ch-A February 20, 2008 19:49 Char Count=

A

aa, amino acid. dent of the German Academy of Natural Scientists Leopoldina in Halle/S. In 1902, AA, antamanide. Abderhalden had joined → Emil Fischer’s Aad, α-aminoadipic acid. group and worked on protein hydrolysates and proteolytic enzymes which led, in 1904, β β -Aad, -aminoadipic acid. to Habilitation. Further scientific activities were mainly directed towards the chemistry AAP, antimicrobial animal peptides. of proteins and physiological chemistry of Aart, a designed Cys2-His2 → zinc finger metabolism [J. Gabathuler (Ed.), Emil Ab- protein (190 aa, Mr 21.4 kDa). It was de- derhalden, Sein Leben und Werk, Ribaux, St. signed and constructed based on the appli- Gallen, 1991]. cation of zinc-finger domains of predeter- mined specificity to bind a 22-base-pair du- Abrin, a highly toxic protein isolated and plex DNA. The aart protein was expressed crystallized from the red seeds of Abrus in E. coli as a C-terminal fusion to maltose- precatorius. It consists of an A-chain (Mr ∼ binding protein (MBP). The fusion protein 30 kDa) and a B-chain (Mr ∼35 kDa), joined contained a factor Xa protease cleavage site by disulfide bridges. The A-chain is a highly for the MBP tag. Aart complexed with its specific N-glucosidase acting as ribosome- DNA target was crystallized followed by X- inactivating protein (RIP), whereas the ray analysis. Aart binds its DNA target with B-chain is a glycoprotein responsible for picomolar affinity. The 1.96 Å structure of anchoring at the cell surface. One of the Aart was described in 2006 [B. Dreier et al., carbohydrate chains forms a bridge be- J. Biol. Chem. 2001, 276, 29466; J. W. Crotty tween two neighboring molecules, whereas et al., Acta Crystallogr. 2005, F61, 573; D. J. another sugar chain covers the surface of Segal et al., J. Mol. Biol. 2006, 363, 405]. the B-chain. A disulfide-cleaving system of the cell releases the A-chain, which enters AatRS, amino acyl tRNA synthetase. the cell by endocytosis. RIP cleaves a single Aβ, amyloid-β. adenine residue from the rRNA, resulting in inhibition of protein synthesis followed Ab, antibody. by cell death. Similar action and structure are possessed by → ricin. The A-chain A2bu, 2,4-diaminobutyric acid. coupled with a monoclonal antibody Abderhalden, Emil (1877–1950), profes- directed against a tumor antigen is used in sor of physiology (1908–1910) at Berlin, drug targeting [J. Y. Lin et al., J. Formosan of biochemistry (1911–1945) at Halle/S. Med. Assoc. 1969, 68, 32; J. Y. Lin et al., (Germany), and of physiological chemistry Nature 1970, 227, 292; A. J. Cumber et al., (1946/47) at Zurich (Switzerland). From Methods Enzymol. 1985, 112, 207; T. H. 1931–1950 Prof. Abderhalden was Presi- Tahirov et al., J. Mol. Biol. 1995, 250, 354].

Peptides from A to Z. Hans-Dieter Jakubke and Norbert Sewald Copyright C 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim ISBN: 978-3-527-31722-6

1 ch-A February 20, 2008 19:49 Char Count=

Abu 2

Abu, α-aminobutyric acid. further generations of abzymes capa- ble of catalyzing the ligation of longer, Abz, aminobenzoic acid. unprotected fragments, combined with Abzyme, catalytic antibody, a monoclonal a general strategy for the development antibody with catalytic activity. An antibody of sequence-specific abzyme ligases [R. raised against a transition-state analogue Hirschmann et al., Science 1994, 265, 234; of a particular reaction can catalyze that J. R. Jacobson, P.G. Schultz, Proc. Natl. reaction. The first abzyme to be generated Acad. Sci. USA 1994, 91, 5888; D. W. was capable of catalyzing the hydrolysis Smithrud et al., J. Am. Chem. Soc. 1997, of esters. Abzymes have been described 119, 278; S. N. Savinov et al., Bioorg. Med. that catalyze, e.g., acyl transfer, C–C bond Chem. Lett. 2003, 13, 1321]. cleavage, β-elimination, and C–C bond Ac, acetyl. formation. From X-ray analyses it could be concluded that antibodies bind peptides ACE, angiotensin-converting enzyme. of various length in elongated grooves ACE 2, angiotensin-converting enzyme 2. using hydrogen bonding, van der Waals forces, and ionic contacts for recognition. ACE inhibitors, pharmaceuticals for the Abzymes are also an interesting choice treatment of hypertension, congestive for → abzyme-catalyzed peptide synthesis heart failure, and myocardial infarction. [L. Pauling, Am. Sci. 1948, 36, 51; W. P. Different types of synthetic ACE inhibitor Jencks, Catalysis in Chemistry and Enzy- have been designed. Synthetic ACE in- mology, McGraw-Hill, New York, 1969;R. hibitors are grouped by their ligand for the → A. Lerner et al., Science 1991, 252, 659; active site of the angiotensin converting D. Hilvert et al. in: Bioorganic Chemistry: enzyme (ACE). The major representative → Peptides and Proteins, S. M. Hecht (Ed.), of this group is captopril bearing a → Oxford University Press, Oxford, 1998]. sulfhydryl moiety, whereas enalapril and lisinopril have a carboxyl moiety, and Abzyme-catalyzed synthesis, the applica- fosinopril a phosphorous group. The bene- tion of catalytic antibodies as catalysts ficial effects of this group of ACE inhibitors for formation of the peptide bond. If an in hypertension and heart failure result abzyme could bind a substrate already in primarily from suppression of the renin- the transition-state conformation, it might angiotensin-aldosterone system. Inhibition act as an enzyme catalyzing the reaction to of ACE causes a decrease in plasma an- which the transition-state conformation is giotensin II (→ angiotensins) level, which predisposed. Analogues of the transition leads to decreased vasopressor activity state were used as haptens to induce and to a small decrease in aldosterone abzymes (catalytic antibodies) with the secretion. However, these synthetic ACE correct arrangement of catalytic groups. inhibitors are known to have strong adverse At present, the main disadvantage of the side effects, such as cough, skin rashes, abzyme approach is the requirement of and angioedema. Attempts to use → a large number of abzyme catalysts to angiotensin-converting enzyme 2 and its accommodate the wide specificity pattern proteolysis product angiotensin-(1–7) for of amino acids in coupling reactions. the regulation of blood pressure are under However, these first interesting results in investigation. Naturally occurring → ACE this field provide an impetus for producing inhibitory peptides have been reported to ch-A February 20, 2008 19:49 Char Count=

3 Achatin

have potential as antihypertensive compo- L. Vercruysee et al., J. Agric. Food Chem. nents in functional foods or nutraceuticals. 2005, 53, 8106]. However, the development of ACE in- hibitors was greatly influenced by natural Acetaldehyde/chloranil test, a monitoring products, e.g., by special members of the method for the control of complete cou- → → bradykinin-potentiating peptides. The pling reaction in solid-phase peptide 9-peptide teprotide,

AchR 4

AchR, acetylcholine receptor. Actinohivin (AH), a sugar-binding anti- human immunodeficiency virus protein Acm, acetamidomethyl. produced by an actinomycete Longispora al- bida gen. nov, sp. nov. AH consists of 114 ACP, acyl carrier protein. aa and is composed of highly conserved ACTH, acronym of adrenocorticotropic hor- three-tandem repeats. Each repeat unit is mone, → corticotropin. built of 38 aa containing a Gln-Xaa-Trp mo- tif at the C-terminus. It has been reported Actin, a contractile protein occurring in that AH inhibits the infection of suscepti- many eukaryotic cell types. Actin and ble cells by various strains of T-lymphocyte → myosin are the major components (T)-tropic and macrophage (M)-tropic HIV of the muscle. Both proteins account types 1 and 2, and both T- and M-tropic for 60–70% and 20–25% of the total syncytium formation via AH binding to muscle protein, respectively. Actin and its the high-mannose-type saccharide chains filaments are the major components of the of HIV gp120. The three tandem-repeat cytoskeleton in eukaryotic cells. Besides structure of AH is essential for potent anti- thrombomyosin and → troponin, actin is syncytium formation activity and gp120- the major constituent of thin filaments. binding [H. Chiba et al., J. Antibiot. 2001, The fibrous F-actin forms the core of 54, 818; Biochem. Biophys. Res. Commun. the thin filament and is formed under 2004, 316, 203; A. Takahashi et al., Arch. physiological conditions by polymerization Biochem. Biophys. 2005, 437, 233]. of the globular G-actin (Mr ∼ 42 kDa; 375 aa). The regulation of the polymer- Actinomycins, peptide antibiotics pro- ization/depolymerization of F-actin is duced by various strains of Streptomyces. essential for cytokinesis, cell mobility, Actinomycins are orange-red bacteriostatic and the control of cell shape and polarity. and cytostatic, but highly toxic, chro- The monomeric G-actin consists of two mopeptides. The chromophore actinocin, domains, each of which is divided into 2-amino-4, 6-dimethyl-3-oxo -phenoxazine- two subdomains. G-actin normally binds 1,9-dicarboxylic acid, is linked to two one molecule of ATP, which is hydrolyzed five-membered peptide lactones by the during polymerization to F-actin, and amino groups of two threonine residues. the resulting ADP remains bound to the The various naturally occurring and F-actin monomer unit. ATP and ADP bind synthetic actinomycins differ mostly in in a cleft between the two domains. The the amino acid sequence of the lactone F-actin helix (diameter 100 Å) has 2.17 moieties. Actinomycin D is one of the actin monomers per left-handed helix turn well-known actinomycins with known (13 subunits in six turns) and a rise per 3D structure. Actinomycin D is a useful turn of 60 Å. The monomeric unit of each F antineoplastic agent that binds tightly to ds- actin is capable of binding a single myosin DNA, and in this manner strongly inhibits S 1 fragment [R. A. Milligan et al., Nature both transcription and DNA replication. It 1990, 348, 217; P. Sheterline, J. C. Sparrow, presumably interferes as an intercalating Protein Profiles 1994,1,1;P.Sheterline agent with the passage of RNA polymerase et al., Actin, Oxford University Press, New and DNA polymerase, respectively. Acti- York, 1998; J.-W. Chu, G. A. Voth, Proc. nomycin D is used as a cytostatic in the Natl. Acad. Sci. USA 2005, 102, 13111]. treatment of the rare types of cancer, e.g., ch-A February 20, 2008 19:49 Char Count=

5 Activity-dependent neurotrophic peptides (ADNP)

M. Bodanszky, in: The Peptides: Analysis, Thr D -Val Pro Sar MeVal Synthesis, Biology, Volume 1, E. Gross, J. O Meienhofer (Eds.), Academic Press, New ON York 1979, 105]. Thr D -Val Pro Sar MeVal Activins, members of the transforming O growth factor-β protein family, originally O NH Actinomycin D 2 discovered in the follicular fluid from ovaries and in leukemic cells. They stim- → Wilms’ carcinoma, chorion carcinoma, ulate the release of follitropin. Activin β → and Hodgkin’s disease [A. B. Mauger, A is a homodimer of the -chains of Topics Antibiot. Chem. 1980, 5, 223]. inhibin-A, whereas activin B consists of the β-chains of inhibin-A and inhibin-B.  Activin is involved in the regulation of a Active ester, R-CO-XR , an amino acid couple of biological events, ranging from or peptide ester bearing an electron-  early development to pituitary function. It withdrawing substituent XR that pro- motes the nucleophilic attack of the amino has numerous functions in both normal and neoplastic cells. Several different cells component during the formation of a peptide bond. The acylating power of an synthesize activin and have a specific binding site for this protein. It has been de- ester moiety increases with the ability of − scribed that the activin-binding protein in its leaving group XR to depart, which in → turn is related to the strength of the acid rat ovary is follistatin. Another activin- → HXR. A very large number of different binding protein in biological fluids is α -macroglobulin. cDNAs coding for an ac- types of active esters have been described, 2 tivin receptor were cloned in order to obtain but only some of these, e.g., thiophenyl-, more information on the cellular mech- pentafluorphenyl- and 4-nitrophenyl es- anisms of activin actions. The resulting ters, have been used much. New types cDNAs code for a receptor protein consist- of active ester are mechanistically based ing of 494 aa comprising a ligand-binding on intramolecular base catalysis. Efforts extracellular domain, a single membrane- to minimize racemization have led to spanning domain, and an intracellular studies of neighboring effects (anchimeric assistance) which led to the development kinase domain with predicted Ser/Thr of active esters capable of discriminating specificity. Recently, regulated production effectively between aminolysis and racem- of activin A and activin B throughout the ization first indicated by 8-quinolyl ester cycle of seminiferous epithelium in the rat and N-hydroxypiperidinyl ester. The same have been described [T. Nakamura et al., situation applies to other active esters of Science 1990, 247, 836; L. S. Mathews, W. high practical importance, such as deriva- W. Vale, Cell 1991, 65, 973; P. G. Knight tives of N-hydroxysuccinimide (HOSu), et al., J. Endocrinol. 1996, 148, 267; Y. 1-hydroxybenzotriazole ((HOBt), and Okuma et al., J. Endocrinol. 2006, 190, 331]. the 7-aza analogue of HOBt, commonly Activity-dependent neurotrophic peptides referred to as 1-hydroxy-7-azabenzotriazole (ADNP), peptides derived from the (HOAt; the correct name is 1-hydroxy- neuroprotective protein, named activity- 1,2,3-triazolo[5,4-b] pyridine) [H.-D. dependent neuroprotective factor (ADNF). Jakubke et al., Chem. Ber. 1967, 106, 2367; ADNF (Mr ∼ 14 kDa; pI 8.3) is a glia-derived ch-A February 20, 2008 19:49 Char Count=

Aculeacins 6

protein and is neuroprotective at femtomo- nitrosation at –10◦C. The azide is ex- lar concentrations. Besides ADNF, even tracted from the aqueous layer with ethyl the related peptide fragment ADNP-14, acetate, washed, dried and reacted with VLGGGSALLR10SIPA, protects neu- the amino component. The azide method rons from multiple neurotoxins. From is still important, especially for segment structure–activity studies it follows that condensations, because of its low ten- ADNP-9, SALLRSIPA, shows greater po- dency towards racemization [J. Meienhofer, tency and a broader effective concentration in: The Peptides: Analysis, Synthesis, Biol- range (10−16–10−13 M) compared with ogy, Volume 1, E. Gross, J. Meienhofer ADNF and ADNP-14 in preventing cell (Eds.), Academic Press, New York, 1979, death with tetrodotoxin treatment of cere- 197]. bral cortical cultures [D. E. Brenneman, I. Acyl enzyme, an intermediate in the Gozes, J. Clin. Invest. 1996, 97, 2299; D. catalytic mechanism of serine proteases, E. Brenneman et al., Pharmacol. Exp. Ther. such as trypsin and chymotrypsin. After 1998, 285, 619]. the serine protease has bound a peptide substrate to form the Michaelis complex, Aculeacins, antifungal peptides affecting Ser195 (in the case of chymotrypsin) glucan synthesis. Aculeacins A to G are nucleophilically attacks the peptide bond produced by Aspergillus aculeantus.The in the rate-determining step, forming a peptides A through D, F, and G show good transition-state complex, known as a tetra- in-vitro activity against C. albicans and hedral intermediate. The latter decomposes Saccharomyces cerevisiae, but reduced the to the acyl enzyme, an extremely unstable growth of only a few filamentous fungi [K. intermediate, that bears the acyl moiety Mizuno et al., J. Antibiot. 1977, 30, 297]. at the hydroxy group of Ser195. The acyl enzyme intermediate is deacylated by water Acyl azide method, one of the oldest cou- during proteolysis, or the attacking nucleo- pling methods in peptide synthesis, in- phile is an amino component in case of troduced by Theodor → Curtius in 1902. kinetically controlled → enzymatic peptide Starting compounds are amino acid or synthesis. peptide hydrazides (R-CO-NH-NH2), eas- ily accessible from the corresponding es- O-Acyl isopeptide method, an approach to ters by hydrazinolysis, which are trans- the efficient synthesis of peptides contain- formed into azides (R-CO-N3)byN- ing → difficult sequences via the O–N

