNA vector immunization. See, e.g., Wang, et al. (1997) of the present invention may be used with or without modi Virology 228:278-284. fication, including chimeric or humanized antibodies. Fre 0688 Monoclonal antibodies may be obtained by various quently, the polypeptides and antibodies will be labeled by techniques familiar to researchers skilled in the art. Typically, joining, either covalently or non-covalently, a Substance spleen cells from an animal immunized with a desired analog which provides for a detectable signal. A wide variety of are immortalized, commonly by fusion with a myeloma cell. labels and conjugation techniques are known and are reported See, Kohler and Milstein (1976) Eur. J. Immunol. 6:51 1-519. extensively in both the scientific and patent literature. Suit Alternative methods of immortalization include transforma able labels include radionuclides, enzymes, Substrates, cofac tion with Epstein Barr Virus, oncogenes, or retroviruses, or tors, inhibitors, fluorescent moieties, chemiluminescent moi other methods known in the art. See, e.g., Doyle, et al. (eds. eties, magnetic particles, and the like. Patents teaching the use 1994 and periodic supplements) Cell and Tissue Culture: of such labels include U.S. Pat. Nos. 3,817,837; 3,850,752: Laboratory Procedures, John Wiley and Sons, New York, 3,939,350; 3,996,345; 4,277,437; 4,275, 149; and 4,366,241. N.Y. Colonies arising from single immortalized cells are Also, recombinant immunoglobulins may be produced, see, screened for production of antibodies of the desired specific Cabilly, U.S. Pat. No. 4,816,567; and Queen, et al. (1989) ity and affinity for the antigen, and yield of the monoclonal Proc. Natl Acad. Sci. USA 86:10029-10033; or made in antibodies produced by such cells may be enhanced by vari transgenic mice, see Mendez, et al. (1997) Nature Genetics ous techniques, including injection into the peritoneal cavity 15:146-156; also see Abgenix and Medarex technologies. of a vertebrate host. Alternatively, one may isolate DNA 0692. The instant invention is related to pharmaceutical sequences which encode a monoclonal antibody or a binding compositions of the instant invention or the pharmaceutical fragment thereof by screening a DNA library from human B acceptable salts derived therefrom that comprise analogs that cells according, e.g., to the general protocol outlined by Huse, comprise isotopes. In some embodiments, the compositions et al. (1989) Science 246:1275-1281. of the claimed invention may contain any isotope described in 0689 Antibodies or binding compositions, including Cyr and Pearson (Stabilization of radiopharmaceutical com binding fragments, single chain antibodies, F, F, single positions using hydrophilic thioethers and hydrophilic 6-hy domain V, disulfide-bridged F, single-chain F or F(.) droxy chromans. Cyr, John E.; Pearson, Daniel A. (Diatide, fragments of antibodies, diabodies, and triabodies against Inc., USA). PCT Int. Appl. (2002), WO 200260491 A2 predetermined fragments of the analogs can be raised by 20020808), which is herein incorporated by reference. In immunization of animals with analogs or conjugates of ana Some embodiments the compositions of the invention com logs or receptor proteins with carrier proteins. Monoclonal prise analog that comprise one or more of the following antibodies are prepared from cells secreting the desired anti isotopes: 125I, 13 II, 2. At, 7Sc, 7Cu, 7°Ga, 90Y. 'Sim, body. These antibodies can be screened forbinding to analogs 159Gd, 165 Dy 166Ho, 175Yb, 177Lu,212 Bi, 213Bi 68Ga, 99Tc, described herein. These monoclonal antibodies will usually '''In, PI, and H. US 2013/0096050 A1 Apr. 18, 2013

0693. The pharmaceutical compositions of the instant Such as sterile water, saline solution, or alcohol, before use. invention or the pharmaceutical acceptable salts derived Preparations may also contain mucosal enhancers. therefrom may be in a liquid or Solid dosage form. Such 0697. In some embodiments, the oral transmucosal solid compositions may include any type of dosage form Such as dosage further comprises a permeation enhancer. In some tablets, capsules, powders, liquid formulations, delayed or embodiments, the permeation enhancer is chosen from: a bile Sustained release, patches, Snuffs, nasal sprays and the like. salt, sodium dodecyl Sulfate, dimethylsulfoxide, Sodium lau The formulations may additionally include other ingredients ryl sulfate, a derivative of a saturated or a unsaturated fatty Such as dyes, preservatives, buffers and anti-oxidants, for acid, a Surfactant, a bile Salt analog, and a derivative of a bile example. The physical form and content of the pharmaceuti salt. In some embodiments the oral transmucosal dosage form cal formulations contemplated are conventional preparations is chosen from: a chewing gum, a patch, a lozenge, a lozenge that can be formulated by those skilled in the pharmaceutical on-a-handle, a tablet, a troche, a pastille, a Sachet, a Sublin formulation field and are based on well established principles gual tablet, and a rapid disintegrating tablet. In some embodi and compositions described in, for example, Remington. The ments, the oral transmucosal Solid dosage form of wherein the Science and Practice of Pharmacy, 19th Edition, 1995; Brit composition further comprises at least one flavoring agent, ish Pharmacopoeia 2000, each of which is incorporated artificial coloring, Sweetener, lubricating agent, disintegra herein by reference. The compositions of the present inven tion agent, lubricating agent, diluent, base, or buffering agent. tion may also include other active agents useful in the treat In some embodiments, the oral transmucosal Solid dosage ment of cardiovascular conditions. Solid forms can be pre form further comprises a Sustained release agent. The inven pared according to any means suitable in the art. For example, tion is directed to an oral transmucosal Solid dosage form capsules are prepared by mixing the analog composition with comprising from wherein the concentration of analog is from a suitable diluent and filling the properamount of the mixture about 0.01% to about 90% of the dry matter weight of the in capsules. Tablets are prepared by direct compression, by composition. wet granulation, or by dry granulation. Their formulations 0698 Solid dosage forms such as lozenges and tablets usually incorporate diluents, binders, lubricants and disinte may also be used for oral transmucosal delivery of pharma grators as well as the compound. Diluents, but are not limited ceuticals. For example, nitroglycerin Sublingual tablets have to, include various types of starch, cellulose, crystalline cel been on the market for many years. The sublingual tablets are lulose, microcrystalline cellulose, lactose, fructose. Sucrose, designed to deliver Small amounts of the potent nitroglycerin, mannitol or other Sugar alcohols, kaolin, calcium phosphate which is almost immediately dissolved and absorbed. On the or Sulfate, inorganic salts such as Sodium chloride and pow other hand, most lozenges or tablets are typically designed to dered sugar. Powdered cellulose derivatives are also useful. dissolve in the mouth over a period of at least several minutes Non-limiting examples of tablet binders include, but are not which allows extended dissolution of the lozenge and absorp limited to, starches, gelatin and Sugars such as lactose, fruc tion of the drug. tose, glucose and the like. Natural and synthetic gums are also 0699 Administration of lozenges or sublingual tablets convenient, including, but are not limited to, acacia, alginates, generally utilize an “open delivery system, in which the drug methylcellulose, polyvinylpyrrolidone and the like. Polyeth delivery conditions are influenced by the conditions of the ylene glycol, ethylcellulose and waxes can also serve as bind Surrounding environment, such as rate of saliva secretion, pH CS. of the saliva, or other conditions beyond the control of the 0694. A lubricant can be used in a tablet formulation to formulation. prevent the tablet and punches from sticking in the die. The 0700. A lozenge-on-a-handle (similar to a lollipop) is lubricant include, but are not limited to, such slippery solids another dosage form Suitable for transmucosal drug delivery. as talc, magnesium and calcium Stearate, Stearic acid and In addition to being non-invasive and providing a particularly hydrogenated vegetable oils. easy method of delivery, the lozenge-on-a-handle (or lozenge 0695 Tablets can be coated with sugar as a flavor and with an integrated oral transmucosal applicator) dosage form sealant, or with film-forming protecting agents to modify the allows a patient or caregiver to move the dosage form in and dissolution properties of the tablet. The compounds may also out of the mouth to titrate the dose. This practice is called be formulated as chewable tablets, by using large amounts of dose-to-effect, in which a patient or caregiver controls the pleasant-tasting Substances such as mannitol in the formula administration of the dose until the expected therapeutic tion, as is now well-established in the art. effect is achieved. This is particularly important for certain 0696. Also contemplated are liquid formulations and solid symptoms, such as pain, nausea, motion sickness, and pre form preparations which are intended to be converted, shortly medication prior to anesthesia because each patient needs a before use, to liquid form preparations. Such liquid forms different amount of medication to treat these symptoms. For include, but are not limited to, solutions, Suspensions, syrups, these types of treatments, the patient is the only one who slurries, and emulsions. Liquid preparations may be prepared knows how much medication is enough. Once the appropriate by conventional means with pharmaceutically acceptable amount of drug is delivered, the patient or caregiver can additives such as Suspending agents (e.g., Sorbitol syrup, cel remove the lozenge-on-a-handle, thus, stopping delivery of lulose derivatives or hydrogenated edible fats or oils); emul the drug. This feature is especially important for particularly Sifying agents (e.g., lecithin or acacia); non-aqueous vehicles potent drugs, which may present a significant advantage of (e.g., almond oil, oily esters, or fractionated vegetable oils); terminating drug administration once the desired effect is and preservatives (e.g., methyl or propyl-p-hydroxyben achieved. Zoates or Sorbic acid). These preparations may contain, in 0701. As used herein, the term “oral transmucosal deliv addition to the active agent, colorants, flavors, stabilizers, ery” (OTD) refers to the delivery of a pharmaceutical agent buffers, artificial and natural Sweeteners, dispersants, thick across a mucous membrane in the oral cavity, pharyngeal eners, Solubilizing agents, and the like. The compositions cavity, or esophagus, and may be contrasted, for example, may be in powderform for constitution with a suitable vehicle with traditional oral delivery, in which absorption of the drug US 2013/0096050 A1 Apr. 18, 2013

occurs in the intestines. Accordingly, routes of administration istering to at least one patient in need thereof, mammal in in which the pharmaceutical agent is absorbed through the need thereof or human in need thereof a composition or buccal, Sublingual, gingival, pharyngeal, and/or esophageal pharmaceutical composition comprising a secretin family mucosa are all encompassed within “oral transmucosal deliv analog in a therapeutically effective amount. The composi ery,” as that term is used herein. Oral transmucosal delivery tions of the invention may also be used at lower doses in order involves the administration of an oral transmucosal Solid to prevent pulmonary hypertension, primary arterial hyper dosage form to the oral cavity of a patient, which is held in the tension, pulmonary hypertension associated to post-ventricu oral cavity and dissolved, thereby releasing the pharmaceu lar septal defect, idiopathic pulmonary fibrosis, idiopathic tical agent for oral transmucosal delivery. Of course, as the pulmonary arterial hypertension, CREST syndrome—Calci Solid dosage form dissolves in the oral cavity, some of the nosis; Raynaud's disease; loss of muscle control of the saliva containing the pharmaceutical agent may be Swal Esophagus; Sclerodactyly; Telangiectasia, Acute respiratory lowed, and a portion of the drug may ultimately be absorbed distress, congestive heart failure, chronic obstructed pulmo from the intestines. nary disorder, asthma, chronic obstructive pulmonary dis 0702. The compositions of the invention can be adminis ease, sarcoidosis, Small lung cell cancer, autoimmune dis tered in a Sustained release composition, such as those ease, inflammatory disease, sepsis, Hirschsprung's Disease, described in, for example, U.S. Pat. No. 5,672,659 and U.S. sexual dysfunction, erectile dysfunction, Parkinson's dis Pat. No. 5,595,760, and herein incorporate by reference. The ease, Alzheimer's disease, circadian rhythm dysfunction, use of immediate or Sustained release compositions depends pain, colorectal cancer, hepatocellular cancer, elevated blood on the type of condition being treated. pressure levels, elevated blood glucose levels, hyperglyce 0703. The pharmaceutical compositions of the instant mia, diabetes, insulin resistance, metabolic acidosis, obesity, invention or the pharmaceutical acceptable salts derived Type I diabetes, Type II diabetes Multiple Sclerosis, therefrom may be in a dosage amount in an effective amount osteoporosis, Sjogren's syndrome, pancreatitis, uveoretinitis, for inducing or increasing the naturally occurring biological osteoporosis, female sexual dysfunction in a subject in need activity of the wild-type polypeptide upon which the analogis thereof. The compositions of the invention may also be used derived. The pharmaceutical compositions of the instant to prevent pulmonary hypertension, primary arterial hyper invention or the pharmaceutical acceptable salts derived tension, pulmonary hypertension associated to post-ventricu therefrom may be in a dosage amount in an effective amount lar septal defect, idiopathic pulmonary fibrosis, idiopathic for inducing or increasing the naturally occurring biological pulmonary arterial hypertension, CREST syndrome—Calci activity of the wild-type secretin polypeptide upon which the nosis; Raynaud's disease; loss of muscle control of the analog is derived. The pharmaceutical compositions of the Esophagus; Sclerodactyly; Telangiectasia, Acute respiratory instant invention or the pharmaceutical acceptable salts distress, congestive heart failure, chronic obstructed pulmo derived therefrom may be in a dosage amount in an effective nary disorder, asthma, chronic obstructive pulmonary dis ease, sarcoidosis, Small lung cell cancer, autoimmune dis amount for increasing the half-life of the composition when ease, inflammatory disease, sepsis, Hirschsprung's Disease, administered to a human being or other Subject. In some sexual dysfunction, erectile dysfunction, Parkinson's dis embodiments the secretin analog is VIP. ease, Alzheimer's disease, circadian rhythm dysfunction, 0704. The present invention also encompasses methods of pain, colorectal cancer, hepatocellular cancer, elevated blood using the compositions comprising a VIP analog. Any of pressure levels, elevated blood glucose levels, hyperglyce these methods may involve the administration of a pharma mia, diabetes, insulin resistance, metabolic acidosis, obesity, ceutical composition comprising a VIP analog wherein the Type I diabetes, Type II diabetes Multiple Sclerosis, VIP analog is in a therapeutically effective dose. Any of these osteoporosis, Sjogren's syndrome, pancreatitis, uveoretinitis, methods may involve the administration of a pharmaceutical osteoporosis, female sexual dysfunction in a Subject Suscep composition comprising a VIP analog wherein the VIP analog tible to those indications. In some embodiments, the method is selective for VPAC1, VPAC2, PAC1, VIPR1, or VIPR2. The of prevention comprising administering the composition or composition comprising an analog of the invention produces pharmaceutical compositions of the invention after the Sub a broad range of activities, depending on the dosage admin ject is tested for Susceptibility or genetic propensity for devel istered. The present invention encompasses methods of treat ing or preventing pulmonary hypertension, primary arterial oping the disease, indication or disorder. hypertension, pulmonary hypertension associated to post 0705 The pharmaceutical composition comprising a Ventricular septal defect, idiopathic pulmonary fibrosis, idio pharmaceutically acceptable carrier/diluent and an analog pathic pulmonary arterial hypertension, CREST syndrome— comprising an O-amino acid and at least one B-amino acid Calcinosis; Raynaud's disease; loss of muscle control of the may beformulated by one having ordinary skill in the art with Esophagus; Sclerodactyly; Telangiectasia, Acute respiratory compositions selected depending upon the chosen mode of distress, congestive heart failure, chronic obstructed pulmo administration. Suitable pharmaceutical carriers are nary disorder, asthma, chronic obstructive pulmonary dis described in the most recent edition of Remington's Pharma ease, sarcoidosis, Small lung cell cancer, autoimmune dis ceutical Sciences, A. Osol, a standard reference text in this ease, inflammatory disease, sepsis, Hirschsprung's Disease, field, which is incorporated herein in its entirety. sexual dysfunction, erectile dysfunction, Parkinson's dis 0706 For parenteral administration, analog can be, for ease, Alzheimer's disease, circadian rhythm dysfunction, example, formulated as a solution, Suspension, emulsion or pain, colorectal cancer, hepatocellular cancer, elevated blood lyophilized powder in association with a pharmaceutically pressure levels, elevated blood glucose levels, hyperglyce acceptable parenteral vehicle. Examples of such vehicles are mia, diabetes, insulin resistance, metabolic acidosis, obesity, water, Saline, Ringer's Solution, dextrose solution, and 5% Type I diabetes, Type II diabetes Multiple Sclerosis, human serum albumin. Liposomes and nonaqueous vehicles osteoporosis, Sjogren's syndrome, pancreatitis, uveoretinitis, such as fixed oils may also be used. The vehicle or lyophilized osteoporosis, female sexual dysfunction comprising admin powder may contain additives that maintain isotonicity (e.g., US 2013/0096050 A1 Apr. 18, 2013

Sodium chloride, mannitol) and chemical stability (e.g., buff ease, inflammatory disease, sepsis, Hirschsprung's Disease, ers and preservatives). The formulation is sterilized by com sexual dysfunction, erectile dysfunction, Parkinson's dis monly used techniques. For example, a parenteral composi ease, Alzheimer's disease, circadian rhythm dysfunction, tion Suitable for administration by injection is prepared by pain, colorectal cancer, hepatocellular cancer, elevated blood dissolving 1.5% by weight of analog in 0.9% sodium chloride pressure levels, elevated blood glucose levels, hyperglyce Solution. mia, diabetes, insulin resistance, metabolic acidosis, obesity, 0707. The present invention relates to routes of adminis Type I diabetes, Type II diabetes Multiple Sclerosis, tration include intramuscular, Sublingual, intravenous, intra osteoporosis, Sjogren's syndrome, pancreatitis, uveoretinitis, peritoneal, intrathecal, intravaginal, intraurethral, intrader osteoporosis, female sexual dysfunction in a subject. In some mal, intrabuccal, via inhalation, via nebulizer and via embodiments, the invention relates to compositions compris Subcutaneous injection. Alternatively, the pharmaceutical ing a secretin family analog for treatment or prevention of composition may be introduced by various means into cells pulmonary hypertension, primary arterial hypertension, pull that are removed from the individual. Such means include, for monary hypertension associated to post-ventricular septal example, microprojectile bombardment and liposome or defect, idiopathic pulmonary fibrosis, idiopathic pulmonary other nanoparticle device. arterial hypertension, CREST syndrome—Calcinosis: 0708 Solid dosage forms for oral administration include Raynaud's disease; loss of muscle control of the Esophagus; capsules, tablets, pills, powders and granules. In solid dosage Sclerodactyly; Telangiectasia, Acute respiratory distress, forms, the analogs are generally admixed with at least one congestive heart failure, chronic obstructed pulmonary disor inert pharmaceutically acceptable carrier Such as Sucrose, der, asthma, chronic obstructive pulmonary disease, sarcoi lactose, starch, or other generally regarded as safe (GRAS) dosis, Small lung cell cancer, autoimmune disease, inflamma additives. Such dosage forms can also comprise, as is normal tory disease, sepsis, Hirschsprung's Disease, sexual practice, an additional Substance other than an inert diluent, dysfunction, erectile dysfunction, Parkinson's disease, e.g., lubricating agent such as magnesium state. With cap Alzheimer's disease, circadian rhythm dysfunction, pain, Sules, tablets, and pills, the dosage forms may also comprise colorectal cancer, hepatocellular cancer, elevated blood pres a buffering agent. Tablets and pills can additionally be pre Sure levels, elevated blood glucose levels, hyperglycemia, pared with enteric coatings, or in a controlled release form, diabetes, insulin resistance, metabolic acidosis, obesity, Type using techniques know in the art. I diabetes, Type II diabetes Multiple Sclerosis, osteoporosis, 0709 Liquid dosage forms for oral administration include Sjogren's syndrome, pancreatitis, uveoretinitis, osteoporosis, pharmaceutically acceptable emulsions, Solutions, Suspen female sexual dysfunction in a Subject in need thereof, sions and syrups, with the elixirs containing an inert diluent wherein said analog comprises an O-amino acid and at least commonly used in the art, such as water. These compositions one B-amino acid. In some embodiments, the secretin family can also include one or more adjuvants, such as wetting agent, analog of the invention comprises an analog of VIP. an emulsifying agent, a suspending agent, a Sweetening 0711. One of skill in the art will recognize that the appro agent, a flavoring agent or a perfuming agent. priate dosage of the compositions and pharmaceutical com 0710. In another embodiment of the invention the compo positions may vary depending on the individual being treated sition of the invention is used to treat a patient Suffering from, and the purpose. For example, the age, body weight, and or Susceptible to, pulmonary hypertension, primary arterial medical history of the individual patient may affect the thera hypertension, pulmonary hypertension associated to post peutic efficacy of the therapy. Further, a lower dosage of the Ventricular septal defect, idiopathic pulmonary fibrosis, idio composition may be needed to produce a transient cessation pathic pulmonary arterial hypertension, CREST syndrome of symptoms, while a larger dose may be needed to produce a Calcinosis; Raynaud's disease; loss of muscle control of the complete cessation of symptoms associated with the disease, Esophagus; Sclerodactyl); Telangiectasia, Acute respiratory disorder, or indication. A competent physician can consider distress, congestive heart failure, chronic obstructed pulmo these factors and adjust the dosing regimen to ensure the dose nary disorder, asthma, chronic obstructive pulmonary dis is achieving the desired therapeutic outcome without undue ease, sarcoidosis, Small lung cell cancer, autoimmune dis experimentation. It is also noted that the clinician and/or ease, inflammatory disease, sepsis, Hirschsprung's Disease, treating physician will know how and when to interrupt, sexual dysfunction, erectile dysfunction, Parkinson's dis adjust, and/or terminate therapy in conjunction with indi ease, Alzheimer's disease, circadian rhythm dysfunction, vidual patient response. Dosages may also depend on the pain, colorectal cancer, hepatocellular cancer, elevated blood strength of the particular analog chosen for the pharmaceuti pressure levels, elevated blood glucose levels, hyperglyce cal composition. mia, diabetes, insulin resistance, metabolic acidosis, obesity, 0712. The dose of the composition or pharmaceutical Type I diabetes, Type II diabetes Multiple Sclerosis, compositions may vary. The dose of the composition may be osteoporosis, Sjogren's syndrome, pancreatitis, uveoretinitis, once per day. In some embodiments, multiple doses may be osteoporosis, female sexual dysfunction due to administra administered to the Subject per day. In some embodiments, tion of a medication that causes onset of or exacerbates Symp the total dosage is administered in at least two application toms of pulmonary hypertension, primary arterial hyperten periods. In some embodiments, the period can be an hour, a Sion, pulmonary hypertension associated to post-ventricular day, a month, a year, a week, or a two-week period. In an septal defect, idiopathic pulmonary fibrosis, idiopathic pull additional embodiment of the invention, the total dosage is monary arterial hypertension, CREST syndrome—Calcino administered in two or more separate application periods, or sis; Raynaud's disease; loss of muscle control of the Esopha separate doses. gus; Sclerodactyly; Telangiectasia, Acute respiratory 0713. In some embodiments, subjects can be administered distress, congestive heart failure, chronic obstructed pulmo the composition in which the composition is provided in a nary disorder, asthma, chronic obstructive pulmonary dis daily dose range of about 0.0001 mg/kg to about 5000 mg/kg ease, sarcoidosis, Small lung cell cancer, autoimmune dis of the weight of the subject. The dose administered to the US 2013/0096050 A1 Apr. 18, 2013

Subject can also be measured in terms of total amount of ments, the composition comprising a VIP analog or pharma analog administered per day. In some embodiments, a subject ceutically acceptable salt thereof is administered in a daily is administered from about 0.001 to about 3000 milligrams of dosage of up about 25 mg/kg of the weight of the Subject. analog per day. In some embodiments, a subject is adminis 0715. In some embodiments, the composition comprising tered up to about 2000 milligrams of analog per day. In some a VIP analog or pharmaceutically acceptable salt thereof is embodiments, a subject is administered up to about 1800 administered in a daily dosage of up about 10 mg/kg of the milligrams of analog per day. In some embodiments, a subject weight of the Subject. In some embodiments, the composition is administered up to about 1600 milligrams of analog per comprising a VIP analog or pharmaceutically acceptable salt day. In some embodiments, a subject is administered up to thereof is administered in a daily dosage of up about 5 mg/kg about 1400 milligrams of analog per day. In some embodi of the weight of the subject. In some embodiments, the com ments, a subject is administered up to about 1200 milligrams position comprising a VIP analog or pharmaceutically of analog per day. In some embodiments, a Subject is admin acceptable salt thereof is administered in a daily dosage of up istered up to about 1000 milligrams of analog per day. In some about 1 mg/kg of the weight of the Subject. In some embodi embodiments, a subject is administered up to about 800 mil ments, the composition comprising a VIP analog or pharma ligrams of analog per day. In some embodiments, a Subject is ceutically acceptable salt thereof is administered in a daily administered from about 0.001 milligrams to about 700 mil dosage of up about 0.1 mg/kg of the weight of the Subject. In ligrams of analog perdose. In some embodiments, a Subject is Some embodiments, the composition comprising a VIP ana administered up to about 700 milligrams of analog per dose. log or pharmaceutically acceptable salt