O O

+ HNO2 1 NH NH R1 N NN R 2 - 2 H2O

Acyl hydrazide O

R1 N NN

O 2 O H 2N-R R1 NH R 2 1 - HN3 R N NN

Peptide Acyl azide ch-A February 20, 2008 19:49 Char Count=

7 Acyl halides

intramolecular acyl migration reaction of switch peptide have been coined. As there O-acyl isopeptides. Such intermediates is a protecting group at the Nα of the isopep- have also been termed → click peptides or tide bond, the O–N acyl migration can not → switch peptides. The sequence-specific only be triggered by acidolytic cleavage of formation of stable β-strands that aggre- the Nα-Boc group, but also, e.g., by the pho- gate and consequently prevent further de- tolysis of photolabile Nα-protecting groups. protection or acylation reactions in SPPS Such compounds will certainly facilitate the is a major problem in peptide synthesis. investigation of, e.g., β-sheet formation. Depending on the amino acid sequence Besides Aβ (1-42), other difficult sequences present in the target peptide, the syn- such as the Jung-Redemann 10-peptide thetic accessibility may be hampered or and 26-peptide, H-(VT)10NH2 and the 37- even rendered impossible. Such → diffi- peptide of the FEP28 WW-domain have cult sequences require special considera- been synthesized [Y. Sohma et al., Biopoly- tion when planning a synthesis. Besides the mers 2007, 88, 253; M. Mutter et al., Angew. introduction of → backbone amide protect- Chem. Int. Ed. 2004, 43, 4172; L. Carpino ing groups or serine/threonine derived → et al., Tetrahedron Lett. 2004, 45, 7519]. pseudo-prolines building blocks, the appli- cation of the O-acyl isopeptide method pro- O-Acylisourea, a reactive intermediate of → vides appropriate measures for obtaining the carbodiimide method. difficult sequences. It relies on an O–N- Acyl halides, derivatives of amino acids in intramolecular acyl migration at serine or which the hydroxy group in the carboxyl threonine residues in strategic positions. group is replaced by a halogen atom. Acyl During the peptide synthesis, a serine or halides are reactive compounds suitable α threonine residue protected at N is in- as acylating agents. First, Fmoc-protected corporated, involving the β-hydroxy func- amino acid chlorides have been used as sta- tionality and giving rise to a depsipeptide ble derivatives for rapid peptide coupling bond (O-acyl isopeptide). Such a single reaction without the danger of racemiza- isopeptide moiety prevents the undesired tion. However, their general application formation of secondary structures. The is somewhat limited, as not all Fmoc- method allowed, e.g., the synthesis of the protected amino acid derivatives are acces- Alzheimer’s disease-related → amyloid β sible. In contrast, Fmoc-protected amino peptide (1-42) [Aβ (1-42)]. The water soluble acid fluorides do not suffer from such lim- Aβ (1-42) isopeptide precursor with Gly25- itations. Further advantages of fluorides Ser26 replacement by the corresponding β- relative to the chlorides include their α depsipeptide undergoes, upon Ser26 N de- greater stability towards water, including protection, an O–N acyl migration forming moisture in the air, and their relative the target Aβ (1-42). Because of this prop- lack of conversion to the corresponding erty, the names → click peptide and → oxazolones on treatment with tertiary

PG O HO HN H O H O N N N O R H O R O-Acyl isopeptide method ch-A February 20, 2008 19:49 Char Count=

Acyltransfer 8

organic bases. The Fmoc-protected amino Trp-Gly-Thr-NH2, was elucidated. Insecta acid fluorides are suited both for solution contain up to three AKH peptides (iso- peptide synthesis and for SPPS [L. A. forms) as demonstrated by the other two Carpino et al., J. Org. Chem. 1986, 51, 3732; peptides produced by the African migratory L. A. Carpino et al., Acc. Chem. Res. 1996, locust: Locmi-AKH-II, pGlu-Leu-Asn-Phe- 29, 268; L. A. Carpino et al., Tetrahedron Ser-Ala-Gly-Trp-NN2, and Locmi-AKH-III, Lett. 1998, 39, 241]. pGlu-Leu-Asn-Phe-Thr-Pro-Trp-Trp-NH2. The mobilization of substrates for high- Acyltransfer, the transfer of an acyl group R- energetic phases is the major function CO- between two molecules in the course of AKH in insects. AKH are involved in of a reaction as takes place, for example, the regulation of the level of circulating in a serine protease-catalyzed cleavage of a metabolites such as lipids, carbohydrates peptide bond (→ acyl enzyme). and proline by activating phosphorylases or AD, Alzheimer’s disease. lipases in the fat body cells. However, AKH Ada, adamantyl. peptides play also a multifunctional role and exert pleiotropic actions. For example, Adaptins, accessory proteins thought to in certain insects (firebug, cricket) AKH bind the membrane-spanning receptors for show an effect on the locomotory activity, those specific proteins that the coated vesi- and are also involved in the immune cle clathrin sequester. response of locusts. Beside the members listed above, a huge number of AKHs Adhesion molecules, proteins responsible such as Phymo-AKH (from Phymateus for interactions between cells and their morbillosus), Emppe-AKH (from Empusa environment, especially, the extracellular pennata), Manto-CC (Mantophasmatodea), matrix and other cells. Several different and others (Psein-AKH, Grybi-AKH) are molecules act as cell adhesion receptors known. Recently, a novel member in a such as → integrins, intercellular adhesion water boatman (Heteroptera, Corixidae), molecules (ICAM), leukocyte LFA-1, Mac-1 named Corpu-AKH, and its bioanalogue and p150/95 molecules, the fibronectin re- inasaucerbug(Heteroptera, Naucoridae), ceptor complex (→ fibronectin), tenascin, code-name Anaim-AKH, have been de- and the position-specific (PS) antigens of scribed. Interestingly, a glycosylated AKH, Drosophila. denoted Carma-HrTH (hypertrehalosemic Adipokinetic hormones (AKH), peptide hor- hormone)-I, synthesized in the CC of the mones belonging to the → AKH/RPCH stick insect, is characterized by an unique peptide hormone family. As early in the modification. The hexose moiety is thought 1960s, it was observed that extracts of to be linked by C-glycosylation to the C-2 the corpus cardiacum (CC) from either atom of the indole ring of tryptophan. On the American cockroach or the migratory the other hand, Trifa-CC isolated of an (Locusta migratoria) and desert locust show extracts of CC from the protea beetle, Tri- metabolic effects such as elevation of chostetha fascicularis, is the first report of a the blood sugar trehalose or of the blood phosphorylated invertebrate neuropeptide lipids (adipokinetic or hyperlipemic effect). [J. V. Stone et al., Nature 1976, 263, 207; In 1976, the complete sequence of the L. Schoofs et al., Peptides 1997, 18, 145; locust’s AKH, today denoted as Locmi- M. J. Lee et al., Regul. Pept. 1997 69, 69; AKH-I, pGlu-Leu-Asn-Phe-Thr-Pro-Asn- G. Gade,¨ Annu. Rev. Entomol. 2004, 49, ch-A February 20, 2008 19:49 Char Count=

9 Adrenomedullin (AM)

93; G. Gade¨ et al., Biochem. Biophys. Res. Adrenomedullin (AM), YRQSMNNFQG10 Commun. 2005, 330, 598; G. Gade¨ et al., LRSFGCRFGT20CTVQKLAHQI30YQFTD Biochem. J. 2006, 393, 705; G. Gade¨ et al., KDKDN40VAPRSKISPQ50GYa (disulfide Peptides 2007, 28, 594]. bond: C16–C21), a vasoactive 52-peptide amide which is a member of the → Adiponectin, adipocyte complement-related calcitonin/calcitonin gene-related peptide protein of 30 kDa (ACRP30), adipoQ, family and shares 24% sequence homology adipose most abundant gene transcript with → calcitonin gene-related peptide 1(apM1), gelantin-binding protein of 28 (CGRP). AM was first discovered in human kDa (GBP28), an adipose-tissue-derived pheochromocytoma tissue in 1993, and protein with important effects in glucose later found in the normal adrenal medul- and lipid homeostasis. The molecular lae, kidneys, lungs, and blood vessels. AM structure of adiponectin is characterized has been reported to be synthesized and by an N-terminal collagen-like domain and secreted by various types of cell, such as vas- a C-terminal globular domain with simi- cular endothelial and smooth muscle cells, larities to the complement factor C1q. It cardiomyocytes, macrophages, fibroblasts, assembles into homotrimers, and higher- neurons, glial cells, and retinal pigment ep- order oligomeric structures resulting by ithelial cells. In humans, its gene is situated interactions between the collagen-like in a single locus on chromosome 11p15.4. domains. The production and/or secretion The amino acid sequence is highly con- of adiponectin is regulated by various served across species. The gene contains mechanisms; e.g., it is increased by both four exons separated by three introns and IGF-1 and insulin in white adipose tissue. codes for a longer preprohormone of 185 The synthesis and secretion of adiponectin aa, which is processed post-translationally, α β are decreased by TNF- , -adrenergic originating AM and proadrenomedullin N- agonists, glucocorticoids, and cAMP. With terminal 20-peptide (PAMP). Both peptides AdipoR1 and AdipoR2 two receptors for participate in many physiological func- adiponectin have been cloned. AdipoR1 oc- tions, including vasodilatation, bronchodi- curs primarily in skeletal muscle, whereas latation, neurotransmission, regulation of AdipoR2 is primarily produced in hepatic hormone secretion, brain functions, renal tissues. It may act also directly on bone, homeostasis, and antimicrobial activities. since receptors are found in osteoblasts Apart from vasodepressive effects in mam- and these cells also secrete adiponectin [L. mals, caused by decreasing peripheral Shapiro, P. E. Scherer, Curr. Biol. 1998, 12, vascular resistance, AM shows diuretic 335; A. H. Berg et al., Trends Endocrinol. and bronchodilatory effects and plays a Metab. 2002, 13, 84; H. S. Berner et al., regulatory role on aldosterone and ACTH Bone 2004, 35, 842; U. Meier, A. M. (→ corticotropin) release. In renal failure, Gressner, Clin. Chem. 2004, 50, 1511]. hypertension, heart failure, pregnancy loss, and septic shock plasma, the AM Adoc, 1-adamantyloxycarbonyl. level has been found to be increased. The Adrenocorticotropic hormone (ACTH), biological actions of AM are mediated → corticotropin. through the calicitonin receptor-like recep- tor (CRLR) complexed with → receptor Adrenocorticotropin, → corticotropin. activity-modifying proteins (RAMPs), ch-A February 20, 2008 19:49 Char Count=

Adrenorphin 10

especially via both CRLR/RAMP2 and diabetic vasculature, and contribute to the CRLR/RAMP3 receptors, respectively (→ development of atherosclerosis. The con- calcitonin/calcitonin gene-related peptide centrations of AGEs are altered in the body, family). Plasma AM concentration is particularly in relation to changes occur- increased in patients with cardiovascular ring with age. AGEs contribute to amyloi- diseases. It has been shown that the source dosis in → Alzheimer’s disease, and AGEs of increased AM levels in cardiac failure is formation is also stimulated by oxidative the heart. AM has hypotensive, diuretic and stress, e.g., in uremia. A decrease in renal natriuretic properties that are in common function increases circulating AGE concen- with → natriuretic peptides; however, trations by reduced clearance [M. P. Vitek the role of AM in cardiac pathologies is et al., Proc. Natl. Acad. Sci. USA 1994, 91, less clear. Sequence analysis of the Fugu 4766; R. Singh et al. Diabetologia 2001, 44, rubripes genome led to the identification of 129; J. M. Bohlender et al., Am. J. Renal three AM orthologues characterized by a Physiol. 2005, 289, F645; A. Goldin et al., 31 aa C-terminal domain sharing 50, 38, Circulation 2006, 114, 597]. and 35% sequence identity with hAM in the mature area. The sequence N-terminal Aequorin, a calcium-sensitive photoprotein to the cystine ring varies greatly among originally obtained from the jellyfish Ae- species. Recently, it has been reported that quorea victoria. This bioluminescent jel- AM and PAMP might be potent inducers lyfish produces a greenish luminescence of angiogenesis which is required for the from the margin of its umbrella using maintained growth of solid tumors [K. aequorin and a chromophore-bearing → Kitamura et al., Biochem. Biophys. Res. green fluorescent protein (GFP). Aequorin 2+ Commun. 1993, 192, 553; C. J. Charles is a Ca -binding protein (Mr ∼21 kDa), et al., Am. J. Hypertens. 1999, 12, 166; S. J. and undergoes an intramolecular reac- Wimalawansa, Crit. Rev. Neurobiol. 1997, tion on binding Ca2+, yielding a blue 11, 167; M. Jougasaki, J. C. Burnett, Jr., fluorescent protein in the singlet excited Life Sci. 2000, 66, 855; T. Eto et al., Regul. state, transferring its energy by resonance Pept. 2003, 112, 61; M. T. Rademaker et al., to GFP. Aequorin consists of four helix- Regul. Pept. 2003, 112,51; C. L. Chang loop-helix “EF-hand” domains, of which et al., Peptides 2004, 25, 1633; A. Martinez, three can bind Ca2+. It also contains coe- Cancer Lett. 2006, 236, 157]. lenterazine as its chromophoric ligand. The addition of Ca2+ causes decomposi- Adrenorphin, → metorphamide. tion of the protein complex into apoae- Advanced glycation end products (AGEs), a quorin, coelenteramide and CO2, accom- heterogeneous group of non-enzymatically panied by the emission of light. Regener- glycated and oxidized proteins or lipids. ation of apoaequorin into active aequorin AGEs are present and accumulated in takes place in the absence of Ca2+ by in- many different cell types, and affect ex- cubation with coelenterazine, oxygen, and tracellular and intracellular structure and a thiol agent. Aequorin is widely used as function. Microvascular and macrovascu- a probe to monitor intracellular levels of lar complications are caused through the Ca2+. The crystal structure of recombi- formation of crosslinks between molecules nant aequorin at 2.3 Å resolution shows a in the basement membrane of the extra- globular molecule containing a hydropho- cellular matrix. AGCs are prevalent in the bic core cavity accommodating the ligand ch-A February 20, 2008 19:49 Char Count=

11 Agouti protein

coelenterazine-2-hydroperoxide [O. Shimo- AG3, AYSSGAPPMP10PF, an inorganic- mura et al., J. Cell. Comp. Physiol. 1962, 59, binding peptide (→ silver-binding pep- 223; H. Morise et al., Biochemistry 1974, 13, tides) that specifically and selectively binds 2656; M. Brini et al., J. Biol. Chem. 1995, to silver. AG3 was immobilized on the sur- 270, 9896; J. F. Head et al., Nature 2000, face of protonated poly(ethylene terephtha- 405, 291]. late) (PET) film which was prepared for biomimetic synthesis of silver particles in Aeruginosins, a main class of → vitro. Silver crystallites have been formatted cyanobacterial peptides characterized on the surface of the AG3-PET film show- by a derivative of hydroxyphenyl lactic ing various shapes 1 to 4 µm in size [Z. Xu acid (Hpla) at the N-terminus, 2-carboxy- et al., J. Inorg. Biochem. 2005, 99, 1692]. 6-hydroxyoctahydroindole (Choi) and the arginine derivative agmatine at the AGaloc, tetra-O-acetyl-β-D-galactopyrano- C-terminus. The aeruginosins 98-A and B syloxycarbonyl. from the blue-green alga Microcystis aerugi- nosa act as trypsin inhibitors [M. Murakami AGE, advanced glycation end product. et al., Tetrahedron Lett. 1995, 36, 2785]. Agloc, tetra-O-acetyl-D-glucopyranosyloxy- Aet, aminoethyl. carbonyl.