thereof is adminis In some embodiments, a subject is administered up to about tered in a daily dosage of up about 0.01 mg/kg of the weight 600 milligrams of analog per dose. In some embodiments, a of the Subject. In some embodiments, the composition com Subject is administered up to about 500 milligrams of analog prising a VIP analog or pharmaceutically acceptable salt per dose. In some embodiments, a subject is administered up thereof is administered in a daily dosage of up about 0.001 to about 400 milligrams of analog per dose. In some embodi mg/kg of the weight of the Subject. The dose administered to ments, a subject is administered up to about 300 milligrams of the Subject can also be measured in terms of total amount of secretin analog per dose. In some embodiments, a Subject is VIP analog administered per day. administered up to about 200 milligrams of analog per dose. 0716. In some embodiments, a subject in need thereof is In some embodiments, a subject is administered up to about administered from about 1 ng to about 500 g of analog or 100 milligrams of analog per dose. In some embodiments, a pharmaceutically salt thereof per day. In some embodiments, Subject is administered up to about 50 milligrams of analog a subject in need thereof is administered from about 1 ng to per dose. about 10 ng of analog or pharmaceutically salt thereof per 0714. In some embodiments, subjects can be administered day. In some embodiments, a subject in need thereof is admin the composition in which the composition comprising a VIP istered from about 10 ng to about 20 ng of analog or pharma analog or pharmaceutically acceptable salt thereof is admin ceutically salt thereof per day. In some embodiments, a Sub istered in a daily dose range of about 0.0001 mg/kg to about ject in need thereof is administered from about 10ng to about 5000 mg/kg of the weight of the subject. In some embodi 100 ng of analog or pharmaceutically salt thereof per day. In ments, the composition comprising a VIP analog or pharma Some embodiments, a Subject in need thereof is administered ceutically acceptable salt thereof is administered in a daily from about 100 ng to about 200 ng of analog or pharmaceu dosage of up about 450 mg/kg of the weight of the Subject. In tically salt thereofper day. In some embodiments, a Subject in Some embodiments, the composition comprising a VIP ana need thereof is administered from about 200 ng to about 300 log or pharmaceutically acceptable salt thereof is adminis ng of analog orpharmaceutically salt thereofper day. In some tered in a daily dosage of up about 400 mg/kg of the weight of embodiments, a subject in need thereof is administered from the Subject. In some embodiments, the composition compris about 300 ng to about 400 ng of analog or pharmaceutically ing a VIP analog or pharmaceutically acceptable salt thereof salt thereof per day. In some embodiments, a Subject in need is administered in a daily dosage of up about 350 mg/kg of the thereof is administered from about 400ng to about 500 ng of weight of the Subject. In some embodiments, the composition analog or pharmaceutically salt thereof per day. In some comprising a VIP analog or pharmaceutically acceptable salt embodiments, a subject in need thereof is administered from thereof is administered in a daily dosage of up about 300 about 500 ng to about 600 ng of analog or pharmaceutically mg/kg of the weight of the Subject. In some embodiments, the salt thereof per day. In some embodiments, a Subject in need composition comprising a VIP analog or pharmaceutically thereof is administered from about 600 ng to about 700 ng of acceptable salt thereof is administered in a daily dosage of up analog or pharmaceutically salt thereof per day. In some about 250 mg/kg of the weight of the subject. In some embodiments, a subject in need thereof is administered from embodiments, the composition comprising a VIP analog or about 800 ng to about 900 ng of analog or pharmaceutically pharmaceutically acceptable salt thereof is administered in a salt thereof per day. In some embodiments, a Subject in need daily dosage of up about 200 mg/kg of the weight of the thereof is administered from about 900 ng to about 1 lug of Subject. In some embodiments, the composition comprising a analog or pharmaceutically salt thereof per day. In some VIP analog or pharmaceutically acceptable salt thereof is embodiments, a subject in need thereof is administered from administered in a daily dosage of up about 150 mg/kg of the about 1 g to about 100 ug of analog or pharmaceutically salt weight of the Subject. In some embodiments, the composition thereof per day. In some embodiments, a subject in need comprising a VIP analog or pharmaceutically acceptable salt thereof is administered from about 100 lug to about 200 g of thereof is administered in a daily dosage of up about 100 analog or pharmaceutically salt thereof per day. In some mg/kg of the weight of the Subject. In some embodiments, the embodiments, a subject in need thereof is administered from composition comprising a VIP analog or pharmaceutically about 200 ug to about 300 g of analog or pharmaceutically acceptable salt thereof is administered in a daily dosage of up salt thereof per day. In some embodiments, a Subject in need about 50 mg/kg of the weight of the subject. In some embodi thereof is administered from about 300 lug to about 400 g of US 2013/0096050 A1 Apr. 18, 2013 analog or pharmaceutically salt thereof per day. In some pharmaceutically salt thereof per dose. In some embodi embodiments, a subject in need thereof is administered from ments, a subject is administered up to about 0.1 milligrams of about 400 ug to about 500 g of analog or pharmaceutically VIP analog or pharmaceutically salt thereof per dose. In some salt thereof per day. In some embodiments, a Subject in need embodiments, a subject is administered up to about 0.001 thereof is administered from about 500 ug to about 600 g of milligrams of VIP analog orpharmaceutically salt thereofper analog or pharmaceutically salt thereof per day. In some dose. embodiments, a subject in need thereof is administered from about 600 ug to about 700 g of analog or pharmaceutically 0719. The dose administered to the subject can also be salt thereof per day. In some embodiments, a Subject in need measured in terms of total amount of VIP analog or pharma thereof is administered from about 800 ug to about 900 g of ceutically salt thereof administered per ounce of liquid pre analog or pharmaceutically salt thereof per day. In some pared. In some embodiments, the VIP analog or pharmaceu embodiments, a subject in need thereof is administered from tically salt thereof is at a concentration of about 2.5 grams per about 900 ug to about 1 mg of analog orpharmaceutically salt ounce of solution. In some embodiments, the VIP analog or thereof per day. pharmaceutically salt thereof is at a concentration of about 2.25 grains per ounce of solution. In some embodiments, the 0717. In some embodiments, a subject in need thereof is VIP analog or pharmaceutically salt thereof is at a concentra administered from about 0.0001 to about 3000 milligrams of tion of about 2.25 grams per ounce of Solution. In some VIP analog or pharmaceutically salt thereof per day. In some embodiments, the VIP analog or pharmaceutically salt embodiments, a subject is administered up to about 2000 thereof is at a concentration of about 2.0 grams per ounce of milligrams of VIP analog or pharmaceutically salt thereof Solution. In some embodiments, the VIP analog or pharma day. In some embodiments, a subject is administered up to ceutically salt thereof is at a concentration of about 1.9 grams about 1800 milligrams of VIP analog orpharmaceutically salt per ounce of solution. In some embodiments, the VIP analog thereof per day. In some embodiments, a Subject is adminis orpharmaceutically salt thereof is at a concentration of about tered up to about 1600 milligrams of VIP analog or pharma 1.8 grams per ounce of Solution. In some embodiments, the ceutically salt thereof per day. In some embodiments, a Sub VIP analog or pharmaceutically salt thereof is at a concentra ject is administered up to about 1400 milligrams of VIP tion of about 1.7 grams per ounce of Solution. In some analog or pharmaceutically salt thereof per day. In some embodiments, the VIP analog or pharmaceutically salt embodiments, a subject is administered up to about 1200 thereof is at a concentration of about 1.6 grams per ounce of milligrams of VIP analog orpharmaceutically salt thereofper Solution. In some embodiments, the VIP analog or pharma day. In some embodiments, a subject is administered up to ceutically salt thereof is at a concentration of about 1.5 grams about 1000 milligrams of VIP analog orpharmaceutically salt per ounce of solution. In some embodiments, the VIP analog thereof per day. In some embodiments, a Subject is adminis orpharmaceutically salt thereof is at a concentration of about tered up to about 800 milligrams of VIP analog or pharma 1.4 grams per ounce of Solution. In some embodiments, the ceutically salt thereof per day. In some embodiments, a Sub VIP analog or pharmaceutically salt thereof is at a concentra ject is administered from about 0.0001 milligrams to about tion of about 1.3 grams per ounce of Solution. In some 700 milligrams of VIP analog or pharmaceutically salt embodiments, the VIP analog or pharmaceutically salt thereof per dose. In some embodiments, a Subject is admin thereof is at a concentration of about 1.2 grams per ounce of istered up to about 700 milligrams of VIP analog or pharma Solution. In some embodiments, the VIP analog or pharma ceutically salt thereof per dose. In some embodiments, a ceutically salt thereof is at a concentration of about 1.1 grams subject is administered up to about 600 milligrams of VIP per ounce of solution. In some embodiments, the VIP analog analog or pharmaceutically salt thereof per dose. In some orpharmaceutically salt thereof is at a concentration of about embodiments, a subject is administered up to about 500 mil 1.0 grams per ounce of Solution. In some embodiments, the ligrams of VIP analog or pharmaceutically salt thereof per VIP analog or pharmaceutically salt thereof is at a concentra dose. In some embodiments, a Subject is administered up to tion of about 0.9 grams per ounce of Solution. In some about 400 milligrams of VIP analog or pharmaceutically salt embodiments, the VIP analog or pharmaceutically salt thereof per dose. In some embodiments, a Subject is admin thereof is at a concentration of about 0.8 grams per ounce of istered up to about 300 milligrams of VIP analog or pharma Solution. In some embodiments, the VIP analog or pharma ceutically salt thereof per dose. In some embodiments, a ceutically salt thereof is at a concentration of about 0.7 grams subject is administered up to about 200 milligrams of VIP per ounce of solution. In some embodiments, the VIP analog analog or pharmaceutically salt thereof per dose. In some orpharmaceutically salt thereof is at a concentration of about embodiments, a subject is administered up to about 100 mil 0.6 grams per ounce of Solution. In some embodiments, the ligrams of VIP analog or pharmaceutically salt thereof per VIP analog or pharmaceutically salt thereof is at a concentra dose. In some embodiments, a Subject is administered up to tion of about 0.5 grams per ounce of Solution. In some about 50 milligrams of VIP analog or pharmaceutically salt embodiments, the VIP analog or pharmaceutically salt thereof per dose. In some embodiments, a Subject is admin thereof is at a concentration of about 0.4 grams per ounce of istered up to about 25 milligrams of VIP analog or pharma Solution. In some embodiments, the VIP analog or pharma ceutically salt thereof per dose. In some embodiments, a ceutically salt thereof is at a concentration of about 0.3 grams subject is administered up to about 15 milligrams of VIP per ounce of solution. In some embodiments, the VIP analog analog or pharmaceutically salt thereof per dose. orpharmaceutically salt thereof is at a concentration of about 0718. In some embodiments, a subject is administered up 0.2 grams per ounce of Solution. In some embodiments, the to about 10 milligrams of VIP analog orpharmaceutically salt VIP analog or pharmaceutically salt thereof is at a concentra thereof per dose. In some embodiments, a Subject is admin tion of about 0.1 grams per ounce of Solution. In some istered up to about 5 milligrams of VIP analog or pharmaceu embodiments, the VIP analog or pharmaceutically salt tically salt thereof per dose. In some embodiments, a subject thereof is at a concentration of about 0.01 grams per ounce of is administered up to about 1 milligram of VIP analog or Solution. In some embodiments, the VIP analog or pharma US 2013/0096050 A1 Apr. 18, 2013