Affinity chromatography, a special variant Agonist, a term given for analogues of na- of adsorption chromatography in which tive peptide hormones that trigger the hor- the adsorbent is biospecific. A molecule, mone signal in the same manner. known as the ligand, that specifically binds, for example to the protein of interest, is Agouti protein, a 131 aa protein encoded by covalently attached to an inert porous ma- the murine agouti gene and expressed in trix, e.g., agarose gel, glass beads, cellulose, the skin. During hair growth, agouti acts polyacrylamide, crosslinked dextrans. The to regulate coat coloration, and abnormal impure protein solution is passed through expression of the agouti protein causes the this stationary phase and the desired pro- yellow phenotype. The agouti protein is a tein with selective affinity to the ligand paracrine signaling molecule that regulates is retained, while other proteins and sub- coat coloration via competitive antagonism stances are immediately eluted. The bound of α-MSH (→ melanocortin peptides) substance can then be recovered in highly binding to its receptor (→ melanocortin purified form by changing the elution con- receptors, MCR). The antagonistic action ditions such that the desired protein is re- of agouti protein prevents the α-MSH- leased from the stationary phase. Specific mediated increase in intracellular cAMP interactions between, e.g., antibodies and that results in the cell switching from the antigens, enzymes and their inhibitors, nu- production of black pigment, eumelanin, cleic acids of complementary sequences, to yellow pigment, phaemelanin. Phar- lectins and polysaccharides, receptors and macologically, agouti is a high-affinity, hormones, avidin and biotin can be utilized competitive antagonist of the melanocortin [P. Cuatrecasas et al., Proc. Natl. Acad. Sci. peptides at melanocortin receptors MC1R, USA 1968, 61, 636]. MC3R, MC4R, and the adrenocortical ACTH (→ corticotropin) receptor, MC2R, Ag, antigen. respectively [D. Lu et al., Nature 1994, 371, ch-A February 20, 2008 19:49 Char Count=

Agouti-related protein (AGRP) 12

799; D. M. Dinulescu, R. D. Cone, J. Biol. tool for elucidating the mechanism of Chem. 2000, 275, 6695]. obesity, and a potentially interesting drug target in combating obesity and related Agouti-related protein (AGRP), a 132 aa co-morbidities [M. M. Ollman et al., Science protein first identified by database 1997, 278, 135; J. R. Shutter et al., Genes searches for molecules with homology Dev. 1997, 17, 75; R. D. Rosenfeld et al., to → agouti protein in 1997. AGRP is Biochemistry 1998, 37, 16041; E. J. Bures expressed predominantly in the adrenal et al., Biochemistry 1998, 37, 12172; C. gland, hypothalamus, and at low levels in Haskell-Luevano,E.K.Monck,Regul. Pept. the lung, testis, and kidney. AGRP has 2001, 99, 1]. been physiologically implicated in the AGRP, agouti-related protein. regulation of food intake, body weight, and energy homeostasis. It is acting Ahx, 2-aminohexanoic acid (norleucine). as a brain melanocortin-4 (MC4R) and eAhx, 6-aminohexanoic acid. melanocortin-3 (MC3R) receptor (→ melanocortin receptor) antagonist. It has AHZ, β-alanyl-histidinato zinc. been reported that AGRP has additional Aib, α-aminoisobutyric acid (α-methyl- targets in the hypothalamus and/or physi- alanine). ologically functions through a mechanism in addition to competitive antagonism AIDS, acquired immunodeficiency syn- of α-MSH at the brain melanocortin drome. receptors. AGRP is a orexigenic (appetite- alIe, allo-isoleucine (2S,3R in the L-series). stimulating) peptide that promotes food intake and is coexpressed with another Aimoto thioester approach, a polypeptide potent orexigenic neuropeptide, → neu- synthesis method characterized by convert- ropeptide Y. The human AGRP gene ing an S-alkyl thioester moiety in the pres- is relatively short, spanning 1.1 kb on ence of a silver salt into an active ester chromosome 16q22. Most investigations derived from HOBt or HODhbt, followed on the in-vivo function of AGRP have by segment condensation of partially pro- used C-terminal AGRP peptide sequences tected segments [S. Aimoto, Biopolymers that mimic the effect of the full-length 1999, 51, 247]. protein. Human AGRP-(87–132): CVRLH Akabori Conference, called in honor of ESCLG10QQVPCCDPCA20TCYCRFFNAF Shiro Akabori, a series of conferences with 30CYCRKLGTAM40NPCSRT (disulfide Japanese and German peptide chemists bonds: C1–C16/C8–C22/C15–C33/C19–C43/ held every two years, alternating be- C23–C31), a synthetic 46-peptide was capa- tween the two countries, founded by Erich ble of binding the melanocortin receptors Wunsch¨ and Shumpei Sakakibara. MC3R, MC4R, and MC5R, thus, inhibit- ing binding of α-MSH. NMR structure Akabori method, an approach to C-terminal analysis of AGRP-(87–132) revealed an amino acid end group analysis of peptides inhibitor cysteine-knot structure which using hydrazine. By treatment of the pep- makes possible contact with the MC3R and tide under investigation with anhydrous MC4R with two loops which are present hydrazine for 90–100 h at 90◦Cinthe in this structure. The appetite-boosting presence of an acidic ion-exchange resin, AGRP-(87–132) may be both an important only the C-terminal amino acid residue ch-A February 20, 2008 19:49 Char Count=

13 Alamethicin

is released as free amino acid, whereas bearing both a blocked N-terminus (pyrog- all other amino acids are converted into lutamate residue) and C-terminus (amide) hydrazides. The resulting C-terminal free respectively. They are characterized by aro- amino acid can be identified chromato- matic amino acids at position four (Phe graphically [S. Akabori et al., Bull. Chem. or Tyr) and eight (Trp). Besides the well- Soc. Japan 1956, 29, 507]. known members of this family, some AKH/RPCH peptides are produced in the Akabori, Shiro (1900–1992), professor of brain and not in the retrocerebral corpora organic chemistry at Osaka University cardiaca (CC), for example in the migratory (1939–1966), known as the father of pep- locust and the African malarial mosquito. tide chemistry in Japan, with outstanding In addition to the modified termini of international achievements in peptide re- the peptides, additional post-translational → search, inter alia Akabori method. From modifications comprise C-glycosylations at 1960 onwards, and even after his retire- Trp and phosphorylation at Thr residues ment in 1966, Professor Akabori continu- [G. Gade,¨ Z. Naturforsch. 1996, 51, 333; G. ously served the scientific community for Gade,¨ H. G. Marco, in: Studies in Natural over 20 years as president of the Protein Product Chemistry (Bioactive Natural Prod- Research Foundation Japan. ucts), Atta-ur-Rahmann (Ed.), Vol. 33, pp. AKH, adipokinetic hormone. 69–139, Elsevier Science Publishers, The Netherlands, 2005]. AKH/RPCH peptide hormone family, ad- Al, allyl ipokinetic hormone/red pigment-concentra- ting hormone family, peptide hormones pro- Ala, alanine duced in the neurosecretory organs of crus- α tacean and insects, and named after the Alanine (Ala, A), -aminopropionic acid, first fully characterized members and their H3C-CH(NH2)-COOH, C3H7NO2,Mr most prominent functions. These include 89.09 Da, a proteinogenic amino acid. the aggregation of pigment in the epider- Alanine scan, systematic substitution of → mal cells of crustaceans by the red each amino acid residue of a native peptide pigment-concentrating hormone (Pando- by a simple amino acid such as alanine. A → RPCH), whereas the adipokinetic hor- first step in structure–activity relationship mones (AKH) in insects regulate the levels studies. of circulating metabolites such as lipids, carbohydrates and proline by activating β-Ala, β-alanine phosphorylases or lipases in the fat body β-Alanine (β-Ala), β-aminopropionic acid, cell. The resulting substrates can subse- a naturally occurring non-proteinogenic quently be used during intense muscular amino acid occurring, e.g., in → carnosine, work, e.g., flight, swimming, or running. → anserine, and coenzyme A. At present, only Pando-RPCH have been found in a relatively large number of crus- Alamethicin, a member of the → peptai- taceans, whereas about 40 analogues (iso- bols produced by the fungus Trichoderma forms), including Panbo-RPCH, have been viride. This is one of the most extensively isolated from all major orders of insects. investigated member of the long peptaibol The members of this peptide hormone fam- antibiotics. Alamethicin consists of a natu- ily consist of 8 to 10 amino acid residues ral microheterogeneous peptaibol mixture ch-A February 20, 2008 19:49 Char Count=

β-Alanyl-histidinato zinc (AHZ) 14

of which 23 members have been se- dependent flip-flop of α-helix dipoles, quenced up to 2004. All alamethicins are postulates that the membrane-inserted 19-peptides blocked at the N-terminus by helices attract each other when oriented an acetyl moiety, and at the C-terminus in anti-parallel fashion. In contrast to the by the 1,2-aminoalcohol L-phenylalaninol flip-flop model, another model assumes (Fol). The acidic alamethicins bear a Glu18 that the gating charge transfer is involved residue, whereas this building block is in the opening-closing mechanisms. The replaced by Gln18 in the neutral alame- mechanisms of membrane permeability by thicins. The alamethicins are classified alamethicin remain the subject of debate into two groups. The major group is called [R. Nagaray, P. Balaram, Acc. Chem. Res. F50 and is composed of neutral peptides 1981, 14, 356; E. Benedetti et al., Proc. Natl. (Gln18), whereas the minor group, termed Acad. Sci. USA 1982, 79, 7951; R. O. Fox, F30, consists of acidic peptides (Glu18). F. M. Richards, Nature 1982, 300, 325; H. Only the F30/6 analogue bears two acidic Bruckner,¨ H. Graf, Experientia 1983, 39, amino acids (Glu7,Glu18), while in all other 528; G. Boheim et al., Biophys. Struct. Mech. alamethicins Gln7 is conserved. The alame- 1983, 9, 181; D. T. Edmonds, Eur. Biophys. thicins are rich (7–10 aa) on the strongly J. 1985, 13, 31; H. Wenschuh et al., J. Org. helicogenic, non-coded α-aminoisobutyric Chem. 1995, 60, 405; M. S. P. Sansom, Mol. acid (Aib), and contain two well-spaced Biol. 1991, 55, 139; J. Kirschbaum et al., J. proline residues in positions 2 and 14. A Peptide Sci. 2003, 9, 799; C. Peggion et al., major component of the natural alame- Biopolymers (Pept. Sci.) 2004, 76, 485]. thicin mixture is the F50/5 analogue with β-Alanyl-histidinato zinc (AHZ), azinc- the following sequence: Ac-Aib-Pro-Aib- chelated dipeptide for the exogenous Ala-Aib-Ala-Gln-Aib-Val-Aib10-Gly-Leu- administration of zinc. The zinc delivery Aib-Pro-Val-Aib-Aib-Glu-Gln-Phe-ol, the potential of AHZ is more effective on bone total synthesis of which in solution by an metabolism than zinc sulfate. In-vitro easily tunable segment condensation ap- studies have established that AHZ causes proach was described in 2004. Besides this complete inhibition of the decrease of bone approach, more than 20 other synthesis calcium in a bone tissue culture system, as variants of alamethicin have been reported. well as in the formation of osteoclast-like Alamethicin is amphiphilic, but of high cells in mouse marrow culture [M. Yam- overall hydrophobicity. It is known to gen- aguchi, Gen. Pharmacol. 1995, 26, 1179]. erate voltage-dependent pores in biological membranes, and to insert spontaneously HO N into lipid bilayers. Some more or less con- H2N OH + vincing models have been postulated. From Zn2 O the crystal structure it could be revealed that NH alamethicin is preferentially α-helical, with N abendinthehelixaxisatPro14. This struc- AHZ ture is in agreement with an early model β-Alanyl-histidinato zinc for the mode of action, in which a certain number (6–12) of molecules form aggre- Alaphosphin, L-alanyl-L-1-aminoethylphos- gates, like the staves of a barrel. However, phonic acid, a → phosphopeptide acting there are also other models for channel as an antibacterial agent. It selectively in- formation. One model, based on a voltage- hibited peptidoglycan biosynthesis in both ch-A February 20, 2008 19:49 Char Count=

15 Albumins

Gram-negative and Gram-positive bacteria. out.” Albumins have been used as a Alaphosphin was selected from a range of model protein for diverse biophysical, bio- phophonopeptides for studies in humans chemical, and physico-chemical studies. on the basis of its antibacterial activity, Serum albumins (Mr ∼ 67.5 kDa) are the pharmacokinetics, and stability against in- most abundant of these proteins in blood testinal and kidney proteases. In vitro,it plasma. These proteins have been one of proved active against the majority of about the most investigated proteins for many 50 strains of Serratia marcescens [J. G. Allen years, and show interesting properties of et al., Antimicrob. Agents Chemother. 1979, binding a variety of hydrophobic ligands, 15, 684; F. R. Atherton et al., Antimicrob. e.g., fatty acids, warfarin, anesthetics, Agents Chemother. 1979, 15, 696; W. H. bilirubin, steroids, lysolecithin, and several Traub, Chemotherapy 1980, 26, 103]. dyes. Furthermore, a high binding capacity for Ca2+,Na+,K+ must be mentioned. O Serum albumins comprise up to 60% of H 2N O N P the dry mass of blood serum, correspond- OH −1 H OH ing to a concentration of 42 g L , and

Alaphosphin provide about 80% of the osmotic pressure of blood. The single peptide chain of about 580 aa forms a secondary structure char- Albomycins, natural siderophores and an- acterized by 67% of α-helix, six turns, and tibiotics first isolated from Streptomyces 17 disulfide bridges. The X-ray structure of griseus and named grisein in 1947. human serum albumin (HSA) shows three Some years later, another microbial iron- domains I, II, and III, which confer to the transport compound, named albomycin, protein a heart-shaped molecular form. was isolated from Streptomyces subtropicus Each domain consists of two subdomains, which had the same structure as grisein. In named IAB, IC, IIAB, IIC, IIIAB, IIIC, 1982, the structure of the albomycins was respectively. Interestingly, the domains firmly established. The linear tripeptide exhibit a certain degree of binding speci- built of N5-acetyl-N5-hydroxy-L-ornithine is ficity. Domain I, also named the warfarin the hexadentate, octahedral ligand for fer- binding site, binds predominantly indole ric ion responsible for intracellular trans- derivatives, several dyes, long-chain fatty port of iron. The albomycins are used for acids, and compounds with alicyclic ring treatment of iron metabolism disorders [G. structures, whereas domain II, termed the Benz et al., Angew. Chem. Int. Ed. 1982, indole or benzodiazepine binding site, is 21, 527; G. Benz, Liebigs Ann. Chem. 1984, specific for the binding of short-chain fatty 1408]. acids, bilirubin, indole derivatives, several Albumins, a group of water-soluble pro- dyes, and steroids. Domain III is specific teins occurring in body liquids, animal for indole derivatives, long-chain fatty tissues and in some plant seeds. They are acids, diazepam and other drugs. Bovine rich in both Glu and Asp (20–25%) as well serum albumin (BSA) shows 76% sequence as Leu and Ile (up to 16%). Albumins have identity with HSA. BSA contains two tryp- a low molecular mass, are easily crystalliz- tophan residues (W214,W131), while HSA able, and their isoelectric points are in the has only one (W214). The consequences are weakly acid range. High concentrations different spectroscopic properties of the of neutral salts are necessary for “salting two proteins. Bovine and human serum ch-A February 20, 2008 19:49 Char Count=

Alkanesulfonamide linker 16

albumin contain 16% nitrogen, and are ing group of the alkyl type is the → triph- used as standard proteins for calibration. enylmethyl (Trt) group. Further important animal and plant albu- All, allyl mins are → lactalbumin, → ovalbumin and → ricin [J. R. Brown, P. Shockley, Lipid- Allatostatins (AST), a family of neuropep- Protein Interactions,Vol.1,Wiley,New tides first isolated from the brain of the York, 1982; D. Carter, J. X. Ho, Advances cockroach Diploptera punctata. There in Protein Chemistry, Vol. 45, Academic are three allotostatin families accord- Press, New York, 1994, p. 153; E. L. Gelano ing to C-terminal sequence homology: et al., Biochim. Biophys. Acta 2002, 1594, (a) the cockroach type (>70 peptides, 84]. consensus sequence FGLa), comprising e.g. Dippu-AST 1 (LYDFGLa), Dippu- 10 Alkanesulfonamide linker, → safety-catch AST 2 (AYSYVSEYKR LPVYNFGLa), linker. Dippu-AST 5); (b) the cricket type (consensus sequence WX6Wa), with Alkene peptidomimetics, peptides, where Grybi-AST 1 (H-Gly-Trp-Gln-Asp-Leu- an amide bond has been replaced to give Asn-Gly-Gly-Trp-NH2) and Grybi-AST E-alkene [M. M. Hahn et al., J. Chem. Soc. 5 (H-Ala-Trp-Asp-Gln-Leu-Arg-Pro-Gly- Commun. 1980, 234; M. Kranz, H. Kessler, Trp-NH2); and (c) the Manduca type Tetrahedron Lett. 1996, 37, 5359]. (consensus sequence PISCF). Members of the latter family are highly homologous 2-Alkoxy-5(4H)-oxazolones, azlactones, ste- (galanin and somatostatin/opioid groups for the amino function of amino receptors [A. P. Woodhead et al., Proc. acids during peptide synthesis based on Natl. Acad. Sci. USA 1989, 86, 5997; W. G. alkyl moieties. The most popular protect- Bendena et al., Ann. N. Y. Acad. Sci. 1989, ch-A February 20, 2008 19:49 Char Count=

17 Alzheimer’s disease (AD)

897, 311; J. G. Yoon, B. Stay, J. Comp. phase synthesis of complex glycopeptides. Neurol. 1995, 363, 475; N. Birgul et al., The allyloxycarbonylaminomethyl (Allocam) EMBO J. 1999, 18, 5892]. group was described as a thiol-protecting group in 1999, while the Nπ -allyl moiety Alloc (Aloc), → allyloxycarbonyl group. was suggested as an imidazole-protecting Allom, Alom, → allyl-type protecting group by the same authors one year later. groups. Last, but not least, the Nπ -allyloxymethyl (Allom) group has also been described as Allopeptide, a word derived from the noun an imidazole-protecting group [A. Loffet, “peptide” that means in immunology a pep- H. X. Zhang, Int. J. Pept. Protein Res. 1993, tide from different individual (Greek allos, 42, 346; A. M. Kimbonguila et al., Tetra- other) of the same species [J. H. Jones, Ed- hedron 1997, 53, 12525; A. M. Kimbonguila itorial, J. Peptide Sci. 2006, 12, 79]. et al., Tetrahedron 1999, 55, 6931; S. J. Hard- Allyl ester, → allyl-type protecting groups. ing, J. H. Jones, J. Peptide Sci. 1999, 5, 368; H. Herzner et al., Chem. Rev. 2000, 100, Allyloxycarbonyl group (Alloc, Aloc), an 4495]. urethane-type protecting group for the amino function during peptide synthesis. Alterobactin, a 19-membered macrocyclic The Alloc group is completely orthogo- → depsipeptide containing two types of nal to Boc and Fmoc, and is especially unusual building block, two L-threo-β- suited for the synthesis of labile deriva- hydroxyaspartic acids and one (3S,4S)-4,8- tives. The group can be smoothly removed diamino-3-hydroxyoctanic acid attached to by treatment with a suitable nucleophile, a catechol carboxylate at the Nω-site. It was e.g., amines, amine-borane complexes, isolated from a open-ocean bacterium Al- organosilanes, in the presence of a palla- teromonas luteoviolacea collected off Chub dium catalyst (palladium(0)-catalyzed allyl Cay, Bahamas. Alterobactin is a depsipep- transfer) [H. Kunz, C. Unverzagt, Angew. tide → siderophore exhibiting extraordi- Chem.Int.Ed.1984, 23, 436; A. Loffet, H. nary affinity for ferric ion. The total syn- X. Zhang, Int. J. Pept. Protein Res. 1993, 42, thesis has been described [R. T. Reid et al., 346; F. Guibe, Tetrahedron 1998, 54, 2967]. Nature 1993, 366, 455; J. Deng et al., Syn- Allyl-type protecting groups, protecting thesis 1998, 627]. groups used in peptides synthesis bear- Alytensin, bombesin family. Alytensin was isolated pletely orthogonal to most other protecting from the skin of the European amphibian groups, and provides an excellent tool Alytes obstetricans in 1971. It is structurally for temporary reversible protection in gly- very similar to → bombesin, and displays → copeptide synthesis. Beside the allyloxy- similar biological activities when applied carbonyl group, allylester (OAll) of amino to mammals [A. Anastasi et al., Experientia acids are very easy to obtain, are stable un- 1971, 27, 166; V. Erspamer, P. Melchiorri, der glycosylation conditions, and can be Trends Biochem. Sci. 1980, 1, 391]. cleaved by RhI catalysis. An even milder method for the selective cleavage of allyl Alzheimer’s disease (AD), the most promi- esters utilizes palladium(0)-catalyzed allyl nent severe dementia in the elderly popula- transfer to morpholine. Allyl-type linker tion, first described by Alzheimer in 1907. moieties are also suited for the solid- AD is a widespread, neurodegenerative, ch-A February 20, 2008 19:49 Char Count=

Amanitins 18

dementia-inducing disorder characterized catalyzed by the glutamyl cyclase activity of mainly by amyloid deposits surrounding → glutaminyl cyclase. It has been reported dying neurons (senile plaques), neu- that, in vitro, these smaller peptides are rofibrillar degeneration with tangles, and more neurotoxic and aggregate more cerebrovascular angiopathies. AD is clin- rapidly than the full-length isoforms. A ically characterized by a progressive loss rational design of inhibitors against glu- of cognitive abilities, progressive memory taminyl cyclase-associated disorders has and intellectual deficits. In 1998, it was been started [R. B. Maccioni et al., Arch. estimated that 25 million people world- Med. Res. 2001, 35, 367; T. Hashimoto wide suffered from AD. Amyloid-β and tau et al., EMBO J. 2002, 21, 1524; C. Morgan protein are responsible for the formation et al., Prog. Neurobiol. 2004, 74, 323; S. of the plaques and tangles of AD. The Schilling et al., FEBS Lett. 2004, 563, 191; mechanism of neurodegeneration caused K.-F. Huang et al., Proc. Natl. Acad. Sci. by → amyloid-β in AD is controversial. USA 2005, 102, 13117; S. Schilling et al., The primary pathogenic event of AD is Biochemistry 2005, 44, 13415; M. Goedert, the progressive cerebral accumulation of M. G. Spillantini, Science 2006, 314, 777]. amyloid-β (Aβ), a proteolytic product of the β-amyloid precursor protein (APP). Amanitins, a group of toxic components of Tau protein is the major component Amanita phalloides (→ amatoxins). of paired helical filaments that form a OH compact filamentous network described as HO “neurofibrally tangles.” From culture ex- H OH H periments there was derived the existence N N of a relationship between fibrillary amyloid N O O and the cascade of molecular signals H N 2 O H that trigger tau hyperphosphorylations. O N O O The cyclin-dependent kinase Cdk5 and S R glycogen synthase kinase GSK3beta are N N OH H O O the two main protein kinases involved H O O in the anomalous tau phosphorylations. N H Inhibitors of both kinases and antisense N H N oligonucleotides exert protection against H α-Amanitin neuronal death. On the other hand, it has been reported that oxidative stress constitutes a main factor in the modifi- Amatoxins, heterodetic bicyclic 8-peptides cation of normal signaling pathways in from Amanita species, but also detected neuronal cells. In brain tissue from AD in Galerina and Lepiota species, which patients, some major species of soluble Aβ are responsible for the fatal intoxications have been identified: the full-length form by the mentioned toadstools. The toxic Aβ(1–42), and at residues Glu3 and Glu11, peptides are readily absorbed by the respectively, truncated Aβ peptides, such intestine, and in humans the lethal dose as Aβ(3–40/42) and Aβ(11–40/42). The of amatoxin is ∼ 0.1 mg kg−1 body weight, shortened forms bear at the N-terminus a or even lower. The gut cells of humans pyroglutamic acid residue which might be seem to be the first cells affected, and the result from the corresponding Glu residues intestinal phase begins about 9 h after ch-A February 20, 2008 19:49 Char Count=

19 Amide-protecting groups

administration of the toxins. There is no design, drug delivery, and the discovery of effective therapy of amanita poisoning, as new pharmaceutical agents. The APS is a the amatoxins inhibit strongly and specif- member of the Federation of American So- ically the eukaryotic RNA-polymerases II cieties for Experimental Biology (FASEB). (B) in the nuclei. To date, nine members of The affiliation with FASEB increases the the amatoxins have been isolated, among visibility of APS in the biomedical research which α-amanitin is the best studied. The community, and allows the participation individuals are derived from the parent in any FASEB public affairs initiatives. The structure, and differ mainly by the number APS sponsors Biopolymers: Peptide Science, of hydroxyl groups and by an amide versus published by Wiley-Interscience, as the carboxy function. Amatoxins contain official journal of the Society. A full year exclusively L-amino acids and glycine, subscription to this journal is automatically together with uncommon moieties such as included with membership in the APS. the bridging 6-hydroxytryptathionine-(R)- One very important activity of the APS is sulfoxides between residues 4 and 8. The the organization of a biennial international fundamental studies on structure elucida- symposium in North America. The 20th tion and biochemical effects were carried American Peptide Society Symposium was out by Theodor Wieland and coworkers held in Montreal, Quebec, Canada, in June [Th. Wieland, Peptides of Poisonous Amanita 2007. The APS Council administers The R. Mushrooms, Springer Series in Molecular Bruce Merrifield Award, which recognizes Biology, Springer-Verlag, New York, the lifetime scientific work of a peptide Berlin, 1986]. chemist, The Vincent du Vigneaud Award for outstanding achievements in peptide American Peptide Society (APS), anon- research, which is presented at the Gordon profit scientific and educational organiza- Research Conferences every two years, tion founded in 1990, providing a forum besides further honors such as the Maki- for advancing and promoting knowledge neni Lectureship,theAchievement Award for of the chemistry and biology of peptides. Scientific and Administrative Excellence,the The near-1000 members of the Society Young Investigator’s Mini-Symposium, and come from North America and from more the Young Investigator’s Poster Competition. than 30 other countries worldwide. The establishment of the American Peptide Amidation, the formation of amides. Society was a result of the rapid worldwide Amino acid and peptide amides are syn- growth that has occurred in peptide-related thesized by reaction of the appropriate research, and of the increasing interaction esters or activated carboxylic acid deriva- of peptide scientists with virtually all tives with ammonia. Amidation of bioac- fields of science. Members of the APS are tive peptides is performed using the involved in research in academia, industry, bifunctional enzyme peptidylglycine α- and government, covering all aspects of amidating monooxygenase (PAM) by N- peptide chemistry, biology, and pharma- oxidative cleavage of a glycine-extended ceutical sciences. Research topics include precursor [S. T. Prigge et al., Science 1997, the synthesis of biologically important tar- 278, 1300]. gets, the isolation and characterization of new products, structure–activity relation- Amide-protecting groups, protecting ship studies, molecular diversity, de-novo groups for C-terminal amides of amino ch-A February 20, 2008 19:49 Char Count=

Amine capture strategy 20

acids and peptides, for backbone amide quinolinium thioester salts. Quinolinium groups (→ backbone amide protecting thioester salts has been designed as a so- groups), as well as for the side-chain called new electrophilic platform capable of ω-carboxamide groups of Gln and Asn. acting as an amine capture device [S. Leleu Although these rather unreactive func- et al., J. Am. Chem. Soc. 2005, 127, 15668]. tionalities usually do not require further Amino acid analysis, determination of protection, side reactions sometimes occur amino acid composition of a peptide by at the side-chain carboxamides of Asn complete hydrolysis followed by the quanti- and Gln during peptide synthesis. Under tative analysis of the liberated amino acids. the strongly dehydrating conditions of For hydrolysis, numerous chemical and en- carbodiimide couplings, unwanted nitrile zymatic protocols are known. Based on formation may prevail. Strongly activating the pioneering studies of → Stein and reagents (BOP, PyBOP, HBTU) also may → Moore, amino acid analysis has been favor this dehydration. Asn in the peptide automated. Nowadays, instruments are in chain has been observed to cyclize, with use for quantitative amino acid analysis release of ammonia, to give aspartimides which are based on partition chromato- that in turn are hydrolyzed to a mixture of graphy, such as HPLC and gas-liquid chro- α-aspartyl and β-aspartyl peptides. Most matography [S. Blackburn, Amino Acid De- side-chain reactions can be suppressed by termination, M. Dekker, New York, 1978; reversible blocking of these functionalities W. S. Hancock, Handbook of HPLC for the with, e.g., substituted N-benzyl derivatives, Separation of Amino Acids, Peptides, and Pro- N-methoxybenzyl residues, or the N- teins, CRC Press, Boca Raton, 1984]. diphenylmethyl moiety, all of which can be cleaved by liquid HF. N-Triphenylmethyl Amino acid anhydrides, → anhydrides. (Trt) and N-trimethoxybenzyl (Tmb) are Amino acid chloride, → acyl halides. very appropriate carboxamide-protecting groups for solid-phase synthesis, in com- Amino acids, the monomeric units of bination with Fmoc as the temporary peptides and proteins. From analysis of the protecting group. The carbonyl and amino vast number of proteins, it follows that 20 groups of a peptide bond potentially act proteinogenic or “standard amino acids” as hydrogen bond acceptors and donors, are the building blocks of all proteins. favoring aggregation and leading to the These amino acids are specified by the formation of secondary structures and genetic code. With → selenocysteine aggregation. This may prevent further and → pyrrolysine two additional mem- reactions of the amino terminus and lead bers have been identified. Besides the to truncated sequences. The phenomenon imino acid proline, all other building → is sequence-dependent ( difficult se- blocks are known as α-amino acids, H2N- quences). In such cases, e.g. → backbone CHR-COOH, but the zwitterion form, + − amide protecting groups with Hnb or H3N -CHR-COO , occurs at physiological Hmb residues is required [P. Sieber, B. pH values. The amino acids can therefore Riniker, Tetrahedron Lett. 1991, 32, 739; B. act as either acids or bases. Depending on Riniker et al., Tetrahedron 1993, 49, 9307]. the side-chain residue R, amino acids can be classified into those with: (a) non-polar Amine capture strategy, a variant of prior side chains [Gly/G; Ala/A; Val/V; Leu/L; capture-mediated ligation by means of Ile/I; Met/M; Pro/P; Phe/F; Trp/W]; ch-A February 20, 2008 19:49 Char Count=

21 Amino protection

(b) uncharged polar side chains [Ser/S; vestigate the conformational requirements Thr/T; Asn/N; Gln/Q; Tyr/Y; Cys/C; of receptors. Furthermore, it plays an im- Sec/U]; and (c) charged polar side chains portant role as building block for the stabi- [Lys/K; Arg/R; His/H; Asp/D; Glu/E; lization of 310-helices [I. L. Karle, Biopoly- Pyl/O]. In brackets are given the three- mers 1996, 40, 157; F. Formaggio et al., in: letter abbreviations and one-letter symbols Houben-Weyl: Methods of Organic Synthesis, of the 22 proteinogenic amino acids. With M. Goodman et al. (Eds.), Volume E22c, the exception of glycine, all proteinogenic Thieme, Stuttgart, Germany, 2003, p. 292]. amino acids are optically active – that β is, they have an asymmetric center or Aminooxy peptides, correlates of -peptides composed of α-aminooxy acids as ana- chiral center localized at the Cα atom. logues of β-amino acids with replacement Threonine and isoleucine each have two β asymmetric centers, and therefore four of C by an oxygen atom. The lone pair re- pulsion of the nitrogen and oxygen atoms possible stereoisomers (L-, D-, L-allo-, and renders the backbone of aminooxy peptides D-allo-). The 22 common amino acids are β not the only amino acids that occur in more rigid than that of -peptides [X. Li, biological systems. The number of non- Chem. Commun. 2006, 3367]. proteinogenic is approaching 300; these O OOO occur mostly in plants [H. B. Vickery, Adv. O O O Protein Chem. 1972, 26, 81; L. Fowden et al., R N N N OR' Adv. Enzymol. 1979, 50, 117; J. S. Davies HHHR 3 R2 R1 (Ed.), Amino acids and Peptides, Chapman Aminooxy peptides & Hall, London, 1985; G. C. Barrat (Ed.), Chemistry and Biochemistry of Amino Acids, Amino protection, the reversible blocking Chapman & Hall, London, 1985]. of the amino function (→ temporary protecting groups ) during peptide syn- Aminoacyl-tRNA, an amino acid intermedi- thesis. The necessity for sequence-specific ate in ribosomal peptide synthesis. The first incorporation of amino acids into a peptide step in the aminoacylation process of tRNA requires protection of the Nα amino func- is activation of the amino acid, catalyzed by tion, together with most functional groups the aminoacyl-tRNA synthetase (aatRS). An present in the side chains. While the latter amino acid reacts with ATP under the elim- usually remain attached throughout the ination of pyrophosphate to yield a mixed synthesis (→ semipermanent protect- anhydride, the aminoacyl adenylate, which inggroups),theNα function requires normally remains tightly bound to the aa- temporary protection by groups that are tRS. In the second step, the highly acti- cleaved after each coupling step in order to vated aminoacyl moiety is transferred to allow for further elongation of the peptide. the appropriate tRNA, thereby forming the Temporary and semipermanent protecting aminoacyl-tRNA and liberating ADP. groups must be cleaved independently α-Aminoisobutyric acid (Aib), Cαα-dimethyl- (→ orthogonal protecting groups) and the glycine, a strongly helicogenic, non-coded, nature of the Nα protection determines Cα-tetrasubstituted amino acid. This occurs the tactics of the peptide synthesis and the naturally, and is a building block in → selection of the side chain-protecting alamethicin and other → peptaibols. Aib groups. The most widely employed is often incorporated into peptides to in- temporary protecting groups are the ch-A February 20, 2008 19:49 Char Count=