ceutically salt thereof is at a concentration of about 0.001 intestinal polypeptide analogs and derivatives thereof (par grams per ounce of solution prepared. In some embodiments, ticularly derivatives in the form of hydrolyzable lower alkyl the VIP analog or pharmaceutically salt thereof is at a con esters), Smooth muscle relaxants, leukotriene inhibitors, cal centration of about 0.0001 grams per ounce of solution pre cium channel blockers, P2-adrenergic agonists, angiotensin pared. In some embodiments, the VIP analog or pharmaceu converting enzyme (ACE) inhibitors, angiotensin II recep tically salt thereof is at a concentration of about 0.00001 tor antagonists, and phosphodiesterase inhibitors. grams per ounce of solution prepared. In some embodiments, Still other suitable vasoactive agents include, but are not the VIP analog or pharmaceutically salt thereof is at a con limited to: nitrates and like compounds such as nitroglycerin, centration of about 0.000001 grams per ounce of solution isosorbide dinitrate, erythrityl tetranitrate, amyl nitrate, mol prepared. sidomine, linsidomine chlorhydrate (“SIN-1), S-nitroso-N- 0720 Dosage may be measured in terms of mass amount acetyl-d. 1-penicillamine (“SNAP) and S-nitroso-N-glu ofanalog per liter of liquid formulation prepared. One skilled tathione (“SNO-GLU); long and short acting C-blockers in the art can increase or decrease the concentration of the Such as phenoxybenzamine, dibenamine, doxazosin, tera analog in the dose depending upon the strength of biological Zosin, phentolamine, tolazoline, prazosin, trimaZosin, alfu activity desired to treat or prevent any above-mentioned dis Zosin, tamsulosin and indoramin; ergot alkaloids such as orders associated with the treatment of subjects in need ergotamine and ergotamine analogs, e.g., acetergamine, braZ thereof. For instance, one embodiment of the invention can ergoline, bromerguride, cianergoline, delorgotrile, disul include up to 0.00001 grams of analog per 5 mL of liquid ergine, ergonovine maleate, ergotamine tartrate, etisulergine, formulation and up to about 10 grams of analog per 5 mL of lergotrile, lysergide, meSulergine, metergoline, metergota liquid formulation. mine, nicergoline, pergolide, propisergide, proterguride and 0721. In some embodiments the pharmaceutical composi terguride; antihypertensive agents such as diaZOxide, tions of the claimed invention comprise at least one other hydralazine and minoxidil; nimodepine; pinacidil; cyclande active agent. in Some embodiments, the active agent is a late; dipyridamole; isoxSuprine; chlorpromazine; haloperi vasoactive agent. In some embodiments the vasoactive agent dol; yohimbine; and traZodone. is chosen from the naturally occurring prostaglandins pros 0722. In some embodiments, the pharmaceutical compo taglandin E0 (PGE0, also referred to 13,14-dihydro-PGE1; sitions of the invention comprise an active agent that is an hereinafter, the abbreviation “PG” is used for “prostaglan inhibitor of rho kinase, an enzyme belonging to the rhoA/rho din”), PGE1, 19-hydroxy-PGE1, PGE2, 19-hydroxy-PGE2, associated kinase pathway, which regulates the state of phos PGA1, 19-hydroxy-PGA1, PGA2, 19-hydroxy-PGA2, phorylation of myosin phosphatase, in turn leading to the PGB1, 19-hydroxy-PGB1, PGG2, 19-hydroxy-PGB2, control of Smooth muscle contraction. One example of a PGB3, PGD2, PGF1a, PGF2a(dinoprost), PGE3, PGF3c., suitable rho kinase inhibitor has the following structural for PGI2 (prostacyclin), and combinations thereof. PGEO, PGE1, mula and is identified as Y-27632. Other suitable rho kinase PGE2, and the hydrolyzable lower alkyl esters thereof (e.g., inhibitors are disclosed, for example, in U.S. Pat. No. 6,218, the methyl, ethyl and isopropyl esters) are, however, particu 410, which is herein incorporated by reference. larly suitable. Other suitable prostaglandins are exemplified, 0723. In some embodiments, the pharmaceutical compo without limitation, by arboprostil, carbaprostacyclin, carbo sitions of the invention comprise an active agent that are prost tromethamine, dinoprost tromethamine, dinoprostone, peptide analogs of C.-melanocyte-stimulating hormone enprostil, iloprost, lipoprost, gemeprost, metenoprost, Sul (C-MSH), also referred to as “melanocortin peptides. Such prostone, tiaprost, Viprostil (CL 115,347), Viprostil methyl peptides include the sequence His-Phe-Arg-Trp. His-D-Phe ester, 16, 16-dimethyl-A2-PGE1 methyl ester, 15-deoxy-16 Arg-Trp. or are homologs thereof, and can be cyclic. A Suit hydroxy-16-methyl-PGE1 methyl ester (misoprostol), 16, 16 able melanocortin peptide is Ac-Nle-cyclo-(-Asp-His-D- dimethyl-PGE1, 11-deoxy-15-methyl-PGE1, 16-methyl-18, Phe-Arg-Trp-Lys)-OH. See U.S. Pat. No. 6,051,555 to 18,19, 19-tetrahydrocarbacyclin, 16(RS)-15-deoxy-16 Hadley and International Patent Publication No. WO hydroxy-16-methyl-PGE1 methyl ester, (+)-4,5-didehydro 01/00224 to Blood et al., assigned to Palatin Technologies, 16-phenoxy-O-tetranor-PGE2 methyl ester, 11-deoxy-11C. Inc. The aforementioned amino acid residues have their con 16, 16-trimethyl-PGE2, (+)-11C, 16C.16 f-dihydroxy-1- ventional meaning as given in Chapter 2422 of the Manual of (hydroxymethyl)-16-methyl-trans-prostene, 9-chloro-16, 16 Patent Examining Procedure (2000). Thus, Arg is arginine, dimethyl-PGE2, 16, 16-d methyl-PGE2, 15 (S)-15-methyl “Nle' is norleucine, “His is histamine, “Phe' is phenylala PGE2, 9-deoxy-9-methylene-16, 16-dimethyl-PGE2. nine, “D-Phe' is D-phenylalanine, “Trp' is tryptophan, and potassium salt, 19(R)-hydroxy-PGE2, and 11-deoxy-16, 16 Ac' refers to an acetyl moiety, i.e., an acetyl moiety present dimethyl-PGE2. Additional vasoactive agents useful as sec in a peptide or amino acid sequence that is acetylated. ondary active agents herein include endothelin-derived relax 0724. In some embodiments, the pharmaceutical compo ation factors (“EDRFs) such as nitric oxide releasing agents, sitions of the invention comprise an active agent that is an e.g., sodium nitroprusside and diazenium diolates, or “NON endothelin antagonists, including antagonists of any or all of Oates.” NONOates include, but are not limited to, (Z)-1-(N- the three isoforms of endothelin, i.e., ET-1, ET-2, and ET-3, methyl-N-(6-(N-methyl-ammoniohexyl)aminodiazen-1- and are exemplified by: phenoxyphenylacetic acids and ium-1,2-diolate (“MAHMA/NO”), (Z)-1-(N-(3- derivatives thereof, such as N-(4-isopropylbenzene-sulfo ammoniopropyl)-N-(n-propyl)amino-diazen-1-ium-1,2- nyl)-O-(4-carboxy-2-n-propylphenoxy)-3.4-methylenediox diolate (“PAPA/NO”), (Z)-1-1%1-3-aminopropyl-N-(4- yphenyl acetamide dipotassium salt, 2-(2,6-dipropyl-4-hy (3-aminopropylammonio)butylaminodiazen-1-ium-1,2- droxymethyl)-phenoxy-2-(4-phenoxyphenyl)-acetic acid, diolate (spermine NONOate or “SPER/NO”) and sodium 2-(2,6-dipropyl-4-hydroxymethyl)phenoxy-2-(4-phe (Z)-1-(N,N-diethylamino)-diazen-1-ium-1,2-diolate (di nylphenyl)acetic acid, 2-(2,6-dipropyl-4-hydroxymethyl) ethylamine NONOate or “DEA/NO”) and derivatives phenoxy-2-(3-carboxyphenyl)-acetic acid, 2-(2,6-dipro thereof). Still other vasoactive agents include vasoactive pyl-4-hydroxymethyl)phenoxy-2-(3,4- US 2013/0096050 A1 Apr. 18, 2013 ethylenedioxyphenyl)acetic acid, 2-(2,6-dipropyl-4- dopamine, epinephrine, 5-hydroxytryptamine, Substance P. hydroxymethyl)phenoxy-2-(3,4,5-trimethoxyphenyl)acetic serotonin, and catecholamines. acid, 2-(2,6-dipropyl-4-hydroxymethyl)phenoxy-2-(3.4- 0728. In some embodiments, the pharmaceutical compo methylenedioxyphenyl)acetic acid, N-(4-dimethylami sitions of the invention comprise an active agent that is a nobenzenesulfonyl)-2-(4-methoxycarbonyl-2-propylphe Suitable serotonin agonists include, but are not limited to noxy)-2-(3.4-methylenedioxyphenyl) acetamide, N-(2- 2-methyl serotonin, buSpirone, ipsaperone, tiaspirone, methylbenzenesulfonyl)-2-(4-methoxycarbonyl-2- gepirone, ergot alkaloids, 8-hydroxy-(2-N,N-dipropyl propylphenoxy)-2-(3.4-methylenedioxyphenyl)acetamide, amino)-tetraline, 1-(4-bromo-2,5-dimethoxyphenyl)-2-ami N-(2-methoxycarbonyl-benzenesulfonyl)-2-(4-methoxy nopropane, cisapride, Sumatriptan, m-chlorophenylpipera carbonyl-2-propylphenoxy)-2-(3.4-methylenedioxy-phenyl) Zine, traZodone, Zacopride, meZacopride, and combinations acetamide, N-(2-chlorobenzene-Sulfonyl)-2-(4-methoxycar thereof. Suitable serotonin antagonists include, for example, bonyl-2-propylphenoxy)-2-(3.4-methylenedioxyphenyl) ondansetron, granisetron, metoclopramide, tropisetron, dola acetamide, and others, as described in U.S. Pat. No. 5,565, setron, palonosetron, trimethobenzamide, methysergide, ris 485; and certain isooxazoles, oxazoles, thiazoles, peridone, ketanserin, ritanserin, clozapine, amitriptyline, isothiazoles and imidazoles, as described, for example, in MDL 100,907 (R(+)-O-(2,3-dimethoxyphenyl)-1-(2-(4- U.S. Pat. No. 6,136,828. fluoropheny Dethyl-4-piperidine-methanol) (Marion Mer 0725. In some embodiments, the pharmaceutical compo rell Dow), azatadine, cyproheptadine, fenclonine, chlorpro sitions of the invention comprise an active agent that is a mazine, mianserin and combinations thereof. peptidyl drug including the peptidyl hormones activin, amy 0729. In some embodiments, the pharmaceutical compo lin, angiotensin, atrial natriuretic peptide (ANP), calcitonin, sitions of the invention comprise an active agent that is an calcitonin gene-related peptide, calcitonin N-terminal flank ergot alkaloids include ergotamine and ergotamine analogs, ing peptide, ciliary neurotrophic factor (CNTF), corticotropin e.g., acetergamine, braZergoline, bromerguride, cianergoline, (adrenocorticotropin hormone, ACTH), corticotropin-releas delorgotrile, dihydroergotamine, disulergine, ergonovine, ing factor (CRF or CRH), epidermal growth factor (EGF), ergonovine maleate, ergotamine tartrate, etisulergine, lergot follicle-stimulating hormone (FSH), gastrin, gastrin inhibi rile, lysergide, mesulergine, metergoline, metergotamine, tory peptide (GIP), gastrin-releasing peptide, gonadotropin nicergoline, pergolide, propisergide, proterguride and tergu releasing factor (GnRF or GNRH), growth hormone releasing ride. factor (GRF, GRH), human chorionic gonadotropin (hCH), 0730. In some embodiments, the pharmaceutical compo inhibin A, inhibin B, insulin, luteinizing hormone (LH), sitions of the invention comprise an active agent that is a luteinizing hormone-releasing hormone (LHRH), C.-melano calcium channel blockers that are Suitable for use according cyte-stimulating hormone, B-melanocyte-stimulating hor to the present invention include, without limitation, amlo mone, Y-melanocyte-stimulating hormone, melatonin, moti dipine, felodipine, isradipine, nicardipine, nifedipine, nimo lin, oxytocin (pitocin), pancreatic polypeptide, parathyroid dipine, nisoldipine, nitrendipine, bepridil, diltiazem, Vera hormone (PTH), placental lactogen, prolactin (PRL), prolac pamil, and combinations thereof. In some embodiments, the tin-release inhibiting factor (PIF), prolactin-releasing factor pharmaceutical compositions of the invention comprise an (PRF), secretin, somatotropin (growth hormone, OH), soma active agent that is a potassium channel openers include, but tostatin (SIF, growth hormone-release inhibiting factor, GIF), are not limited to, pinacidil, diazoxide, cromakalim, nic thyrotropin (thyroid-stimulating hormone, TSH), thyrotro orandil, minoxidil, (N-cyano-N'-(1,1-dimethylpropyl)-N'-3- pin-releasing factor (TRH or TRF), thyroxine, and vaso pyridyl-guanidine (P-1075), and N-cyano-N'-(2-nitroxy pressin. Other peptidyl drugs are the cytokines, e.g., colony ethyl)-3-pridinecarboximidamide monomethanesulfonate stimulating factor 4, heparin binding neurotrophic factor (KRN 2391). (HBNF), interferon-C, interferon C-2a, interferon C-2b, 0731. In some embodiments, the pharmaceutical compo interferon C.-n3, interferon-?3, etc., interleukin-1, interleukin sitions of the invention comprise an active agent that is a 2, interleukin-3, interleukin-4, interleukin-5, interleukin-6, potassium channel blockers include tedisamil, agitoxin-2, etc., tumor necrosis factor, tumor necrosis factor-C., granu apamin, BDS-I, BDS-II, charybdotoxin, C.-dendrotoxin, loycte colony-stimulating factor (G-CSF), granulocyte-mac B-dendrotoxin, y-dendrotoxin, Ö-dendrotoxin, dendrotoxin-I. rophage colony-stimulating factor (GM-CSF), macrophage dendrotoxin-K, E-4031, iberiotoxin, kaliotoxin, MCD-pep colony-stimulating factor, midkine (MD), and thymopoietin. tide, margatoxin, noxiustoxin, paxilline, penitrem A, Sticho 0726. In some embodiments, the pharmaceutical compo dactyla, tertiapin, tityustoxin K alpha, Verruculogen, and sitions of the invention comprise an active agent that is a combinations thereof. Although all of the active agents are selective androgen receptor modulators (SARMs) include available commercially, most of the listed potassium channel LGD2226 and/or LGD1331, both available from Ligand blockers are available from Alomone Labs (Jerusalem, Pharmaceuticals (San Diego, Calif.). See Negro-Villaretal.J. Israel). Clin. Endocrinol. & Metabol. 84(10):3459-62 (1999). 0732. In some embodiments, the pharmaceutical compo 0727. In some embodiments, the pharmaceutical compo sitions of the invention comprise an active agent that is a sitions of the invention comprise an active agent that is a dopamine agonist including, for example, levodopa, bro Suitable neuropeptide including bradykinin, kallidin, des mocriptine, pergolide, apomorphine, piribedil, pramipexole, Arg9-bradykinin, des-Arg10-kallidin, des-Arg9-Leu8 ropinirole, and combinations thereof. Dopamine antagonists bradykinin, D-Phe7}-bradykinin, HOE 140, neuropeptide include, without limitation, spiroperidol, benperidol, triflu Y, calcitonin gene-related peptide (CGRP), enkaphalins and peridol, pimozide, fluiphenazine, droperidol, haloperidol. related opioid peptides such as Met5-enkaphalin, Leu5-en thiothixene, trifluperazine, moperone, prochlorperazine, kephalin, Cl-, 3- and Y-endorphin, C.- and B-neo-endorphin, molindone, thioridazine, clozapine, chlorpromazine, pro and dynorphin, as well as the neurotransmitters GABA mazine, Sulpiride, clebopride, chlorpromazine, spiperone, (y-aminobutyric acid), glycine, glutamate, acetylcholine, flupenthixol, and combinations thereof. US 2013/0096050 A1 Apr. 18, 2013