AMP 22

→ benzyloxycarbonyl group (Z), → fections and other diseases that involve tert.-butoxycarbonyl (Boc), and → 9- both cell proliferation and allergy, such as fluorenylmethoxycarbonyl (Fmoc) groups. asthma [M. Shoyab et al., Science 1989, 243, Side-chain amino groups (e.g., Lys Nω) 1074; D. M. Zaiss et al., Science 2006, 314, must be protected with semipermanent 1746]. protecting groups. In the Fmoc approach, ω Boc protection for Lys N is most appro- Amphomycins, a group of lipopeptide priate. If completely orthogonal protection antibiotics that are highly active against ω → of the N -amino group is necessary, the multi-resistant bacteria. Amphomycin,the → → Tfa, Dde, Alloc, or Npys groups are first member of this group was discovered available. Tfa and Npys are well compatible during the early 1950s. In 1968, there with Boc chemistry, as cleavage occurs in followed the isolation of tsushimycin, the first case with piperidine and in the and later more members of this group latter case with triphenylphosphine. Dde of lipopeptides – such as friulimicin B and the related ivDde are orthogonal to and laspartomycin – are described. Am- Boc and Fmoc, as they are removed with phomycins are characterized by a peptide dilute hydrazine solutions. framework consisting of a 10-membered AMP, acronym for a) → antimicrobial pep- cyclopeptide and an exocyclic amino acid tides, or b) adenosine monophosphate. acylated at the amino group by a fatty acid residue. Members of this group differ prin- Amphiregulin (AR), a bifunctional cell cipally in the type of fatty-acid substituent. → growth modulator belonging to the epi- The lipopeptide antibiotic → daptomycin  dermal growth factor (EGF) family. Hu- (Cubicin R ), which was approved in the man amphiregulin contains 84 aa, while USA for the treatment of skin infections a truncated form consists of 78 aa. The in 2003, may also belong to this group due amino-terminal region is extremely hy- to the 10-membered cyclopeptide core and drophilic, and contains a huge number of the fatty acid constituent. However, the lysine, arginine, and asparagine, whereas amino acid sequence is markedly different. amphiregulin-(46-84) exhibits striking se- Amphomycins have been found to be quence homology to the members of the active against Gram-positive bacteria, but EGF family. AR binds to the EGF receptor, the exact mechanism of action remains but exhibits a weaker affinity compared to an ongoing debate. Tsushimycin has been EGF. In murine keratinocyte growth, AR crystallized and its X-ray structure deter- fully supplants the requirement for EGF mined at 1.0 Å resolution. The backbone of α or transforming growth factor- . However, the cyclopeptide core adopts a saddle-like in other cell systems it is a much weaker conformation that is stabilized by a Ca2+ growth stimulator. Recently, it has been re- ion bound within the peptide ring, while ported that T helper 2 cells, but not other an additional Ca2+ links the molecule to T-cell subsets, express AR. EGF receptor dimers enclosing an empty space resem- ligands induce epithelial cell proliferation, bling a binding cleft [B. Heinemann et al., and a lack of AR delayed expulsion of the Antibiot. Chemother. 1953, 3, 1239; J. Shoji nematode Trichuris muris.Thenewlinkbe- et al., J. Antibiot. 1968, 21, 439; G. Bunkoczi tween T helper 2 cells and epithelial prolif- et al., Acta Crystallogr. 2005, D61, 1160]. eration provides new aspects for planning therapeutic interventions for helminth in- AM-PS, aminomethyl polystyrene. ch-A February 20, 2008 19:49 Char Count=

23 Amyloid-β (Aβ)

Amylin, KCNTATCATQ10RLANFLVHSS20 tonin/calcitonin gene-related family. It NNFGAILSST30NVGSNTYa (human also acts as an agonist at the calcitonin amylin; disulfide bond: C2–C7), islet amy- receptor, but efficient signaling of amylin loid polypeptide (IAPP), diabetes-associated requires the formation of a receptor peptide (DAP), a 37-peptide amide which complex of the calcitonin receptor with belongs to the → calcitonin/calcitonin → receptor activity-modifying proteins gene-related peptide family. Amylin is (RAMP). Despite being less potent than generated from a gene located on chro- insulin, amylin shows growth factor-like mosome 12p12.3 sharing 46% sequence effects and inhibits insulin-stimulated homology with the two → calcitonin incorporation of glucose into muscle gene-related peptides and 20% with glycogen. An action in the brain to reduce human → calcitonin. Amylin was first body weight has been reported, resulting in isolated from an insulinoma and from a hypothesis that amylin acts as a signal to pancreatic amyloid deposits of patients the brain contributing to the maintenance with non-insulin-dependent (type II) of long-term energy balance [R. Muffet diabetes mellitus (NIDDM). It may be et al., Eur. J. Endocrinol. 1995, 133, 17; S. J. involved in the pathogenesis of type II Wimalawansa, Crit. Rev. Neurobiol. 1997, diabetes by deposition as amyloid within 11, 167; P.A. Rushing et al., Endocrinology the pancreas, which leads to β-cell de- 2000, 141, 850]. struction. It shows calcitonin-like activity on bone metabolism and a CGRP-like Amyloid-β (Aβ), β-amyloid, amyloid-β activity (→ calcitonin gene-related peptide) peptide, a physiological peptide occurring action on the vasculature. From studies in the brain, and enzymatically released on knockout mice, it follows that amylin from the amyloid precursor protein should be important for the regulation of (APP). APP is an ubiquitously expressed glucose-induced insulin secretion and the membrane-bound protein with elusive rate of blood glucose elimination. Human function. The accumulation of Aβ in the amylin and other mammalian amylins are brain is a triggering primary event to the synthesized as relatively small precursor pathological cascade for → Alzheimer’s proteins. Mature amylin is liberated from disease (AD). The accumulation of Aβ the 89-polypeptide precursor by proteolytic appears to be caused by an increase in the processing, in a similar way to that of anabolic activity, as demonstrated in famil- proinsulin and other islet prohormones. ial AD, or by a decrease in catabolic activity. Amylin is co-synthesized with insulin, The predominant forms of Aβ consist of stored in the β-cell secretory granules the 40- and 42-peptides, termed Aβ-(1-42), (in analogy to insulin), and secreted with DAEFRHDSGY10EVHHQKLVFF20AEDV insulin from the islet β-cells. Normally, GSNKGA30IIGLMVGGVV42IA, and Aβ- the rate of synthesis is only about 1% (1-40), respectively. In normal, non-AD, of that of insulin, but this can increase individuals the principal Aβ forms are Aβ- after prolonged stimulation in vivo with (1-40) and Aβ-(1-42), of which the former increased concentrations of glucose. This constitutes about 90%. The N-terminal behavior seems to be a link to the contri- partial sequence 1-28 stems from the bution of amylin in the pathogenesis of extracellular domain of APP and is type II diabetes. Amylin has a vasodilatory predominantly hydrophilic, whereas the effect like other members of the calci- C-terminal part 29-39/43 stems from the ch-A February 20, 2008 19:49 Char Count=

Amyloid-forming proteins 24

transmembrane domain and is character- subtypes of AD inhibit significantly the ized by hydrophobic amino acids. Aβ-(1-42) progress in understanding of AD. In order is thought to have a more critical function to develop new methods to prevent and than Aβ-(1-40) in amyloid formation and treat AD, it must be possible to diagnose pathogenesis of AD, whereas Aβ-(1-40) the preclinical stage of AD using biological is the major component secreted from markers, before the brain damage becomes cultured cells, and occurs in cerebrospinal irreversible. Suitable markers may include fluid. Most of the knowledge about APP high plasma concentrations of Aβ-(1-42) processing derives from studies with cul- and findings of hippocampal atrophy on tured cells. The α-, β- and γ -secretases are magnetic resonance imaging (MRI) of the involved in APP processing. α-Secretase brain. Solid-state NMR has been developed action provides a large soluble ectodomain, as a useful probe of amyloid structure. Cur- termed sAPPα. The remaining C-terminal rently, there are no known cures for AD, part of the protein is subject of γ -secretase although some drugs have been approved cleavage that does not produce full-length for its treatment, such as donepezil (Pfizer), Aβ peptides, but leads to a truncated form galantamine (Sanochemia), and rivastig- known as p3 fragment comprising the mine (Novartis). According to the “amyloid residues 17- 40/2 of Aβ. In an alternative cascade hypothesis,” the reduction of Aβ in pathway, β-secretase cleaves the bond the brain is discussed as being a therapeu- between 671 and 672 of APP, thereby tic intervention in AD. Disaggregation of releasing the soluble ectodomain, sAPPβ, the senile plaques found in the brain is an- whereas the Aβ sequence remains bound other strategy. For example, the 5-peptide, to the membrane with the C-terminal Leu-Pro-Phe-Phe-Asp, has attracted atten- domain of the protein. Finally, cleavage tion as a β-sheet-breaking peptide. Further by γ -secretase within the membrane- future targets may be the inhibition of the spanning region of APP provides several activity of β-secretase, besides alternative C-terminal variants of the Aβ peptide treatment strategies [J. Kang et al., Nature bearing 39 to 43 residues. Mutations in 1987, 325, 733; J. Wiltfang et al., Gerontol- APP can cause either increased overall ogy 2001, 47, 65; A. B. Clippingdale et al., secretion of Aβ or secretion of “long” (42- J. Peptide Sci. 2001, 7, 227; K. Fassbender to 43-residue) forms of Aβ-(1-42) relative et al., Naturwissenschaften 2001, 88, 261; N. to the shorter Aβ-(1-40) form. Despite the Iwata et al., Pharm. Ther. 2005, 108, 129; increasing production of research data, AD A. K. Tickler et al., Prot. Pept. Lett. 2005, remains an enigma. AD is characterized 12, 513; Y. Sohma, Y. Kiso, ChemBioChem. by a variety of pathological features, such 2006, 7, 1549; R. Tycko, Prot. Pept. Lett. as extracellular senile plaques, synaptic 2006, 13, 229]. loss, intracellular neurofibrillary, and brain atrophy. The senile plaques are mainly Amyloid-forming proteins, mainly in native composed of Aβ with 40–43 aa, whereas state α-helical proteins undergoing α-helix the neurofibrillary tangles consist of to β-strand conversion before or during twisted filaments of hyperphosphorylated fibril formation. Partially unfolded or tau protein. Especially, the heterogeneity misfolded β-sheet fragments are discussed of this neuropathology and the lack of as precursors of amyloids. Protein aggre- screening of AD patients on an early stage gation combined with other events leads and a better delineation of pathological to the deposition of insoluble protein ch-A February 20, 2008 19:49 Char Count=

25 Ancovenin

forms, causing an increasing number of growth of Gram-positive bacteria, includ- neurodegenerative diseases such as → ing the methicillin-resistant Staphylococcus Alzheimer’s disease, Parkinson’s, and aureus (MRSA), and the action of elonga- Creutzfeld-Jakob disease. The molecular tion factor Tu (EF-Tu), a GTP-dependent structures of amyloid fibrils are of consid- translation factor. Amythiamicin A is the erable interest for an understanding of the most potent inhibitor (IC50 0.01 µM) interactions that drive amyloid formation. against Plasmodium falciparum, the parasite The conformational transition shifting the that causes the majority of malarial infec- equilibrium from the functional to the tions in humans. It has been reported that pathological protein isoform can occur amythiamicin binds to the EF-Tu of the par- sporadically. However, the conformational asite, thereby blocking protein synthesis. change can also be triggered by mutations The total synthesis of amythiamicin D was as well as by changes of the environ- reported in 2005 [K. Shimanaka et al., An- mental conditions (oxidative stress, ionic tibiotics 1994, 47, 1153; R. A. Hughes et al., strength, free radicals, pH, metal ions, J. Am. Chem. Soc. 2005, 127, 15644]. protein concentration) or physiological or pathological chaperones (→ molecular Anabaenopeptins, a main class of cyanobac- chaperones). Furthermore, misfolded terial peptides. These cyclic peptides are protein fragments acting as a structural characterized by a peptide bond between ε 2 α template can be involved in the initiation of the -amino group of Lys with the - the conformational conversion that causes carboxyl function of the amino acid in po- the disease. Recent investigations with sition 6. An amino acid unit is attached to solid-state NMR of fibrils have indicated the ring by an ureido bond formed between α 2 α that the β-sheets in amyloid fibrils have the -amino group of Lys and the -amino structures that tend to maximize contacts function of the appropriate building block among hydrophobic residues. Amyloid [K.-I. Harada et al., Tetrahedron Lett. 1995, fibrils formed by peptides and proteins 36, 1511; M. Welker, H. von Dohren,¨ FEMS lacking hydrophobic segments may be Rev. 2006, 30, 530]. stabilized by different sets of interactions. Anchoring group, linker, a group bound to Protein fragments that are rich in Gln the polymeric support for the attachment of or Asn are of special interest because of the first amino acid in polymer-supported their involvement in Huntington’s disease, peptide synthesis. The chloromethyl group spinocerebellar ataxis, and particularly in was the first anchoring moiety in the → amyloid-forming yeast prion proteins polystyrene/divinylbenzene resin for solid- [D. J. Selkoe, Nature 2003, 426, 900; C. phase peptide synthesis developed by Bruce Soto, Nat. Rev. Neurosci. 2003, 4, 49; R. Ty- Merrifield [R. B. Merrifield, J. Am. Chem. cko, Prot. Pept. Lett. 2006, 13, 229; J. P. Sipe Soc. 1963, 85, 2149]. (Ed.), Amyloid Proteins, Wiley-VCH, 2005]. Ancovenin, a member of the subclass B → Amythiamicins, naturally occurring → lantibiotics first isolated from the culture thiopeptide antibiotics isolated from a broth of a Streptomyces sp. (No. A647P-2) strain of Amycolatopsis sp. MI481-42F4. The acting as an inhibitor of → angiotensin- amythiamicins A–D belong to the very few converting enzyme. In the biosynthesis thiopeptides that do not contain a dehy- of ancovenin, the 19-prepeptide (CVQSCS droalanine moiety. They inhibit both the FGPL10TWSCDGNTK) is first modified ch-A February 20, 2008 19:49 Char Count=

Androctonin 26

and processed by enzyme systems that of chemical biology in the National Insti- are involved in the transformation of tute of Arthritis, Metabolism, and Diges- the acyclic precursors. It contains un- tive Diseases from 1963 to 1982. Anfinsen usual amino acids such as (2S,3S,6R)-3- was a professor of biology at Johns Hopkins methyllanthionine, meso-lanthionine, and University from 1982 until his death. dehydroalanine [T. Wakamiya et al., Tetra- Angiotensin-converting enzyme (ACE), pep- hedron Lett. 1985, 26, 665; R. Kellner et al., tidyl dipeptidase A, a zinc metallopeptidase Eur. J. Biochem. 1988, 177, 53]. with great importance in the regulation of Androctonin, RSVCRQIKIC10RRRGGCY blood pressure as well as fluid and salt YKC20TNRPY (disulfide bonds: C4–C20/ balance in mammals. ACE is a dipeptidyl- C10–C16), a hydrophilic antimicrobial pep- carboxypeptidase that catalyzes the conver- tide (→ antimicrobial peptides) isolated sion of the inactive 10-peptide angiotensin from the blood of the scorpion Androctonus I into the potent vasoconstrictor, the 8- australis. Androctonin inhibits the growth peptide angiotensin II (→ angiotensins). of both Gram-positive and Gram-negative In addition, ACE inactivates → bradykinin, bacteria, and displays a large spectrum of a vasodilatory peptide; hence, ACE raises activity against filamentous fungi. In con- blood pressure. The function of ACE in trast to amphipathic α-helical antimicrobial blood pressure control and water and salt peptides that bind and permeate negatively metabolism has been elucidated mainly by charged vesicles, androctonin binds only to the use of highly specific → ACE inhibitors. negatively charged lipid vesicles; this might Approaches for regulation of blood pres- explain the selective lytic activity towards sure based on the ACE homologue → bacteria but not to red blood cells [L. Ehret- angiotensin-converting enzyme 2 are in Sabatier et al., J. Biol. Chem. 1996, 271, progress [N. M. Hooper, Int. J. Biochem. 29537; C. Hetru et al., Biochem. J. 2000, 1991, 23, 641; A. Turner, N. M. Hooper, 345, 653; L. P. Silva, Lett. Drug Design Dis- Trends Pharmacol. Sci. 2002, 23, 177; J. F. Ri- cov. 2004, 1, 230]. ordan, Genome Biol. 2003, 4, 225; D. Coates, Int. J. Biochem. Cell Biol. 2003, 35, 769; K. ANF, atrial natriuretic factor. M. Esalad et al., Hypertension 2005, 46, 953; L. S. Zisman, Eur. Heart J. 2005, 26, 322]. Anfinsen, Christian, (1916–1995), Ameri- can biochemist and winner of the Nobel Angiotensin-converting enzyme 2 (ACE 2), Prize in Chemistry 1972 (shared with → a novel human zinc metalloprotease orig- Moore and → Stein) for his work on ri- inally discovered in the testis, heart and bonuclease (RNase), especially concerning kidney, but later found in a wide variety the connection between the amino acid of tissues and seeming to be localized in sequence and the biologically active con- much the same places as → angiotensin- formation. Anfinsen demonstrated that converting enzyme (ACE). ACE 2 is a gly- RNase could be refolded after denaturation coprotein of 120 kDa, contains a single without loss of enzymatic activity. In 1943, HEXXH zinc-binding domain, and shows Anfinsen received his Ph.D from Harvard considerable homology to human ACE University, and then held various research (40% identity and 61% similarity). How- and teaching positions. In 1950, he joined ever, it differs greatly in substrate specificity the staff of the National Institute of Health and its activity is not inhibited by classi- (Bethesda, MD), and headed the laboratory cal → ACE inhibitors, but by EDTA. It has ch-A February 20, 2008 19:49 Char Count=

27 Angiotensins (AT)

been reported that ACE 2 belongs to several in the regulation of blood pressure and enzymes that catalyze the degradation of fluid homeostasis. Two AT II receptors, angiotensin I (AT I, → angiotensins) to an- AT1 and AT2, with similar binding affinity giotensin 1-9 [AT I(1-9)] and angiotensin II for AT II, are known that belong to the to angiotensin 1-7 [AT I(1-7)], respectively. superfamily of seven membrane-spanning ACE 2 functions as a carboxypeptidase. It G protein-coupled receptors. The AT II ef- has been suggested that ACE 2 and the pro- fects, including vasoconstriction, increased teolysis product AT I(1-7) play an impor- aldosterone secretion and sympathetic tant role in the renin-angiotensin system, tone and cardiac and vascular hypertrophy, setting the balance of pressor/depressor are predominantly mediated via the AT1 tone, and have both cardioprotective and receptor. However, the functions of the renoprotective potential. ACE 2 functions AT2 receptor have not been clearly charac- as a novel target for gene therapy for hy- terized. AT II is formed in many tissues, pertensive disorders [S. R. Tipnis et al., J. including most peripheral organs and the Biol. Chem. 2000, 275, 33238; M. Donoghue brain. It has been reported that local AT et al., Circ. Res. 2000, 87,1;M.A.Crack- II systems are regulated independently ower et al., Nature 2002, 417, 822; J. L. Guy from the classical RAS. The effects of both et al., Biochemistry 2003, 42, 13185; M. J. Ka- circulating and locally formed AT II seems tovich et al., Exp. Physiol. 2005, 90, 299; L. S. to be more complex and widespread than Zisman, Eur. Heart J. 2005, 26, 322; C. M. initially envisioned. Although, in the brain Ferrario, Hypertension 2006, 47, 515; K. M. all components of RAS (e.g., angiotensino- Elased et al., Hypertension 2006, 47, 1010]. gen, renin, ACE and AT II) are present, it has been suggested that the brain may pos- Angiotensinogen, → angiotensins. sess alternative enzymatic mechanisms for Angiotensins (AT), angiotonins, hyper- the formation of AT II distinct from those tensins, tissue peptide hormones occurring occurring in the classical RAS. One-fifth of both in the periphery and in the brain, with the adult population suffers from chronic influence on blood pressure. The source hypertension. The application of AT II of the AT is angiotensinogen, a plasma inhibition either by → ACE inhibitors protein (Mr ∼ 60 kDa) of the α2-globulin or by AT1 receptor blockade with specific fraction which is initially cleaved by the non-peptidic antagonists for treatment kidney aspartyl protease → renin, yielding of hypertension, ischemic heart disease, the inactive 10-peptide angiotensin I, AT and heart failure, was started during the I, H-Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His- early 1970s and remains important to Leu10-OH. Angiotensin II, AT II, H-Asp- the present day. AT II is inactivated in Arg-Val-Tyr-Ile-His-Pro-Phe-OH, is for- the blood by angiotensinase. On the basis med by proteolytic cleavage of AT I of structure–activity relationship studies catalyzed by → angiotensin-converting it could be established that, according to enzyme (ACE). Angiotensin was initially modifications of AT II in positions 8 (type described as a peripheral hormone that I) and 4 (type II), two classes of antagonists mediates the effects of the classical renin- can be synthesized. Type I antagonists angiotensin system (RAS). Circulating AT show protracted effects on smooth muscle II induces vasoconstriction, aldosterone tissue, whereas type II antagonists are release, sodium and water retention, competitive antagonists at AT II receptors. increases fluid intake, and plays a key role Furthermore, cyclic analogues of AT II ch-A February 20, 2008 19:49 Char Count=

Angiotonin 28

characterized by their conformational to the early investigations of Theodor → constraint show high activity and selectiv- Curtius in 1881. In the course of hippuric ity. There are no significant differences acid synthesis from benzoyl chloride and in the central effects of AT II and its silver glycinate, Curtius had carried out the linear analogues, but cyclic analogues pro- first peptide bond formation of all. About duce sedation or neuroleptic-like activity. 70 years later, Theodor Wieland made the Angiotensin III, AT III, H-Arg-Val-Tyr-Ile- → mixed anhydride method available for His-Pro-Phe-OH, is formed by cleavage peptide synthesis. Besides this method, → of the N-terminal Asp of AT II under the symmetrical anhydrides and → N-carboxy catalysis of aminopeptidase A. Angiotensin anhydrides are used in peptide coupling. IV, AT IV, H-Val-Tyr-Ile-His-Pro-Phe-OH, Anorectin, → somatoliberin. results from the cleavage of AT III with aminopeptidase N. AT III acts as a central Anorexigenic peptide, natriuretic peptide. (1-7). The latter is involved in the activation Ans, anthracene-9-sulfonyl. of peripheral vasodilator mechanisms, and shows antitrophic effects mediated Anserine, β-alanyl-L-1-methylhistidine, a by the inhibition of protein synthesis. naturally occurring analogue of → carno- Furthermore, AT II(1-7) amplifies the sine exhibiting numerous biological activ- vasodilator actions of → bradykinin, and ities, e.g., pH buffering, complexation of it has been suggested that it reduces the zinc, cobalt and ferrous ions, scavenging release of norepinephrine acting via a of free radical species [E. C. Bate-Smith, J. bradykinin/nitric oxide-mediated mecha- Phys. 1938, 92, 336; E. J. Baran, Biochemistry nism[I.H.Page,Hypertension Mechanisms, (Moscow) 2000, 65, 789; A. Guiotto et al., Grune & Stratton, New York, 1987, 1102; Curr. Medicinal Chem. 2005, 12, 2293]. K. Sasaki et al., Nature 1991, 351, 230; J. M. Antagonist, an analogue of a biological Saavedra, Endocr. Rev. 1992, 13, 329; R. L. active peptide that acts as competitive Davisson et al., Circ. Res. 1998, 83, 1047; Z. inhibitor. It occupies the appropriate Lenkei et al., Front. Neuroendocrinol. 1997, receptor and displaces the → agonist from 18, 383; A. Reaux et al., Trends Endocrinol. the receptor, but does not transmit the Metab. 2001, 12, 157; H. Gavras, H. R. biological signal. Brunner, Hypertension 2001, 37 (part 2), 342; J. M. Saavedra, Cell. Mol. Neurobiol. Antamanide (AA), “anti-amanita peptide”, 2005, 25, 485; C. M. Ferrario, Hypertension cyclo-(-Val-Pro-Pro-Ala-Phe-Phe-Pro-Pro- 2006, 47, 515]. Phe-Phe10-), a non-toxic cyclic 10-peptide from Amanita phalloides. Antamanide was Angiotonin, → angiotensins. isolated from the lipophilic part of extracts Anhydrides, species that readily react with of A. phalloides by chromatographic a huge number of nucleophiles. Basic con- procedures, structurally characterized, siderations towards the application of an- and synthesized by Th. Wieland and hydrides in peptide synthesis date back co-workers in 1968. Administration at ch-A February 20, 2008 19:49 Char Count=

29 Antifreeze proteins (AFPs)

0.5 mg kg−1 causes full protection of mice tions [J. Kuby, Immunology 2nd edn., Free- from death by phalloidin (→ phallotoxins) man, 1994]. after injection about 1 h before or, at the → latest, simultaneously with 5 mg kg−1 of Antibody-catalyzed synthesis, abzyme- the toxin. Antamanide is a competitive catalyzed synthesis. inhibitor of the transport system for phal- Anticancer peptides, peptides displaying lotoxins and amatoxins in the parenchyma antitumor activity on the basis of different cells of the liver [Th. Wieland, Peptides of modes of action. They may be derived Poisonous Amanita Mushrooms,Springer from sites of protein interaction, phos- Series in Molecular Biology, Springer Ver- phorylation, or cleavage and, e.g., interfere lag, Berlin, New York, 1986;K.Munster¨ with apoptotic pathways. Peptide-based et al., Biochem. Biophys. Acta 1986, 860, 91]. approaches are reported to target, e.g., MDM2, p53, NF-κB, ErbB2, MAPK, Antho-Kamide, L-3-phenyllactyl-Phe-Lys- Smac/DIABLO, IAP BIR domains, and Ala-NH2, a neuropeptide isolated from the Bcl-2 interaction domains. Proteasome simple sea anemone Anthopleura elegan- inhibitors, → integrin binding →RGD tissima [K. Morihara, H. Tsuzuki, Arch. peptides (cilengitide), cationic amphipathic Biochem. Biophys. 1971, 146, 291]. peptides, → somatostatin analogues such Anthopleurin A, GVSCLCDSDG10PSVR as octreotide, →gastrin-releasing peptide GNTLSG20TLWLYPSGCP30SGWHNCKA antagonists, →gonadotropin-releasing HG40PTIGWCCKQ, a 49-peptide contain- hormone agonists, → histone deacetylase ing three disulfide bridges isolated from (HDAC) inhibitors, → atrial natriuretic the sea anemone species Anthopleura. peptides, DNA-binding peptides (→ acti- Anthopleurin-A causes, in nanomolar nomycins), antimitotic peptides (→crypto- concentration, a positive ionotropic effect. phycins, →dolastatins, phomopsin A), and This peptide is a member of the → Ras farnesyl transferase inhibitors form β-defensin-fold family [M. W. Pennington therapeutically important classes. Marine et al., Int. J. Pept. Protein Res. 1994, 43, 463; peptides such as → didemnins, → kaha- P. K. Pallaghy et al., Biochemistry 1995, 34, lalides, → hemiasterlin, → dolastatins, 3782; A. M. Torres et al., Toxicon 2004, 44, cemadotin, soblidotin, and aplidine have 581]. also been clinically tested. In addition, peptide conjugates with antimitotic agents Antho-RIamide I, L-3-phenyllactyl-Tyr-Arg- or radioactive isotopes for tumor-selective Ile-NH2, a neuropeptide isolated from the delivery must be mentioned [Y. L. Janin, sea anemone species Anthopleura elegantis- Amino Acids 2003, 25, 1]. sima [C. J. P. Grimmelikhuijzen et al., Proc. Natl. Acad. Sci. USA 1990, 87, 5410]. Antifreeze proteins (AFPs), and antifreeze glycoproteins (AFGPs), synthesized from Antibodies, proteins (→ immunoglobu- teleost fish that encounter extreme cold lins) produced by B lymphocytes or B seawater conditions for protection against cells responsible for humoral immunity. freezing. All fish AFPs lower the so- An enormously diverse collection of related lution freezing point through a non- proteins mediates humoral immunity that colligative mechanism. Antifreeze proteins is most effective against bacterial infections bind to particular surfaces of ice crys- and the extracellular phases of viral infec- tals, thereby modifying the crystal structure ch-A February 20, 2008 19:49 Char Count=

Antigens 30

followed by inhibition of further ice growth. Antimicrobial peptides (AMP), host defense Thermal hysteresis is used as a measure of peptides, HDP, small (<50 aa), cationic antifreeze activity. AFPs are divided into (mostly due to the presence of two four distinct classes: types I to IV. The to nine positively charged Arg and Lys different classes of AFPs are synthesized residues), amphiphilic peptides containing by various taxonomic groups. For exam- up to 50% hydrophobic amino acids with ple, type I AFPs are characterized by a microbicidal activity against both bacteria high alanine content (>60 mol.%) and an and fungi. AMP play an important role amphipathic α-helical secondary structure. in protection from invading microorgan- They occur in sculpins, right-eye flounders, isms. They have been isolated from all the and snailfish. Usually, the type I AFPs are phyla investigated, such as plants, inverte- synthesized in the liver for transfer into brates, vertebrates, and humans, including blood, providing extracellular freeze protec- microbes themselves. In amphibians, AMP tion. Furthermore, a novel subclass of type are usually secreted by the dermal glands I AFPs, designated skin-type AFPs, have located in the outer layer of the skin. In been found in the skin of winter floun- mammals, including humans, AMP are lo- der, shorthorn, and longhorn; these AFPs cated in the granules of neutrophils and in are encoded by a separate subset of genes epithelial cells throughout the body. AMP from liver-expressed proteins [K. V. Ewart are an essential part of the innate immu- et al., Cell. Mol. Life Sci. 1999, 55, 271; nity that has evolved in most living organ- G. L. Fletcher et al., Annu. Rev. Physiol. isms over 2.6 billion years to combat mi- 2001, 63, 359; R. P. Evans, G. L. Fletcher, J. crobial challenge. It has been suggested Mol. Evol. 2005. 61, 417]. that AMP are effective adjuvants, syner- gistic with other immune effectors, polar- izing the adaptive response, and support Antigens, foreign macromolecules, pre- wound healing. The antimicrobial peptides dominantly proteins, carbohydrates and show potent antimicrobial activity against nucleic acids, that trigger the immune re- Gram-positive and Gram-negative bacte- sponse, usually performed by production of ria, fungi, parasites, and some enveloped → defense proteins, known as antibodies viruses. Cationic AMP interact with the [J. Kuby, Immunology (2nd edn.), Freeman, negatively charged bacterial phospholipids 1994]. and permeate the membrane via the for- mation of transmembrane pores. Further- Antihemophilic factor, Factor VIII, a pro- more, it has been verified that AMP can tein (Mr ∼ 265 kDa) acting as component also use the passive transport system to of the blood clotting cascade in humans. enter bacteria, from where they are ca- Activated Factor VIIIa acts as an accessory pable of disrupting multiple cellular pro- factor during the activation of Factor X (→ cesses within the bacteria. However, the Stuart factor) by activated christmas fac- vast majority of the cationic peptides appear tor IXa. Factor VIII forms a complex with to act by permeabilization of the bacterial the Willebrandt factor during circulation cell membrane. Despite the fact that AMP in blood [T. Halkier, Mechanisms in Blood are considered as endogenous antibiotics, Coagulation, Fibrinolysis and the Comple- several additional features have recently ment System, Cambridge University Press, become clear. Some AMP are chemotac- 1991]. tic for leukocytes, or are involved in the ch-A February 20, 2008 19:49 Char Count=