0733. In some embodiments, the pharmaceutical compo VIP or a VIP agonist, i.e., the androgenic agent is adminis sitions of the invention comprise an active agent that is a tered as a pretreatment. In some embodiments, such a method non-androgenic steroid including progestins and estrogens. involves administration of an androgenic agent, e.g., via oral Suitable estrogens include synthetic and natural estrogens or topical (Vulvar and/or vaginal) administration, followed by such as: estradiol (i.e., 1,3,5-estratriene-3,173-diol, or “17B topical (again, Vulvar and/or vaginal) administration of VIP estradiol) and its esters, including estradiol benzoate, Valer or a VIP agonist. ate, cypionate, heptanoate, decanoate, acetate and diacetate; 17C-estradiol; ethinylestradiol (i.e., 17O-ethinylestradiol) 0737. In some embodiments, the formulations herein are and esters and ethers thereof, including ethinylestradiol 3-ac administered by topical application to the Vulvar region and/ etate and ethinylestradiol 3-benzoate; estriol and estriol suc or by vaginal drug administration. These pharmaceutical for cinate; polyestrol phosphate; estrone and its esters and deriva mulations may typically contain one or more pharmaceuti tives, including estrone acetate, estrone Sulfate, and cally acceptable carriers Suited to the particular type of piperazine estrone sulfate; quinestrol; mestranol; and conju formulation, i.e., gel, ointment, Suppository, or the like. The gated equine estrogens. Suitable progestins include acetox vehicles are comprised of materials of naturally occurring or ypregnenolone, allylestrenol, anagestone acetate, chlormadi synthetic origin that do not adversely affect the active agent or none acetate, cyproterone, cyproterone acetate, desogestrel, other components of the formulation. Suitable carriers for use dihydrogesterone, dimethisterone, ethisterone (17C.-ethinylt herein include water, silicone, waxes, petroleum jelly, poly estosterone), ethynodiol diacetate, fluorogestone acetate, ethylene glycol, propylene glycol, liposomes, Sugars Such as gestadene, hydroxyprogesterone, hydroxyprogesterone acetate, hydroxyprogesterone caproate, hydroxymethyl mannitol and lactose, and a variety of other materials, again progesterone, hydroxymethylprogesterone acetate, 3-ke depending, on the specific type of formulation used. As todesogestrel, levonorgestrel, lynestrenol, medrogestone, described in Section IV, infra, dosage forms used for admin medroxyprogesterone acetate, megestrol, megestrol acetate, istration to the Vulvar region and/or vagina may be used to melengestrol acetate, norethindrone, norethindrone acetate, deliver drug on an as-needed, on-demand basis, and/or norethisterone, norethisterone acetate, norethynodrel, norg throughout an extended, Sustained release profile. estimate, norgestrel, norgestrienone, normethisterone, and 0738. The pharmaceutical compositions may also include progesterone. It is generally desirable to co-administer a a chemical compound to enhance permeation of the active progestin along with an estrogen so that the estrogen is not agent through the mucosal tissue, i.e., a “permeation “unopposed. As is well known in the art, estrogen-based enhancer.” Suitable permeation enhancers include those gen therapies are known to increase the risk of endometrial hyper erally useful in conjunction with topical, transdermal or trans plasia and cancer, as well as the risk of breast cancer, in mucosal drug delivery. Examples of Suitable permeation treated individuals. Co-administration of estrogenic agents enhancers include the following: Sulfoxides Such as dimeth with a progestin has been found to decrease the aforemen ylsulfoxide (DMSO) and decylmethylsulfoxide (C10MSO); tioned risks. ethers such as diethylene glycol monoethyl ether (available 0734 The pharmaceutical compositions of the present commercially as TRANSCUTOL(R) (Gattefosse S.A., Saint invention may also include one or more chemotherapeutic Priest, France) and diethylene glycol monomethyl ether; sur agents. Suitable chemotherapeutic agents include, but are not factants such as Sodium laurate, Sodium lauryl Sulfate, cetyl limited to, platinum coordination compounds, topoisomerase trimethylammonium bromide, benzalkonium chloride, inhibitors, antibiotics, antimitotic alkaloids and difluoro Poloxamer (231, 182, 184), TWEENR (20, 40, 60, 80) (ICI nucleosides. Chemicals, Bridgewater, N.J.), and lecithin (U.S. Pat. No. 0735. In one embodiment of the present invention, the 4,783.450); the 1-substituted azacycloheptan-2-ones, par chemotherapeutic agent is a platinum coordination com ticularly 1-n-dodecylcyclaza-cycloheptan-2-one (available pound. The term “platinum coordination compound” refers to under the trademark AZONER) (Durham Pharmaceuticals, any tumor cell growth inhibiting platinum coordination com LLC, Durham, N.C.); see U.S. Pat. Nos. 3,989,816, 4,316, pound that provides the platinum in the form of an ion. Suit 893, 4,405,616 and 4.557,934); alcohols such as ethanol, able platinum coordination compounds include, but are not propanol, octanol, decanol, benzyl alcohol, and the like; fatty limited to, cis-diamminediaquoplatinum (II)-ion; chloro (di acids such as lauric acid, oleic acid and Valeric acid; fatty acid ethylenetriamine)-platinum (II) chloride; dichloro (ethylene esters such as isopropyl myristate, isopropyl palmitate, meth diamine)-platinum (II): diammine (1,1-cyclobutanedicar ylpropionate, and ethyl oleate; polyols and esters thereofsuch boxylato) platinum (II) (carboplatin); spiroplatin: iproplatin: as propylene glycol, ethylene glycol, glycerol, butanediol. diammine (2-ethylmalonato)-platinum (II): ethylenedi polyethylene glycol, and polyethylene glycol monolaurate aminemalonatoplatinum (II); aqua (1,2-diaminodyclohex (PEGML; see, e.g., U.S. Pat. No. 4,568.343): amides and ane)-sulfatoplatinum (II); (1,2-diaminocyclohexane) mal other nitrogenous compounds such as urea, dimethylaceta onatoplatinum (II): (4-caroxyphthalato) (1.2- mide (DMA), dimethylformamide (DMF), 2-pyrrolidone, diaminocyclohexane) platinum (II): (1.2- 1-methyl-2-pyrrolidone, ethanolamine, diethanolamine and diaminocyclohexane)-(isocitrato) platinum (II); (1.2- triethanolamine; terpenes; alkanones; and organic acids, par diaminocyclohexane) cis (pyruvato) platinum (II); (1.2- ticularly salicylic acid and salicylates, citric acid and Succinic diaminocyclohexane) oxalatoplatinum (II); ormaplatin; and acid. Mixtures of two or more enhancers may also be used. tetraplatin 0739. In some embodiments, the pharmaceutical compo 0736. In some embodiments, the secretin analog and the sitions may include an enzyme inhibitor, i.e., a compound additional active agent or agents may be incorporated into a effective to inhibit enzymes present in the vagina or vulvar single formulation, or they may be administered separately, area that could degrade or metabolize the active agent. That is, either simultaneously or sequentially. In one embodiment, an inhibitors of enzymes that decrease or eliminate the activity androgenic agent is administered prior to administration of of the active agent may be included in the formulation so as to US 2013/0096050 A1 Apr. 18, 2013

effectively inhibit the action of those enzymes. Such com effective amount of active agent upon administration of a pounds include, for example, fatty acids, fatty acid esters, and selected Volume of composition. NAD inhibitors. 0744. The subject can be any animal, including but not 0740. In some embodiments, the pharmaceutical compo necessarily limited to mammals such as a human, mouse, rat, sition may be in the form of an ointment, cream, emulsion, hamster, guinea pig, rabbit, cat, dog, monkey, cow, horse, pig, lotion, gel, Solid, Solution, Suspension, foam or liposomal and the like. In some embodiments, the Subject is a human. formulation. Alternatively, the formulations may be con 0745. According to some embodiments of the invention, tained within avaginal ring (e.g., as disclosed in U.S. Pat. No. the formulation may be supplied as part of a kit. The kit 5,188,835 to Lindskogetal. assigned to Kabi Pharmacia AB), comprise comprising an analog, wherein the analog com or within a tampon, Suppository, sponge, pillow, puff, or prises an O-amino acid and at least one B-amino acid. In osmotic pump system; these platforms are useful solely for another embodiment, the kit comprises a pharmaceutically vaginal delivery. Ointments are semisolid preparations that acceptable salt of an analog with a rehydration mixture. In are typically based on petrolatum or other petroleum deriva another embodiment, the pharmaceutically acceptable salt of tives. The specific ointment base to be used, as will be appre an analog are in one container while the rehydration mixture ciated by those skilled in the art, is one that will provide for is in a second container. The rehydration mixture may be optimum drug delivery. As with other carriers or vehicles, an supplied in dry form, to which water or other liquid solvent ointment base should be inert, stable, non irritating and non may be added to form a Suspension or solution prior to admin sensitizing. As explained in Remington. The Science and istration. Rehydration mixtures are mixtures designed to Practice of Pharmacy, supra, at pages 1034–1038, ointment solubilize a lyophilized, insoluble salt of the invention prior to bases may be grouped in four classes: oleaginous bases; administration of the composition to a subject takes at least emulsifiable bases; emulsion bases; and water-soluble bases. one dose of a purgative. In another embodiment, the kitcom Oleaginous ointment bases include, for example, vegetable prises a pharmaceutically acceptable salt in orally available oils, fats obtained from animals, and semisolid hydrocarbons pill form. obtained from petroleum. Emulsifiable ointment bases, also 0746 The kit may contain two or more containers, packs, known as absorbent ointment bases, contain little or no water or dispensers together with instructions for preparation and and include, for example, hydroxyStearin Sulfate, anhydrous administration. In some embodiments, the kit comprises at lanolin and hydrophilic petrolatum. Emulsion ointment bases least one container comprising the pharmaceutical composi are either water-in-oil (W/O) emulsions or oil-in-water tion or compositions described herein and a second container (O/W) emulsions, and include, for example, cetyl alcohol, comprising a means for delivery of the compositions such as glyceryl monostearate, lanolin and Stearic acid. Suitable a syringe. In some embodiments, the kit comprises a compo water-soluble ointment bases are prepared from polyethylene sition comprising an analog in Solution or lyophilized or dried glycols of varying molecular weight; again, reference may be and accompanied by a rehydration mixture. In some embodi had to Remington. The Science and Practice of Pharmacy for ments, the analog and rehydration mixture may be in one or further information. more additional containers. 0741. In one aspect of the invention, a method is provided 0747 The compositions included in the kit may be sup for treating sexual dysfunction in a female individual com plied in containers of any sort such that the shelf-life of the prising administering to the vagina and/or Vulvar area a phar different components are preserved, and are not adsorbed or maceutical formulation comprising a secretin family analog. altered by the materials of the container. For example, suit In some embodiments, the secretin family analog is a vasodi able containers include simple bottles that may be fabricated lator, with vasodilators selected from the group consisting of from glass, organic polymers, such as polycarbonate, poly VIP and vasoactive intestinal polypeptide analogs and com styrene, polypropylene, polyethylene, ceramic, metal or any binations of any of the foregoing. Any number of drug deliv other material typically employed to hold reagents or food; ery platforms may be used, e.g., Suppositories, ointments, envelopes, that may consist of foil-lined interiors, such as creams, gels, solutions and the like. Also, one or more addi aluminum or an alloy. Other containers include test tubes, tional types of drugs, i.e., pharmacologically active agents vials, flasks, and Syringes. The containers may have two com may be incorporated into the pharmaceutical formulations. In partments that are separated by a readily removable mem other aspects of the invention, vaginal administration of a brane that upon removal permits the components of the com vasoactive agent as just described is used to improve vaginal positions to mix. Removable membranes may be glass, muscle tone and tissue health, to enhance vaginal lubrication, plastic, rubber, or other inert material. or to minimize collagen misdeposition resulting from 0748 Kits may also be supplied with instructional mate hypoxia as well as the associated lack of elasticity resulting rials. Instructions may be printed on paper or other Substrates, from the collagen misdeposition. and/or may be supplied as an electronic-readable medium, 0742. In another embodiment of the invention, a method is such as a floppy disc, CD-ROM, DVD-ROM, Zip disc, vid provided for improving memory by administering a secretin eotape, audio tape, or other readable memory storage device. family analog. Detailed instructions may not be physically associated with 0743. In another aspect of the invention, pharmaceutical the kit; instead, a user may be directed to an internet web site compositions and dosage forms are provided for carrying out specified by the manufacturer or distributor of the kit, or the aforementioned methods. The compositions and dosage Supplied as electronic mail. forms contain a vasoactive agent as described above, a phar 0749. In another embodiment, a packaged kit is provided maceutically acceptable vehicle, and, optionally, one or more that contains the pharmaceutical formulation to be adminis additional pharmacologically active agents. The formulations tered, i.e., a pharmaceutical formulation containing VIP ana contain a therapeutically effective amount of the active agent, log or a for enhancing female sexual desire and responsive or a therapeutically effective concentration of the active ness, a container (e.g., a vial, a bottle, a pouch, an envelope, a agent, i.e., a concentration that provides a therapeutically can, a tube, an atomizer, an aerosol can, etc.), optionally US 2013/0096050 A1 Apr. 18, 2013 sealed, for housing the formulation during storage and prior to compositions comprising a secretin family analog for treat to use, and instructions for carrying out drug administration in ment or prevention of chronic obstructive pulmonary disease, a manner effective to enhance sexual desire and responsive pulmonary hypertension, primary arterial hypertension, pull ness. The instructions will typically