31 Antisense peptide

regulation of cell proliferation, angiogen- the cryptidin-related sequence (CRS) pep- esis, wound healing, epithelialization, or tides. The → cathelecidins, originally iden- adaptive immunity. AMP are being con- tified in myeloid cells, comprise a protein sidered as potential alternatives to cur- family with members in all of the four rent antibacterial agents, especially with groups [T. Ganz, R. Lehrer, Curr. Opin. Im- the emerging problem of drug-resistant munol. 1998, 10, 41; H. G. Boman, Scand. pathogenic bacteria. Therefore, they are J. Immunol. 1998, 48, 15; A. Tossi et al., promising candidates for drug develop- Biopolymers 2000, 55, 4; A.M. Cole, T. Ganz, ment. Up until 2006, approximately 900 BioTechology 2000, 29, 822; M. Zasloff, Na- AMP have been isolated; details may be ture 2002, 415, 389; H. Ulvatne, Am. J. Der- found in a periodically updated data base on matol. 2003, 4, 591;R. E. Hancock, D. R. the Internet, for example, at http://www. Devine, Mammalian Host Defence Peptides, bbcm.units.it/∼tossi/pag1.htm. AMP can Cambridge University Press, Cambridge, be divided into classes based on the UK, 2004; C. Beisswenger, R. Bals, Curr. mechanism of their biosynthesis: non- Prot. Pept. Sci. 2005, 6, 255; J. B. McPhee, R. ribosomally synthesized and ribosomally E. W. Hancock, J. Peptide Sci. 2005, 11, 677; synthesized peptides. According to their K. A. Brogden, Nat. Rev. Microbiol. 2005, 3, secondary structure, eukaryotic AMP usu- 238; K. L. Brown, R. E. W. Hancock, Curr. ally can be grouped into four main Opin. Immunol. 2006, 18, 24]. classes: (i) linear peptides with an α- α -Antiplasmin, → α -macroglobulin. helix structure, which do not contain Cys 2 2 residues; the → cecropins (insects, pigs), Antisense peptide, complementary peptide, → magainins (frogs), LL-37, a human a peptide sequence hypothetically deduced cathelicidin-derived antimicrobial peptide, from the nucleotide sequence that is com- and CAP18 (rabbits) are members of the plementary to the nucleotide sequence cod- first group. (ii) β-Sheets stabilized by disul- ing for a naturally occurring peptide (sense fide bridges; representatives of the second sequence). It could be demonstrated that an- group are the → defensins, divided into α- tisense peptide exerts biological responses defensins (humans, rats, guinea pigs, rab- through the interaction with the receptors bits), β-defensins (humans, cattle, mice), for the sense peptides. Potential applica- θ-defensins and insect defensins, as well tions of antisense peptide lie in the area as → protegrins (pigs), → tachyplesins of biomedical research. For example, anti- (crabs), and insect defensins. (iii) Extended sense peptide (or antibodies against it) may structure with a predominance of certain promote the purification of both endoge- amino acid residues, especially Pro, Arg, nous ligands as well as receptors. Further- Trp; examples of the group are → drosocin more, the development of highly selective (insects), → bactenecin-5 (cattle, sheep, antisense peptides against tumor cell mark- goats), → indolicidin (cattle), and → PR- ers may aid in the diagnosis and therapeu- 39 (pigs). (iv) Loop structures with an in- tic modalities of the appropriate state of the tramolecular disulfide bridge, represented disease. The in vivo administration of anti- by → brevinins (frogs), esculentin (frogs), sense peptides may help in better modula- and → bactenecin (cattle). AMP that may tion of biological responses caused by their belong to either all or none of these four endogenous sense counterparts. The con- groups include the family of host-defense- cept of antisense peptides was suggested related ribonucleases, angiogenin 4, and by Mekler in 1969, and three years later ch-A February 20, 2008 19:49 Char Count=

Antistatin (ATS) 32

independently proposed and tested by functions as a reactive center residue, pro- Jones using a synthetic peptide that was viding a cleavage site of choice for leuko- antisense to the C-terminal tetrapeptide of cyte elastase. Interestingly, in a pathologi- gastrin [L. B. Mekler, Biophys. USSR (Engl. cal variant of α1-antitrypsin found in a child Trans.) 1969, 14, 613; D. S. Jones, J. Chem. with a bleeding disorder, Met358 was substi- Soc. Perkin Trans. I 1972, 1407; K. L. Bost, J. tuted by an arginine, thus converting this E. Blalock, Methods Enzymol. 1989, 168, 16; protein from an inhibitor of elastase to a Y. Shai et al., Biochemistry 1989, 28, 8804; highly effective inhibitor of thrombin [H. R. S. Root-Bernstein, D. D. Holsworth, J. Loebermann et al., J. Mol. Biol. 1984, 177, Theoret. Biol. 1998, 190, 107]. 531; W. Bode et al., Protein Sci. 1992, 1, 426; P. R. Elliott et al., Nature Struct. Biol. 1996, Antistatin (ATS), an anticoagulant protein 3, 676]. (M ∼ 15 kDa) isolated from the salivary r → glands of the Mexican leech Haementeria Anxiety peptide, diazepam-binding in- officinalis. ATS has been reported to be hibitor peptide. → a potent inhibitor of Factor Xa ( Stu- Aoc, 1-azabicyclo[3.3.0]octane-2-carboxylic art factor). The C-terminal region ATS- acid. (109-119) has been suggested to be an im- AOC, (S)-2-amino-8-oxo-(S)-9,10-epoxi- portant determinant of inhibitory potency. decanoic acid. Structure–activity relationship studies of fragment analogues have been described AOP, 7-azabenzotriazol-1-yloxytris(di- [S. S. Mao et al., Thromb. Haemost. 1993, methylamino)phosphonium hexafluoro- 69, 1046; D. L. Danalev et al., Bioorg. Med. phosphate. Chem. Lett. 2005, 15, 4217]. Apa, 6-aminopenicillanic acid. Antithrombin III (AT3), a protein (432 aa, Apamin, CNCKAPETAL10CARRCQQHa ∼ 1 11 3 15 Mr 58 kDa) acting as inhibitor of throm- (disulfide bonds: C –C /C –C ), a 18- bin and all active proteases of the blood peptide amide of the bee venom (1–3% of clotting system (→ serpins) except Factor the venom) causing neurotoxic effects. The VIIa by binding to them in 1:1 complex in two arginine residues are of essential im- similar manner as BPTI binds to trypsin. portance for the biological activity. Similar The presence of heparin enhances the in- to the → mast cell-degranulating peptide, hibitory activity of antithrombin by several apamin blocks selectively Ca2+-dependent hundredfold. In antithrombin, Arg393 is the K+ channels in neurons; this results in reactive center residue that provides a spe- serious disturbances of CNS function [R. cific cleavage site for thrombin [T. Halkier, C. Hider, Endeavour, New Series 1988, 12, Mechanisms in Blood Coagulation, Fibrinoly- 60; E. Moczydlowski et al., J. Membr. Biol. sis and the Complement System,Cambridge 1988, 105]. University Press, 1991]. Apelin, human apelin: LVQPRGSRNG10 20 30 α1-Antitrypsin, a glycoprotein (394 aa, Mr PGPWQGGRRK FRRQRPRLSH KGP ∼ 51 kDa) acting as an effective inhibitor MPF, a 36-peptide acting as the endo- of → trypsin, but its prime physiological genous ligand of the orphan G protein- function is as an inhibitor of the elastase coupled receptor APJ (putative receptor released by leukocytes. It is the archetype of protein related to the → angiotensin II 358 the serpin family. In α1-antitrypsin, Met receptor AT1). APJ consists of 377 aa and ch-A February 20, 2008 19:49 Char Count=

33 Apoptotic protease-activating factor 1 (Apaf-1)

seven transmembrane domains, the gene a mechanism that includes stereoselective of which is localized on the long arm elements but differs completely from any of chromosome 11. Angiotensin II does pore-forming activity. Apidaecin Ia, GNNR not bind APJ. Apelin and APJ mRNA are PVYIPQ10PRPPHPRIa, has been isolated widely expressed in several human and from honeybee (Apis mellifera) [P. Casteels, rat tissues, and exhibit functional effects P. Tempst, Biochem. Biophys. Res. Commun. in both the CNS and periphery. A 77-aa 1994, 199, 339; M. Castle et al., J. Biol. preproprotein can be cleaved into a 55 Chem. 1999, 46, 32555]. aa fragment and then into shorter forms. Apelin-36 is the physiologically active form, Apm, 2-aminopimelinic acid. although shorter C-terminal sequences also increase extracellular acidification Apolipoprotein, → lipoproteins. rates and inhibit cAMP production in Chi- nese hamster ovary cells. Synthetic human Apopeptide, a word derived from the noun [pGlu24]-apelin-(24-36), corresponding to peptide that means the free peptide com- the C-terminal 13 residues with pGlu at ponent of a bioactive peptide missing a co- the N-terminus, shows a much higher factor complex, the cofactor having been re- acidification rate than that of parental moved (Greek apo-, away from) [J. H. Jones, apelin. The primary structure of apelin was Editorial, J. Peptide Sci. 2006, 12, 79]. determined by cDNA cloning. The bovine peptide differs in only two residues from Apoptotic protease-activating factor 1 (Apaf- the human apelin. Apelin and its receptor 1), a protein controlling → caspase acti- have been discovered in heart, large or vation during apoptosis. Apaf-1 consists small conduit vessels, and endothelial cells. of an N-terminal caspase recruitment do- Apelin has been reported to be involved in main (CARD), a central nucleotide-binding the regulation of cardiovascular functions, oligomerization domain (NOD), and mul- fluid homeostasis, vessel formation and tiple WD40 repeats at the C-terminal half. cell proliferation. Furthermore, it has been The WD40 repeats have been reported to shown that apelin inhibits insulin secretion be responsible for cytochrome c binding in mice. Recently, it has been reported that and fulfill a regulatory role on Apaf-1 func- apelin is a newly identified adipokine up- tion. Apaf-1 occurs in cells in an inactive regulated by insulin and obesity. However, conformation and requires ATP/dATP for despite some very interesting effects, and activation. It binds to cytochrome c and, in the demonstration that apelin circulates the presence of ATP/dATP, forms a apop- in plasma, the functions of apelin in vivo tosome that leads to the recruitment and ac- remains unknown [K. Tatemoto et al., tivation of the initiator caspase, caspase-9. Biochem. Biophys. Res. Commun. 1998, The hydrolysis of ATP/dATP causes con- 251, 471; B. Masri et al., Cell. Signal. 2005, formational changes which are essential 17, 415; M. Sorhede Winzell et al., Regul. for the formation of the apoptosome and Pept. 2005, 131, 12; E. A. Ashley et al., the activation of caspase-9. The fine mech- Cardiovasc. Res. 2005, 65, 73]. anism of Apaf-1 function remains to be investigated. The 2.2 Å crystal structure Apidaecins, proline-rich short peptides of ADP-bound, WD40-deleted Apaf-1, were from insects. These are highly bacterici- described in 2005 [P. Li et al., Cell 1997, 91, dal against Gram-negative organisms via 479; S. J. Riedl, Y. Shi,Nature Rev. Mol. Cell ch-A February 20, 2008 19:49 Char Count=

Apratoxin A 34

Biol. 2004, 5, 897; S. J. Riedl et al., Nature By inhibiting fibrinolysis and preserv- 2005, 434, 926]. ing platelet function, aprotinin has been shown to reduce blood loss and transfusion Apratoxin A, a 25-membered cyclodep- requirements in cardiac surgery, lung, and sipeptide (→ depsipeptides) isolated liver transplantations, and surgery for hip from the marine cyanobacterium Lyngbya replacement. Additional indications are majuscule, and exhibiting potent cyto- hyperfibrinolytic hemostatic disorders and toxic activity. Apratoxin A consists of a complications of thrombolytic therapies. proline, three methylated amino acids In Europe, aprotinin has been in clinical (N-methylisoleucine, N-methylalanine, O- use for about 40 years, but in the United methyltyrosine), an α,β-unsaturated mod- States it has been approved for intravenous ified cysteine residue (moCys) and a dihy- applications only since 1993 [M. Kunitz, droxylated fatty acid moiety, 3,7-dihydroxy- J. H. Northrop, J. Gen. Physiol. 1936, 19, 2,5,8,8-tetramethylnonanoic acid (Dtena) 991; H. Fritz, G. Wunderer, Arzneim. [H. Luesch et al., J. Am. Chem. Soc. 2001, Forsch./Drug Res. 1983, 33, 479; W. Geb- 123, 5418; H. Luesch et al., J. Bioorg. Med. hard et al., in: Proteinase Inhibitors,A. Chem. 2002, 10, 1973; J. Chen, C. J. Forsyth, Barret, G. Salvesen (Eds.), p. 375, Elsevier, Proc. Natl. Acad. Sci. USA 2004, 101, 12067; Amsterdam, 1986; W. Beierlein et al., Ann. T. Doi et al., Org. Lett. 2006, 8, 531; D. Ma Thorac. Surg. 2005, 79, 741]. et al., Chem. Eur. J. 2006, 12, 7615]. AQP, aquaporin. OMe Aquaporins (AQP), members of the major intrinsic protein (MIP) superfamily of O integral membrane proteins, which are O found throughout Nature. AQP facilitate N water transport in various eukaryotes and O NH N prokaryotes. The archetypal aquaporin, moCys ∼ ON AQP1 (Mr 28 kDa), also known as CHIP, O channel-forming integral membrane pro- N tein of 28 kDa, forms a partly glycosylated S O water-selective channel that is widely expressed in the plasma membranes of OH Dtena various water-permeable epithelial and endothelial cells. The three-dimensional Apratoxin A structure (7 Å resolution) of the de- glycosylated human erythrocyte AQP1 Aprotinin, bovine pancreatic trypsin inhibitor shows that the structure has an in-plane, (Kunitz), BPTI, a bovine protein consisting intramolecular 2-fold axis of symmetry of 58 aa residues and three disulfide located in the hydrophobic core of the bridges (Mr ∼ 6512 kDa). Aprotinin be- bilayer. The monomer is composed of longs to the serpins, and acts as inhibitor six membrane-spanning, tilted α-helices for serine proteases, but not for → throm- forming a right-handed bundle surround- bin and Factor Xa. In the past, aprotinin ing a central density. From these results, was used for the treatment of acute pan- a model is suggested that identifies the creatitis, but today this is no longer valid. aqueous pore in the AQP1 molecule and ch-A February 20, 2008 19:49 Char Count=

35 Arrestins

indicates the organization of the tetrameric pNbs, dNbs, Bts) cleavable by treatment complex in the membrane. Five mem- with thiophenol or alkanethiols, and bers of the mammalian aquaporins are hence are orthogonal to tert.-butyl and described. AQP1 acts as an osmotically 9-fluorenylmethyl-type protecting groups. driven, water-selective pore, while AQP2 For the guanidino protection, the arene mediates vasopressin-dependent renal sulfonyl moiety has been modified with re- collecting duct water permeability. AQP3, spect to acid lability by the introduction of located in the basolateral membrane of electron-donating substituents on the aryl the collecting duct, forms an exit pathway residue. 4-Methoxybenzenesulfonyl (Mbs), for reabsorbed water. AQP4 is abundant 2,4,6-trimethylbenzenesulfonyl (Mts), in brain and seems to participate in the 4-methoxy-2,3,6-trimethylbenzenesulfonyl reabsorption of cerebrospinal fluid and (Mtr), 2,2,5,7,8-pentamethylchroman-6- osmoregulation, whereas AQP5 mediates sulfonyl (Pmc) and 2,2,4,6,7-pentamethyl- fluid secretion in salivary and lacrimal dihydrobenzofuran-5-sulfonyl (Pbf) have glands [J. S. Jung et al., Proc. Natl. Acad. become very popular in SPPS. Acid lability Sci. USA 1994, 91, 13052; J. H. Park, M. increases in the series Tos < Mbs < Mts H. Saier, J. Membr. Biol. 1996, 153, 171; T. < Mtr < Pmc < Pbf, with Pbf display- Walz et al., Nature 1997, 38, 624; A. Cheng ing the best deprotection kinetics. The et al., Nature 1997, 38, 627]. 9-anthracenesulfonyl (Ans) is cleavable by mild reducing agents. Ar, aryl. Arenesulfonamide linker, → safety-catch Arenastatin A, cryptophycin-24, a 16- linker. membered cyclodepsipeptide (→ dep- sipeptides) isolated from the Okinawan ma- Arg, arginine. rine sponge Dysidea arenaria with struc- Arginine (Arg, R), α-amino-δ-guanidino- tural similarity to → cryptophycins and valeric acid, C H N O ,M 174.2 Da, the identical with cryptophycin-24. Arenastatin 6 14 4 2 r most basic of the proteinogenic amino A inhibits microtubule assembly in vitro.It acids. binds to tubulin at the rhizoxin/maytansine binding site. The total synthesis was de- Argiotoxin-636, a polyamine amide spider scribed in 2000 [M. Kobayashi et al., Chem. toxin. This is a glutamate receptor antag- Pharm. Bull. 1994, 42, 2196; M. J. Eggen onist with potential as a neuroprotective et al., Org. Chem. 2000, 65, 7792]. agent. The toxin paralyzes insects by block- ing the neuromuscular transmission me- Arene sulfonyl-type protecting groups, Ar- diated via glutamate receptors. The total SO -NH-R, sulfonamide-based protecting 2 synthesis by a practical reductive alkylation groups used preferentially for reversible strategy was described [I. S. Blagbrough, E. blocking of the guanidino side-chain of Moya, Tetrahedron Lett. 1995, 36, 9393]. arginine, and also for the amino function. In the past, mainly the toluene-4-sulfonyl Arrestins, a family of intracellular proteins (tosyl, Tos) group has been used, though playing an important role in quench- this suffers from the disadvantage that ing signal transduction initiated by G it is only cleavable with liquid HF or protein-coupled receptors (GPCRs). Mem- Na/NH3. o- and p-nitro substituents in bers of this family are visual arrestin, the phenyl moiety led to residues (oNbs, β-arrestin 1, and β-arrestin 2.Allof ch-A February 20, 2008 19:49 Char Count=