be written instructions on monary hypertension associated to post-ventricular septal a package insert, a label, and/or on other components of the defect, idiopathic pulmonary fibrosis, idiopathic pulmonary kit. arterial hypertension, CREST syndrome—Calcinosis: 0750 Depending on the type of formulation and the Raynaud's disease; loss of muscle control of the Esophagus; intended mode of administration, the kit may also include a Sclerodactyly; Telangiectasia, Acute respiratory distress, device for administering the formulation (e.g., a transdermal congestive heart failure, chronic obstructed pulmonary disor delivery device). The administration device may be a dropper, der, asthma, chronic obstructive pulmonary disease, sarcoi a Swab, a stick, or the nozzle or outlet of an atomizer or dosis, Small cell lung carcinoma, autoimmune disease, aerosol can. The formulation may be any suitable formulation inflammatory disease, sepsis, Hirschsprung's Disease, sexual as described herein. For example, the formulation may be an dysfunction, erectile dysfunction, Parkinson's disease, oral dosage form containing a unit dosage of the active agent, Alzheimer's disease, circadian rhythm dysfunction, pain, or a gel or ointment contained within a tube. The kit may colorectal cancer, hepatocellular cancer, elevated blood pres contain multiple formulations of different dosages of the Sure levels, elevated blood glucose levels, hyperglycemia, same agent. The kit may also contain multiple formulations of diabetes, insulin resistance, metabolic acidosis, obesity, Type different active agents. I diabetes, Type II diabetes Multiple Sclerosis, osteoporosis, 0751. The present kits will also typically include means Sjogren's syndrome, pancreatitis, uveoretinitis, osteoporosis, for packaging the individual kit components, i.e., the phar female sexual dysfunction in a Subject in need thereof. maceutical dosage forms, the administration device (if 0753. The present invention relates to inhibiting secretion included), and the written instructions for use. Such packag of TNF-C. in a Subject comprising administering a composi ing means may take the form of a cardboard or paper box, a tion comprising an analog to a Subject wherein said analog plastic or foil pouch, etc. comprises an O-amino acid and at least one B-amino acid. In 0752. The invention relates to the use of an analog in the Some embodiments the analog is a secretin family analog. In preparation of a medicament for treating or preventing Some embodiments the analog is a VIP analog. chronic obstructive pulmonary disease, pulmonary hyperten The present invention relates to inhibiting binding of VIP to a Sion, primary arterial hypertension, pulmonary hypertension VIP receptor in a Subject comprising administering a compo associated to post-ventricular septal defect, idiopathic pull sition comprising an analog to a subject, wherein said analog monary fibrosis, idiopathic pulmonary arterial hypertension, comprises an O-amino acid and at least one B-amino acid. In CREST syndrome—Calcinosis; Raynaud's disease; loss of Some embodiments the analog is a secretin family analog. In muscle control of the Esophagus; Sclerodactyly; Telangiecta Some embodiments the analog is a VIP analog. sia, Acute respiratory distress, congestive heart failure, The present invention relates to inhibiting biological effect of chronic obstructed pulmonary disorder, asthma, chronic GHRH in a subject comprising administering a composition obstructive pulmonary disease, sarcoidosis, Small cell lung comprising an analog to a subject, wherein said analog com carcinoma, autoimmune disease, inflammatory disease, sep prises an O-amino acid and at least one B-amino acid. In some sis, Hirschsprung's Disease, sexual dysfunction, erectile dys embodiments the analog is a secretin family analog. In some function, Parkinson's disease, Alzheimer's disease, circadian embodiments the analog is a VIP analog. rhythm dysfunction, pain, colorectal cancer, hepatocellular The present invention relates to inhibiting chemotaxis of T cancer, elevated blood pressure levels, elevated blood glucose cells in a subject comprising administering a composition levels, hyperglycemia, diabetes, insulin resistance, metabolic comprising an analog to a subject, wherein said analog com acidosis, obesity, Type I diabetes, Type H diabetes Multiple prises an O-amino acid and at least one B-amino acid. In some Sclerosis, osteoporosis, Sjogren's syndrome, pancreatitis, embodiments the analog is a secretin family analog. In some uVeoretinitis, osteoporosis, female sexual dysfunction due to embodiments the analog is a VIP analog. administration of a medication that causes onset of or exac The present invention relates to inhibiting expression of LPS erbates Symptoms of pulmonary hypertension, primary arte in a subject comprising administering a composition com rial hypertension, pulmonary hypertension associated to prising an analog to a subject, wherein said analog comprises post-ventricular septal defect, idiopathic pulmonary fibrosis, an O-amino acid and at least one B-amino acid. In some idiopathic pulmonary arterial hypertension, CREST syn embodiments the analog is a secretin family analog. In some drome—Calcinosis; Raynaud's disease; loss of muscle con embodiments the analog is a VIP analog. trol of the Esophagus; Sclerodactyly; Telangiectasia, Acute The present invention relates to modulating the amount of respiratory distress, congestive heart failure, chronic cyclic cAMP in a subject comprising administering a com obstructed pulmonary disorder, asthma, chronic obstructive position comprising an analog to a Subject, wherein said pulmonary disease, sarcoidosis, Small cell lung carcinoma, analog comprises an O-amino acid and at least one B-amino autoimmune disease, inflammatory disease, sepsis, Hirschs acid. In some embodiments the analog is a secretin family prung's Disease, sexual dysfunction, erectile dysfunction, analog. In some embodiments the analog is a VIP analog. Parkinson's disease, Alzheimer's disease, circadian rhythm The present invention relates to increasing the activity or dysfunction, pain, colorectal cancer, hepatocellular cancer, expression of adenylate cyclase in a Subject comprising elevated blood pressure levels, elevated blood glucose levels, administering a composition comprising an analog to a Sub hyperglycemia, diabetes, insulin resistance, metabolic acido ject, wherein said analog comprises an O-amino acid and at sis, obesity, Type I diabetes, Type II diabetes Multiple Scle least one B-amino acid. In some embodiments the analog is a rosis, osteoporosis, Sjogren's syndrome, pancreatitis, uveo secretin family analog. In some embodiments the analog is a retinitis, osteoporosis, female sexual dysfunction in a subject secretin family analog and a VPAC1 antagonist. In some in need thereof. In some embodiments, the invention relates embodiments the analog is a secretin family analog. and a US 2013/0096050 A1 Apr. 18, 2013 90

VPAC2 agonist. In some embodiments the analog is a VIP 0759. The present invention also relates measuring the analog. In some embodiments, the composition or pharma modulation of activity of a secretin receptor molecule by ceutical composition of the claimed invention comprises a measuring receptor activity comprising: VIP analog, wherein the VIP analog is a VIPR1 agonist, and 0760 a) contacting a human secretin family receptor with has substantially reduced selectivity or no selectivity for a secretin family analog, wherein the analog comprises an VIPR2 or PAC1 receptors. In some embodiments, the com C.-amino acid and at least one B-amino acid; position orpharmaceutical composition of the claimed inven 0761 b) measuring the association of the secretin family tion comprises a VIP analog, wherein the VIP analog is a analog to the secretin receptor in the presence and absence of PAC1 agonist, and has substantially reduced selectivity or no an unknown compound; and selectivity for VIPR2 or VIPR1 receptors. In some embodi 0762 c) comparing the rate of association of the secretin ments, the composition or pharmaceutical composition of the family analog to the human secretin receptor in the presence claimed invention comprises a VIP analog, wherein the VIP of an unknown compound to the rate of association of the analog is a VIPR2 agonist, and has substantially reduced secretin analog to the human secretin receptor in the absence selectivity or no selectivity for VIPR1 or PAC1 receptors. In of an unknown compound. Some embodiments, the composition orpharmaceutical com 0763 The present invention also relates identifying a position of the claimed invention comprises a VIP analog, modulator of activity of a secretin receptor molecule by mea wherein the VIP analog is a VIPR2 antagonist, but does not Suring receptor activity comprising: antagonize VIPR1 or PAC1 receptors. In some embodiments, 0764 a) contacting a human secretin family receptor with the composition or pharmaceutical composition of the a secretin family analog, wherein said analog comprises an claimed invention comprises a VIP analog, wherein the VIP analog is a VIPR1 antagonist, but does not antagonize VIPR2 C.-amino acid and at least one B-amino acid; or PAC1 receptors. In some embodiments, the composition or 0765 b) measuring the association of the secretin family pharmaceutical composition of the claimed invention com analog to the secretin receptor in the presence and absence of prises a VIP analog, wherein the VIP analog is a PAC1 antago an unknown compound; and nist, but does not antagonize VIPR2 or VIPR1 receptors. Any 0766 c) comparing the rate of association of the secretin of the above-mentioned selective agonist or antagonists may family analog to the human secretin receptor in the presence be used in any of the method claims provided herein. of an unknown compound to the rate of association of the 0754. The present invention relates to modulating the secretin analog to the human secretin receptor in the absence amount of PLD in the nervous system of a subject comprising of an unknown compound. administering a composition comprising an analog to a Sub 0767 The present invention also relates to a method of ject, wherein said analog comprises an O-amino acid and at measuring the modulation of activity of a human VIP receptor least one B-amino acid. In some embodiments the analog is a molecule by measuring receptor activity comprising: secretin family analog. In some embodiments the analog is a 0768 a) contacting a human VIP family receptor with a VIP analog. VIP analog, wherein the analog comprises an O-amino acid 0755. The present invention relates to modulating the and at least one B-amino acid; amount of antibody production of a B cell in a Subject com 0769 b) measuring the association of the VIP analog to the prising administering a composition comprising an analog to VIP receptor in the presence and absence of an unknown a Subject, wherein said analog comprises an O-amino acid and compound; and at least one B-amino acid. In some embodiments the analog is 0770 c) comparing the rate of association of the VIP ana a secretin family analog. In some embodiments the analog is log to the human VIP receptor in the presence of an unknown a VIP analog. compound to the rate of association of the VIP analog to the 0756. The present invention relates to modulating the human VIP receptor in the absence of an unknown com amount of antibody production of a B cell or a B cell hybri pound. doma cell in vitro comprising treating a culture containing B 0771. The present invention also relates identifying a cells or a hyVridoma with a composition comprising an ana modulator of activity of a VIP family receptor molecule by log to a subject, wherein said analog comprises an O-amino measuring receptor activity comprising: acid and at least one B-amino acid. In some embodiments the 0772 a) contacting a human VIP family receptor with a analog is a secretin family analog. In some embodiments the VIP analog, wherein said analog comprises an O-amino acid analog is a VIP analog. and at least one B-amino acid; 0757. The present invention relates to modulating the 0773 b) measuring the association of the VIP analog to the immune response of a Subject comprising administering a VIP receptor in the presence and absence of an unknown Subject with a composition comprising an analog to a subject, compound; and wherein said analog comprises an O-amino acid and at least 0774 c) comparing the rate of association of the VIP ana one B-amino acid. In some embodiments the analog is a log to the human VIP receptor in the presence of an unknown secretin family analog. In some embodiments the analog is a compound to the rate of association of the VIP analog to the VIP analog. human VIP receptor in the absence of an unknown com 0758. The present invention relates to modulating the acti pound. In some embodiments, the VIP family receptor is Vation of cystic fibrosis transmembrane conductance regula chosen from VIPR1, VIPR2, VPAC, VPAC, or PAC. tor (CFTR) in a Subject comprising administering a subject 0775. The present invention also relates identifying a with a composition comprising an analog to a Subject, modulator of activity of a VIP family receptor molecule by wherein said analog comprises an O-amino acid and at least measuring receptor activity comprising: one B-amino acid. In some embodiments the analog is a 0776 a) contacting a VIP family receptor with a VIP ana secretin family analog. In some embodiments the analog is a log in a known concentration, wherein said analog comprises VIP analog. an O-amino acid and at least one B-amino acid; US 2013/0096050 A1 Apr. 18, 2013

0777 b) measuring the binding affinity of the VIP analog function, Parkinson's disease, Alzheimer's disease, circadian to the VIP family receptor in the presence and absence of a rhythm dysfunction, pain, colorectal cancer, hepatocellular compound that binds to the VIP family receptor; and cancer, elevated blood pressure levels, hyperglycemia, diabe 0778 c) comparing the binding affinity of the VIP analog tes, insulin resistance, metabolic acidosis, obesity, Type I to the VIP receptor in the presence of a compound that binds diabetes, Type II diabetes Multiple Sclerosis, osteoporosis, to the VIP family receptor to the binding affinity of the VIP Sjogren's syndrome, pancreatitis, uveoretinitis, osteoporosis, analog to the VIP receptor in the absence of a compound that female sexual dysfunction in a Subject in need thereof. binds to the VIP family receptor. In some embodiments, the 0780. The present invention also relates to a method of VIP family receptor is chosen from VIPR1, VIPR2. VPAC, treating or preventing cancer in a subject in need thereof VPAC, or PAC. comprising administering a VIP analog to the Subject, 0779. The invention also relates to the use of an analog wherein said analog comprises an O-amino acid and at least with selectivity for VPAC1, PAC1, or VPAC2 in the prepara one B-amino acid and wherein said analog is a VPAC1, tion of a medicament for treating or preventing chronic VPAC2, or PAC1 receptor antagonist or agonist with obstructive pulmonary disease, pulmonary hypertension, pri increased selectivity for the VPAC1, VPAC2, or PAC1 recep mary arterial hypertension, pulmonary hypertension associ tor as compared to the other receptors. In some embodiments, ated to post-ventricular septal defect, idiopathic pulmonary the cancer is chosen from the following: non-Small cell lung fibrosis, idiopathic pulmonary arterial hypertension, CREST carcinoma, Small cell lung carcinoma, colorectal carcinoma, syndrome—Calcinosis; Raynaud's disease; loss of muscle breast carcinoma, gastric carcinoma, prostate carcinoma, control of the Esophagus; Sclerodactyly; Telangiectasia, liver carcinoma, ductal pancreatic carcinoma, bladder carci Acute respiratory distress, congestive heart failure, chronic noma, Non-Hodgkin’s lymphoma, maningioma, leiomyoma, obstructed pulmonary disorder, asthma, chronic obstructive endometrial carcinoma, pheochromocytoma, paragan pulmonary disease, sarcoidosis, Small cell lung carcinoma, glioma. The present invention also relates to a method of autoimmune disease, inflammatory disease, sepsis, Hirschs treating or preventing inflammatory disease comprising prung's Disease, sexual dysfunction, erectile dysfunction, administering a VIP analog to a Subject in need thereof, Parkinson's disease, Alzheimer's disease, circadian rhythm wherein said analog comprises an O-amino acid and at least dysfunction, pain, colorectal cancer, hepatocellular cancer, one B-amino acid and wherein said analog is a VPACl, elevated blood glucose levels, elevated blood pressure, hyper VPAC2, or PAC1 receptor antagonist or agonist with glycemia, diabetes, insulin resistance, metabolic acidosis, increased selectivity for the VPAC1, VPAC2, or PACT recep obesity, Type I diabetes, Type II diabetes Multiple Sclerosis, tor as compared to the other receptors. In some embodiments osteoporosis, Sjogren's syndrome, pancreatitis, uveoretinitis, the inflammatory disease is rheumatoid arthritis. In some osteoporosis, female sexual dysfunction due to administra embodiments, the VIP analog is administered at a therapeu tion of a medication that causes onset of or exacerbates Symp tically effective dose. toms of pulmonary hypertension, primary arterial hyperten Sion, pulmonary hypertension associated to post-ventricular 0781. The present invention also relates to a method of septal defect, idiopathic pulmonary fibrosis, idiopathic pull treating or preventing cancer in a subject in need thereof monary arterial hypertension, CREST syndrome—Calcino comprising administering a VIP analog to the Subject, sis; Raynaud's disease; loss of muscle control of the Esopha wherein said analog comprises an O-amino acid and at least gus; Sclerodactyly; Telangiectasia, Acute respiratory one B-amino acid and wherein said analog is a VPAC1 recep distress, congestive heart failure, chronic obstructed pulmo torantagonist with increased selectivity for the VPAC1 recep nary disorder, asthma, chronic obstructive pulmonary dis tor. The present invention also relates to a method of treating ease, sarcoidosis, Small cell lung carcinoma, autoimmune or preventing inflammatory disease comprising administer disease, inflammatory disease, sepsis, Hirschsprung's Dis ing a VIP analog to a subject in need thereof, wherein said ease, sexual dysfunction, erectile dysfunction, Parkinson's analog comprises an O-amino acid and at least one B-amino disease, Alzheimer's disease, circadian rhythm dysfunction, acid and wherein said analog is a VPAC1 receptor antagonist pain, colorectal cancer, hepatocellular cancer, elevated blood with increased selectivity for the VPAC1 receptor. In some pressure levels, elevated blood glucose levels, hyperglyce embodiments the inflammatory disease is rheumatoid arthri mia, diabetes, insulin resistance, metabolic acidosis, obesity, tis. In some embodiments, the VIP analog is administered at Type I diabetes, Type II diabetes Multiple Sclerosis, a therapeutically effective dose. osteoporosis, Sjogren's syndrome, pancreatitis, uveoretinitis, 0782. The present invention also relates to a method of osteoporosis, female sexual dysfunction in a subject in need treating or preventing Small cell lung carcinoma comprising thereof. In some embodiments, the invention relates to com administering a VIP analog to a Subject in need thereof, positions comprising a secretin family analog with selectivity wherein said analog comprises an O-amino acid and at least for VPAC1, PAC1, or VPAC2 for treatment or prevention of one B-amino acid and wherein said analog is a VPAC1, chronic obstructive pulmonary disease, pulmonary hyperten VPAC2, or PAC1 receptor antagonist or agonist with Sion, primary arterial hypertension, pulmonary hypertension increased selectivity for at least one VPAC1, VPAC2, or PAC1 associated to post-ventricular septal defect, idiopathic pull receptor. The present invention also relates to a method of monary fibrosis, idiopathic pulmonary arterial hypertension, treating or preventing inflammatory disease comprising CREST syndrome—Calcinosis; Raynaud's disease; loss of administering a VIP analog to a Subject in need thereof, muscle control of the Esophagus; Sclerodactyly; Telangiecta wherein said analog comprises an O-amino acid and at least sia, Acute respiratory distress, congestive heart failure, one B-amino acid and wherein said analog is a VPAC1, chronic obstructed pulmonary disorder, asthma, chronic VPAC2, or PAC1 receptor antagonist or agonist with obstructive pulmonary disease, sarcoidosis, Small cell lung increased selectivity for at least one of the following: VPAC1, carcinoma, autoimmune disease, inflammatory disease, sep VPAC2, or PAC1 receptors. In some embodiments, the VIP sis, Hirschsprung's Disease, sexual dysfunction, erectile dys analog is administered at a therapeutically effective dose. US 2013/0096050 A1 Apr. 18, 2013 92

0783 The present invention also relates to a method of thereof, wherein said analog comprises an O-amino acid and treating or preventing primary arterial hypertension (PAH) at least one B-amino acid and wherein said analog is a VPAC1 comprising administering a VIP analog to a Subject in need receptor antagonist or agonist with increased selectivity for thereof, wherein said analog comprises an O-amino acid and the VPAC1 receptor. The present invention relates to a at least one B-amino acid and wherein said analog is a VPAC1, method of treating or preventing COPD comprising admin VPAC2, or PAC1 receptor antagonist or agonist with istering a VIP analog to a subject in need thereof, wherein said increased selectivity for at least one VPAC1, VPAC2, or PAC1 analog comprises an O-amino acid and at least one B-amino receptor. The present invention relates to a method of treating acid and wherein said analog is a VPAC1 receptor antagonist or preventing inflammatory disease comprising administer or agonist with increased selectivity for the VPAC1 receptor. ing a VIP analog to a subject in need thereof, wherein said In some embodiments, the VIP analog is administered at a analog comprises an O-amino acid and at least one B-amino therapeutically effective dose via nebulizer or inhaler. acid and wherein said analog is a VPAC1, VPAC2, or PAC1 0791. The invention also relates to a method of preventing receptor antagonistoragonist with increased selectivity for at or inhibiting activation of alveolar macrophages comprising least one of the following: VPAC1, VPAC2, or PAC1 recep administering a VIP analog to a Subject, wherein said analog tors as compared to its selectivity for the other receptors. In comprises an O-amino acid and at least one B-amino acid and Some embodiments, the VIP analog is administered at a thera wherein said analog is a VPAC1 receptor antagonist or ago peutically effective dose. nist with increased selectivity for the VPAC1 receptor. In 0784 The present invention also relates to a method of Some embodiments, the VIP analog is administered at a thera treating or preventing inflammatory disease comprising peutically effective dose via nebulizer or inhaler. administering a VIP analog to a subject in need thereof, 0792. The present invention relates to a method of treating wherein said analog comprises an O-amino acid and at least or preventing chronic obstructive pulmonary disease (COPD) one B-amino acid and wherein said analog is a VPAC1 recep comprising administering a VIP analog to a Subject in need toragonist with increased selectivity for the VPAC1 receptor. thereof, wherein said analog comprises an O-amino acid and 0785. The present invention relates to a method of treating at least one B-amino acid and wherein said analog is a VPAC2 or preventing inflammatory disease comprising administer receptor agonist with increased selectivity for the VPAC2 ing a VIP analog to a subject in need thereof, wherein said receptor. The present invention relates to a method of treating analog comprises an O-amino acid and at least one B-amino or preventing COPD comprising administering a VIP analog acid and wherein said analog is a to a subject in need thereof, wherein said analog comprises an 0786 VPAC1 receptor agonist with increased selectivity C.-amino acid and at least one f3-amino acid and wherein said for the VPAC1 receptor. In some embodiments the inflamma analog is a VPAC2 receptoragonist with increased selectivity tory disease is rheumatoid arthritis. In some embodiments, for the VPAC2 receptor. In some embodiments, the VIP ana the VIP analog is administered at a therapeutically effective log is administered at a therapeutically effective dose via dose. nebulizer or inhaler. The invention relates to a method of 0787. The present invention also relates to a method of preventing or inhibiting activation of alveolar macrophages treating or preventing inflammatory disease comprising comprising administering a VIP analog to a Subject, wherein administering a VIP analog to a subject in need thereof, said analog comprises an O-amino acid and at least one wherein said analog comprises an O-amino acid and at least B-amino acid and wherein said analog is a VPAC2 receptor one B-amino acid and wherein said analog is a VPAC2 recep agonist with increased selectivity for the VPAC2 receptor. In toragonist with increased selectivity for the VPAC2 receptor. Some embodiments, the VIP analog is administered at a thera 0788. The present invention relates to a method of treating peutically effective dose via nebulizer or inhaler. or preventing inflammatory disease comprising administer 0793. The present invention also relates to methods of ing a VIP analog to a subject in need thereof, wherein said identifying a selective modulator of activity of a VIP family analog comprises an O-amino acid and at least one B-amino receptor molecule by measuring receptor activity compris acid and wherein said analog is a VPAC2 receptor agonist 1ng: with increased selectivity for the VPAC2 receptor. In some 0794 a) contacting a human VIP family receptor with a embodiments the inflammatory disease is rheumatoid arthri VIP analog, wherein said analog comprises an O-amino acid tis. In some embodiments, the VIP analog is administered at a therapeutically effective dose. and at least one B-amino acid; 0789. The present invention also relates to a method of 0795 b) measuring the association of the VIP analog to the treating or preventing chronic obstructive pulmonary disease, VIP receptor in the presence and absence of an unknown pulmonary hypertension, primary arterial hypertension, pull compound; and monary hypertension associated to post-ventricular septal 0796 c) comparing the rate of association of the VIP ana defect, idiopathic pulmonary fibrosis, idiopathic pulmonary log to the human VIP receptor in the presence of an unknown arterial hypertension comprising administering a VIP analog compound to the rate of association of the VIP analog to the with selectivity for VPAC2 to a subject in need thereof, human VIP receptor in the absence of an unknown com wherein said analog comprises an O-amino acid and at least pound. one B-amino acid and wherein said analog is a VPAC2 recep 0797 The present invention also relates to methods of tor agonist with increased selectivity to VPAC2 receptor. In identifying a selective modulator of activity of a VIP family all methods of treatment or prevention, analogs of the present receptor molecule by measuring receptor activity compris invention may be administered in therapeutically effective ing: doses. 0798 a) contacting a first and a second VIP family recep 0790. The present invention relates to a method of treating tor with a VIP analog in a known concentration, wherein said or preventing chronic obstructive pulmonary disease (COPD) analog comprises an O-amino acid and at least one B-amino comprising administering a VIP analog to a Subject in need acid; US 2013/0096050 A1 Apr. 18, 2013

0799 b) measuring the rate association of the VIP analog but are not limited to, platinum coordination compounds, to the first and second VIP receptors in the presence and topoisomerase inhibitors, antibiotics, antimitotic alkaloids absence of an unknown compound; and and difluoronucleosides. 0800 c) comparing the rate of association of the VIP ana 0808. The present invention also relates to a method of log to the first VIP receptor in the presence of an unknown treating or preventing cancer cell growth in a subject in need compound to the rate of association of the VIP analog to the thereof comprising the steps of administering a VIP analog second VIP receptor in the absence of an unknown com or functional fragment thereof the subject, wherein the VIP pound. analog or functional fragment comprises at least one B-amino 0801. The present invention also relates to methods of acid, wherein the VIP analog or functional fragment thereof is identifying a selective modulator of activity of a VIP family selective or has increased selectivity to VPAC; wherein the receptor molecule by measuring receptor activity compris VIP analog is a VPAC antagonist; and wherein the cancer ing: cell is a bladder, breast, colon, liver, lung, prostate, stomach, thyroid or uterine cancer cell. The present invention relates to 0802 a) contacting a first and a second VIP family recep a method of treating or preventing cancer in a Subject in need tor with a VIP analog in a known concentration, wherein said thereof comprising the steps of administering a VIP analog analog comprises an O-amino acid and at least one famino or functional fragment thereof the subject, wherein the VIP acid; analog or functional fragment comprises at least one B-amino 0803 b) measuring the binding affinity of the VIP analog acid, wherein the VIP analog or functional fragment thereof is to the first and second VIP receptors in the presence and selective or has increased selectivity to VPAC1; wherein the absence of an unknown compound; and VIP analog is a VPAC antagonist; and wherein the cancer is 0804 c) comparing the binding affinity of the VIP analog a bladder, breast, colon, liver, lung, prostate, stomach, thy to the first VIP receptor in the presence of an unknown com roid, hepatocellular, or uterine cancer. In some embodiments, pound to the binding affinity of the VIP analog to the second the cancer has been diagnosed as being malignant. In some VIP receptor in the absence of an unknown compound. In embodiments, the Subject may have an increased risk or some embodiments, the VIP family receptor is chosen from increased Susceptibility to contracting a malignant cancer. VIPR1, VIPR2, VPAC, VPAC, or PAC. 0809. The present invention also relates to a method of 0805. The present invention also relates to methods of treating or preventing cancer cell growth in a subject in need inhibiting the immune response against a transplanted organ thereof comprising the steps of administering a VIP analog in a subject, wherein the subject is an organ donor recipient. or functional fragment thereof the subject, wherein the VIP in some embodiments, the Subject is a mammal. In some analog or functional fragment comprises at least one B-amino embodiments, the Subject is a human. In some embodiments, acid, wherein the VIP analog or functional fragment thereof is the Subject is a human experiencing organ rejection after selective or has increased selectivity to VPAC; wherein the transplantation. VIP analog is a VPAC, antagonist; and wherein the cancer 0806. In another embodiment, the present invention also cell is a lung, breast, stomach cancer cell. In some embodi relates to a method for inhibiting the growth of a tumor cell, ments the cancer cell is derived from a stomach leiomyoma. the method comprising: contacting the tumor cell with an 0810. The present invention also relates to a method of effective amount of a secretin family analog, wherein the treating or preventing cancer in a subject in need thereof secretin family analog or functional fragment thereof com comprising the steps of administering a VIP analog or func prises at least one f-amino acid. In some embodiments, the tional fragment thereofthe subject, wherein the VIP analog or method comprises contacting the tumor cell with an effective functional fragment comprises at least one B-amino acid, amount of a combination of a chemotherapeutic agent and a wherein the VIP analog or functional fragment thereof is secretin family analog. In some embodiments, the secretin selective or has increased selectivity to VPAC; wherein the analog is a VIP analog. Suitable chemotherapeutic agents VIP analog is a VPAC, antagonist; and wherein the cancer a include, but are not limited to, platinum coordination com lung, breast, stomach, or heptocellular cancer. In some pounds, topoisomerase inhibitors, antibiotics, antimitotic embodiments, the cancer has been diagnosed as being malig alkaloids and difluoronucleosides. In some embodiments, the nant. In some embodiments, the Subject may have an secretin analog is a VPAC1 antagonist with selectivity for increased risk or increased Susceptibility to contracting a VPAC1. In some embodiments, the tumor cell is a tumor cell malignant cancer. derived from a breast cancer, a lung cancer, a colon cancer, a 0811. The present invention also relates to a method of prostate cancer, or a pancreatic cancer. treating or preventing airway constriction comprising admin 0807. In another embodiment, the present invention also istering a VIP analog or functional fragment thereof to a relates to a method of inhibiting the growth of a tumor cell in Subject in need thereof, wherein said analog comprises an a mammalian Subject in need thereof, the method comprising: C.-amino acid and at least one B-amino acid and wherein said administering to the Subject an effective amount of a secretin analog is a VPAC2 receptor agonist. In some embodiments, family analog or functional fragment thereof, wherein the the VIP analog or functional fragment thereof has increased secretin family analog or functional fragment thereof com selectivity to VPAC2 receptor. In all methods of treatment or prises at least one B-amino acid. In some embodiments, the prevention, analogs of the present invention may be admin method comprises administering to the Subject an effective istered in therapeutically effective doses. amount of a combination of a chemotherapeutic agent and a 0812. The present invention also relates to a method of secretin family analog. In some embodiments, the secretin treating or preventing asthma, comprising administering a analog is a VIP analog. In some embodiments, the tumor cell VIP analog or functional fragment thereof to a subject in need is a tumor cell derived from a breast cancer, a lung cancer, a thereof, wherein said analog comprises an O-amino acid and colon cancer, a prostate cancer, hepatic cancer (HCC) or a at least one B-amino acid and wherein said analog is a VPAC2 pancreatic cancer. Suitable chemotherapeutic agents include, receptor agonist. In some embodiments, the VIP analog or US 2013/0096050 A1 Apr. 18, 2013 94 functional fragment thereof has increased selectivity to neuroblastoma, adrenal, pituitary, catecholamine-secreting VPAC2 receptor. In all methods of treatment or prevention, tumors, pheochromocytomas, paragangliomas, endometrial analogs of the present invention may be administered in cancers, or breast cancer. In some embodiments, the cancer therapeutically effective doses. In some embodiments, the has been diagnosed as being malignant. In some embodi ments, the Subject may have an increased risk or increased VIP analog or functional fragment thereof may be adminis Susceptibility to contracting a malignant cancer. tered via an inhaler or nebulizer. 0814. The invention also relates to methods of treating or 0813 The present invention also relates to a method of preventing the aforementioned diseases using the analogs of treating or preventing cancer cell growth in a subject in need the present invention. Any analog described in the present thereof comprising the steps of administering a VIP analog invention may or may not have preferred selectivity of one of or functional fragment thereof the subject, wherein the VIP its receptors versus another. analog or functional fragment comprises at least one B-amino 0815. The invention relates to analogs based upon the acid, wherein the VIP analog or functional fragment thereof is polypeptide sequences identified in Tables 1, 2, 3, and 4. All selective or has increased selectivity to PAC; wherein the modified and unmodified variants of the sequences listed in VIP analog is a PAC antagonist; and wherein the cancer cell Table 4 are contemplated as being part of the invention. For is a nerve cell, adrenal cell, pituitary cell, or breast cell. The instance, the sequence of Biotin-Bombesin is listed in Table 4 present invention also relates to a method of treating or pre as Biotin-EQRLGNQWAVGHLM-NH. Not only do ana venting cancer in a subject in need thereof comprising the logs of the claimed invention include biotinylated sequence steps of administering a VIP analog or functional fragment above with an amidated methionine, but the analogs of the thereof the subject, wherein the VIP analog or functional present invention also relate to the unmodified or modified fragment comprises at least one B-amino acid, wherein the polypeptide backbone EQRLGNQWAVGHLM as well as VIP analog or functional fragment thereof is selective or has functional fragments thereof. In some embodiments the increased selectivity to PACs; wherein the VIP analog is a polypeptide analog is derived from one of the following PAC antagonist; and wherein the cancer is a glioblastoma, amino acid sequences of Table 4: TABLE 4 Targets from which the Analogs are derived 1. Galanin neurokinin. A 3. neurokinin B 5. Osteogenic growth peptide Parathyroid hormone 7. Kallidin 8. T cell receptor peptide 9. PDGF 10. Amylin 11. Calcitonin 12. GHRH 13. Thymopoietin 14. Cecrop in 15. TRH 16. EPO 17. FGF 18. Stem Cell Factor 19. Gp120 2O. Gp160 21. CD4 22. IGF 23. IGF receptor 24. Insulin 25. GMCSF 26. GCSF 27. MCSF 28. Kentsin 29. LAP 30. Tuftsin 31. Prolactin 32. Angiotensin II 33. Angiotensin II receptor 34. Dynorphin 35. Calcitonin 36. Cholecystokinin 37. Pepstatin 38. Bestatin 39. Lieupeptin 4 O. Luteinizing hormone 41. Neurotensin 42. Motilin 43. TGF-alpha 44. TGF-beta 45. BMP-1 46. BMP-2 47. BMP-3 48. BMP-4. 49. BMP-5 50 BMP-7 51. BMP-8 52. BMP-9 53. Bombesin 54. Enterostatin 55. Glucagon 56, GLP-1 57. Beta-Endorphin 58. ACTH 59. Alpha-MSH 6O. Y-MSH 61. adrenal peptide E 62. alpha casein fragment 63. beta casomorphin 64. dermorphin 65. kyotorphin 66. metophamide 67. neuropeptide FF (NPFF) 68. melanocyte inhibiting factor 69. vasotocin 70. Protein kinase C 71. Amyloid 72. Amyloid fibrin 73. Calpain 74. Charybdotoxin 75. Apamin 76. Phospholipase A2 77. Phospholipase A2 receptor 78. ENaC-alpha 79. ENaC-beta 80. ENaC-gamma 81. IgG subunit 82. Endotoxin 83. ADNF 84. Adrenomedullin 85. Apelin 86. Ghrelin 87. Mastoparan (MCD peptides) US 2013/0096050 A1 Apr. 18, 2013 95

TABL H 4- Continued Targets from which the Analogs are derived 88. Melanin concentrating hormone 89. Nociceptin 90. Noci Statin 91. Orexin 92. Receptor activity modulating protein, 93. Urotensin 94. Glycoprotein IIb/IIIa inhibitors 95 cfBE3 Fal 96. Apo-lipoprotein A-I 97. IL-1 98. IL-2 99. IL-3 OO. IL-4 O1. IL-5 O2. IL-6 O3. IL-7 O4. IL-8 Os. IL-9 O6. IL-1 O O7. IL-12 O8. IL-15 O9. IL-18 1O. IL-22 11. IL-23 12. IL-24 13. IL-26 14. IL-27 15. IL-28 16... brain-derived neurotrophic factor 17. nerve growth factor (BDNF) 18. neurotrophin 3 19. Corticotropin releasing factor 20. MHC I bind protei 21. P- Selectin 22. LFA-1 23. LFA-3 24. EPGF 25. EPGF receptor 26. Oxytocin 27. Vasopress in 28. Defensin, alpha 1. 29. Neutrophil defensin 3 30. Neutrophil defensin 4 31. Defensin- 5 32. Defesin- 6 33. Beta-defensin. I 34. Beta-defensin-3 35. Beta defensin 103 36. Beta-defensin 107 37. Beta-defensin 110 38. Beta-defensin 136 39 RK-1 (MPCSCKKYCDPWEVIDGSCGLFNSKYIC CREK) 4 O. dermasept in S4 41. magainin 1 42. magainin 2 43. magainin. A 44. magainin B 45. magainin G 46. MSI-78 47. MSI-99 48. MSI-130 49. MSI-511 50. Myp3 O 51. Pexiganan 52. Laminin 53. YIGSR 54. Gastrin 55. Gastrin releasing peptide 56. GnRH 57. Secretin 58. Bradykinin 59. Substance P 60 RANTES 61. MCP-1 62. MIP-1alpha 63. MIP-1beta 64. PDWHF 65. CRF 66. Endothelin 67. Integrin 68. Neuropeptide Y 69. LHRH 70. Enkephilin 71. alpha-neo- endorphin, porcine 72. beta-neoendorphin 73. Ac-beta-endorphin, camel, bovine, ovine 74. Ac-beta-endorphin 1-27, camel, 75. Ac-beta-endorphin, human bovine, ovine 76. Ac-beta-endorphin 1-26, human 77. Ac-beta-endorphin 1-27, human 78. Ac-gamma-endorphin (Ac-beta 79. acetyl-alpha- endorphin ipotropin 61-77) 8O. alpha- endorphin (beta-lipotrop in 61 81. alpha-neo- endorphin analog 76) 82. alpha-neo- endorphin 1-7 83. {Arg-alpha-neoendorphin 1-8 84. beta-endorphin (beta-lipotropin 61 85. beta-endorphin 1-27, camel, bovine, 91), camel, bovine, ovine ovine 86. beta-endorphin, equine 87. beta-endorphin (beta-lipotropin 61-91) human 88. beta-endorphin (1-5) + (16-31), human 89. beta-endorphin 1-26, human 90. beta-endorphin 1-27, human 91. beta-endorphin 6-31, human 92. beta-endorphin 18-31, human 93. beta-endorphin, porcine 94. beta-endorphin, rat 95. beta-lipotrop in 1-10, porcine 96. beta-lipotropin 60-65 97. beta-lipotropin 61-64 98. beta-lipotropin 61-69 99. beta-lipotropin 88-91 2 OO ... biotinyl-beta-endorphin (biotinyl 2O1. biocytin-beta-endorphin, human bets - lipotropin 61-91 2O2. gamma-endorphin (beta-lipotropin 2O3. {DAla-alpha-neo-endorphin 1-2, amide 61-77) 204. {DAla-beta-lipotropin 61-69 205. {DAla}-gamma-endorphin 206. {Des-Tyr'}-beta-endorphin, human 2O7. {Des-Tyr'}-gamma-endorphin (beta lipotropin 62-77) 208. {Leu}-beta-endorphin, camel, 209. {Met, Lys-alpha-neo-endorphin 1-6 bovine, ovine 210. {Met, Lys - alpha-neo-endorphin 211. {Met, Lys, Arg'}-alpha-neo-endorphin 1-7 1-7