Aschheim-Zondek reaction 36

these arrestins desensitize GPCRs, while methods have been developed including β-arrestin 1 and β-arrestin 2 additionally thermolysin-catalyzed synthesis [Y. Isowa target desensitized receptors to clathrin- et al., Tetrahedron Lett. 1979, 28, 2611; K. coated pits for endocytosis. Visual arrestin, Oyama et al., J. Org. Chem. 1981, 46, 5242]. first named retinal S antigen, is a 48-kDa α protein. The 2.8 Å crystal structure shows Aspartic acid (Asp, D), -aminosucci- a bipartite molecule with an unusual polar nic acid, HOOC-CH2-CH(NH2)-COOH core. Furthermore, arrestin is described C4H7NO4,Mr 133.10, an acidic proteino- as being a dimer of two asymmetric genic amino acid. molecules. In the photoreceptor cell, Aspartic peptidases, aspartic proteases, as- the activation of rhodopsin by a photon partic proteinases, → peptidases catalyzing initiates signal transduction and signal the hydrolysis of peptide bonds without the termination. Arrestin binds selectively to use of nucleophilic attack by a functional the light-activated rhodopsin in its phos- group of the enzyme. The nucleophile at- phorylated form, thereby shutting down tacking the scissile peptide bond is, in this the phototransduction cascade by blocking case, an activated water molecule, and no transducing activation [T. Shinohara et al., covalent intermediate will be formed be- Proc. Natl. Acad. Sci. USA 1987, 84, 6975; tween the enzyme and a fragment of the J. A. Hirsch et al., Cell 1999, 97, 257; substrate. The name of this group of peptid- R. H. Oakley et al., J. Biol. Chem. 2000, ases is based on the catalytic apparatus 275, 17201; V. V. Gurevich, J. L. Benovic, which consists of two aspartic acid side Methods Enzymol. 2000, 315, 422; M. Han chains (Asp32 and Asp215 of the porcine et al., Structure 2001, 9, 869]. pepsin numbering system) activating di- Aschheim-Zondek reaction, → chorionic rectly the water molecule. These two side- gonadotropin. chain carboxyl groups are close enough to share a hydrogen bond between two of Asn, asparagine. their oxygens, holding the water in place. However, not all members of aspartic pep- Asp, aspartic acid. tidases include two Asp residues in the Asparagine (Asn, N), β-semiamide of aspar- catalytic dyad. An endopeptidase from no- tic acid, H2N-CO-CH2-CH(NH2)-COOH, davirus has an Asp and an Asn as catalytic C4H8N2O3,Mr 132.12, a non-polar pro- residues, whilst in a related tetravirus en- teinogenic amino acid. dopeptidase the Asp residue is replaced by Glu. It is interesting to note that all the en- Aspartame (APM), H-Asp-Phe-OMe, a non- zymes so far described are endopeptidases. nutritive high-intensity sweetener. APM is Members of aspartic peptidases are, for ex- about 200 times sweeter than sucrose. It ample, pepsin, cathepsin, and → renin [V. was first approved by the FDA in 1981 as Kostka (Ed.), Aspartic Proteinases and their a table-top sweetener and an additive, for Inhibitors, de Gruyter, Berlin, 1985]. example, in dry-based beverages, dry cere- als, chewing gum, gelatins, puddings, in- Aspartimide, cyclization product of as- stant coffee, and tea. APM was discovered paragine in a peptide chain involving accidentally during the recrystallization of the β-carboxamide group with release of an intermediate of the synthesis of the C- ammonia. The aspartimide derivative may terminal tetrapeptide of → gastrin at Searle subsequently undergo hydrolysis to give & Co. For commercial synthesis, various a mixture of α-aspartyl and β-aspartyl ch-A February 20, 2008 19:49 Char Count=

37 Ataxin-7

O O R 3 O N R 2 R1 N R1 N R 2 N H O H O H α-Aspartyl peptide Aspartimide

H 2O

O O H R 2 OH N + R1 N R1 OH N R 2 N H H O H O

α-Aspartyl peptide β-Aspartyl peptide

Aspartimide

peptides. The side reaction can be sup- both of CCK-33 (→ cholecystokinin) in rat pressed by reversible blocking of the pancreatic tissue, and it inhibits CCK-8 in- side-chain carboxamide group. An aspar- duced guinea pig gallbladder contractions timide derivative can also be formed from [R.S.L.Changetal.,Science 1985, 230, 177]. an Asp side-chain ester by nucleophilic at- tack of the nitrogen atom of the amino acid Asu, α-aminosuberic acid. located C-terminally with respect to the At, azabenzotriazolyl. Asp residue in the peptide chain. Aspar- timide formation appears to be sequence- AT, angiotensin. dependent, and leads to β-aspartyl moieties Ataxin-7, the SCA7 gene product consisting and deamidation of L-asparagine. It occurs of 897 aa with an expandable polyglutamine in peptides and proteins at alkaline, neutral tract close to the N-terminus. Spinocere- and acidic pH, both in vitro and in vivo [S. bellar ataxia type 7 (SCA7) is a member Capasso, P. Di Cerbo, J. Peptide Res. 2000, of a family of neurodegenerative diseases 56, 382; R. Dolling¨ et al., J. Chem. Soc. characterized by a CAG DNA triplet re- Chem. Commun. 1994, 853; P. Stathopoulos peat expansion leading to polyglutamine et al., J. Peptide Sci. 2005, 11, 658]. expansion in the gene product. The mu- β-Aspartylpeptides, aspartic acid- tant ataxin-7 protein may contain poly- containing peptides in which the β- glutamine repeats from 38 to 300 residues carboxyl group is a constituent of the in length. Further members of this polyg- peptide bond. The unwanted formation of lutamine expansion disease family are, β-aspartylpeptides occurs by nucleophilic e.g., Huntington’s disease and spinobul- ring opening of → aspartimide [M. Bodan- bar muscle atrophy. Although the precise szky et al., Int. J. Pept. Protein Res. 1978, biological function of ataxin-7 is unknown 12, 57]. beside other described actions, it appears to be a transcription factor and a compo- Asperlicin, isolated from Aspergillus alli- nent of the STAGA transcription coacti- aceus acting as a competitive antagonist vator complex. Furthermore, ataxin-7 has ch-A February 20, 2008 19:49 Char Count=

Atosiban 38

the capability to export from the nucleus man circulating 28-peptide ANP, and the via a conserved exportin-dependent signal N-terminal pro-AFP-(1-98). The latter con- [J. Taylor et al., J. Biol. Chem. 2006, 281, tains three peptide hormones: long-acting 2730]. natriuretic peptide, LANP, AFP-(1-30); vessel dilator, AFP-(31-67); and kaliuretic peptide,  Atosiban, Tractocile R (Europe), Mpa-D- AFP-(79-98). The main known biological properties of these peptide hormones Tyr(Et)-Ile-Thr-Asn-Cys-Pro-Orn-Gly-NH2 (disulfide bond: Mpa1-Cys6), an → oxy- are blood pressure regulation and the tocin (OT) antagonist that is produced maintenance of plasma volume in animals by large-scale, solution-phase synthesis and humans. In the atria, the quantity of with an future annual production scale ANP is orders of magnitude higher than in the range of 50–100 kg. It is used to in extracardiac tissues such as CNS and → treat preterm labor and delivery. However, kidney. Receptors ( natriuretic peptides) have been found in blood vessels, kidney, the combined → vasopressin V1a and OT receptor antagonist atosiban is not and adrenal cortex. In the adrenal cortex, an ideal OT antagonist, as it is highly ANP mediates the decrease of aldosterone non-selective for OT receptors versus VP release, while in the kidney it increases glomerular filtration rate, renal blood V1a receptors. For example, in human receptor binding assays, atosiban exhibits flow, urine volume and sodium excretion [T. G. Flynn et al., Biochem. Biophys. Res. 15-fold greater affinity for the V1a receptor than for the OT uterine receptor [P. Melin Commun. 1983, 117, 859; K. Kangawa et al., J. Endocrinol. 1986, 111, 125; C. et al., Biochem. Biophys. Res. Commun. Johansson et al., Peptides 1994,H.L.S. 1984, 118, 131; K. Kangawa et al., Nature Maia (Ed.), Escom, Leiden, 1995, 34; P. 1985, 313, 397; A. J. deBold, Science 1985, Melin, Baillieres Clin. Obstet. Gynaecol. 230, 767; G. McDowell et al., Eur. J. Clin. 1993, 7, 577; M. Manning et al., J. Peptide Invest. 1995, 25, 291; M. Forero McGrath Sci. 2005, 11, 593]. et al., Trends Endocrinol. Metab. 2005, 16, 469; D. L. Vesely, Clin. Exp. Pharmacol. ATP, adenosine triphosphate. Physiol. 2006, 33, 169].

Atrial natriuretic peptide (ANP), atrial natri- Atriopeptide, → atrial natriuretic peptide. uretic factor, ANF, atriopeptide, atriopeptin, cardionatrin I, SLRRSSCFGG10RMDRIGA Atriopeptin, → atrial natriuretic peptide. QSG20LGCNSFRY (disulfide bridge: C7–C23), a 28-peptide hormone isolated Aurelin, AACSDRAHGH10ICESFKSFCK20 from the atrium of the mammalian heart. DSGRNGVKLR30ANCKKTCGLC40, an an- It belongs to the family of → natriuretic timicrobial 40-peptide (Mr 4297 Da) iso- peptides. ANP is a potent hypotensive lated from the mesoglea of the scyphoid and natriuretic agent. It is synthesized jellyfish Aurelia aurita. The six cysteines as prepro-ANP (human: 151 aa), and form three disulfide bonds. Aurelin is syn- stored as 126-polypeptide pro-ANP (also thesized as a 84 aa prepro-aurelin contain- termed: atriopeptigen, cardionatrin IV) in ing a 22 aa signal peptide and a propeptide specific granules of atrial cardiocytes. The segment of the same size. Aurelin exhibits latter is secreted from the atria and then activity against Gram-positive and Gram- processed proteolytically by corin, a type II negative bacteria. It shows structural fea- transmembrane serine protease, to the hu- tures of → defensins and channel-blocking ch-A February 20, 2008 19:49 Char Count=

39 Azapeptides

−15 toxins [T. V. Ovchinnikova et al., Biochem. sociation constant, Kd ∼10 M). Each Biophys. Res. Commun. 2006, 348, 514]. monomer is an eight-stranded antiparal- lel β-barrel, remarkably similar to that of Aureobasidins, a family of cyclodep- the genetically distinct bacterial analogue → sipeptides ( depsipeptides) produced by → streptavidin. The resulting complex is Aureobasidium pullulans consisting of more stable against proteolysis, and prevents its than 20 members. Aureobasidin A, consists intestinal adsorption. Avidin inhibits the of eight lipophilic amino acid residues growth of microorganisms in egg whites. and one hydroxy acid in its 27-membered Together with biotin, avidin is used for the macrocycle. Aureobasidins A, B. C, S2b, immobilization of ligands in immunoas- S3, and S4 have been shown to be potent, says and in affinity chromatography [N. M. µ −1 with MICs of 0.05 to 3.12 gmL for Green, Methods Enzymol. 1990, 184, 51; O. Candida species and C. neoformans isolates. Livnah et al., Proc. Natl. Acad. Sci. USA Aureobasidins are characterized by several 1993, 90, 5076]. desirable properties, including lethality for growing C. albicans with a low level of AVP, arginine vasopressin. acute toxicity, and improved survival and sterilization of kidneys in a murine model. Azadepsipeptides, a new class of pseudo- Aureobasidin A was one of the few peptides peptides. Analogously to → azapeptides, that had appreciable oral bioavailability [K. the α-carbon atom in → depsipeptides is Takesako et al., J. Antibiot. 1991, 44, 919; K. replaced isoelectronically by a trivalent ni- Takesako et al., J. Antibiot. 1993, 46, 1414; trogen. Synthesis and structure evaluation T. Kurome et al., J. Antibiot. 1998, 51, 353]. have been demonstrated using a bis-aza Australian Peptide Association (APA), a analogue of the antiparasitic cyclooctadep- non-profit scientific organization founded sipeptide PF 1022A as a model [H. Dyker in 1992 providing a forum for advancing et al., J. Org. Chem. 2001, 66, 3760]. and promoting peptide research through- out Australia by way of support for an- Azapeptides, -NH-CHR1-CO-NH-NR2-CO- nual local one-day meetings, as well as a NH-CHR3-CO-, a class of backbone- biennial symposium. The first Australian modified peptides in which the α-CH of Peptide Symposium was held in 1994, and one or more amino acid residues in the has been held biennially since then. The peptide chain is isoelectronically replaced 2007 symposium was held jointly with the by a trivalent nitrogen atom. This alteration 2nd Asia-Pacific and 4th International Pep- results in a loss of asymmetry associated tide Symposia. The Association’s website with the α-CH, and yields a structure that is http://www.peptideoz.org. Membership can be considered intermediate in configu- of the association is free to any interested ration between D- and L-amino acids. This people from anywhere in the world, upon α-carbon replacement is connected with registration at this site. the capability to provide resistance to en- zymatic cleavage, and the capacity to act Avidin, a glycoprotein in the egg white as selective inhibitor of serine and cysteine of many birds and amphibians. Chicken proteases [J. Gante, Synthesis 1989, 405; J. ∼ avidin (Mr 66 kDa) consists of four identi- Magrath et al., J. Med. Chem. 1992, 35, 4279; ∼ cal subunits (without carbohydrate: Mr 14 R. Xing et al., J. Med. Chem. 1998, 41, 1344; kDa; 128 aa). Avidin binds four molecules E. Wieczerzak et al., J. Med. Chem. 2002, of the vitamin biotin with high affinity (dis- 45, 4202]. ch-A February 20, 2008 19:49 Char Count=

Azatides 40

Cl H H N 3 N N O N 3 R H 2N R O O H 2NR α-Azido acid chloride method

α-Azido acid chloride method, an approach Azatides, -NH-NR1-CO-NH-NR2-CO-NH- especially useful for the incorporation of NR3CO-, biopolymer mimetics consisting α,α-disubstituted amino acids into pep- of α-aza-amino acids (hydrazine carboxy- tides. It employs α-azido acid chlorides lates). In contrast to an → azapeptide, as masked equivalents of activated Nα- an azatide is a so-called pure azapep- protected amino acids; the azido group can tide. The earliest attempts to synthesize easily be reduced to a free amine, even un- pure azatides using hydrazine units was der SPPS conditions [M. Jost et al., Angew. described by Gante and coworkers in Chem. Int. Ed. 2002, 41, 4267]. 1965, but stepwise chain lengthening of monomeric α-aza-amino acids in a repetitive manner, both as solution and Azirine/oxazolone method, asynthetic liquid-phase approach, was performed in method for the introduction of sterically 1996 [J. Gante, Chem. Ber. 1965, 98, 3340; highly hindered α,α-disubstituted α-amino J. Gante et al., Proc. 13th American Peptide acids into peptides. The synthesis of, e.g., Symposium 1994, 299; H. Han, K. D. Janda, Aib-rich peptides requires either highly re- J. Am. Chem. Soc. 1996, 118, 2539]. active coupling reagents (e.g., amino acid halides) or special derivatives (such as 3- Aze, azetidine-2-carboxylic acid. amino-2H-azirines or α-azido carboxylic acid chlorides). The azirine/oxazolone Azide coupling, → acyl azide method. method utilizes an amino component that

1 RH RH H O R 3 4 NR R N 3 4 R 2 NCO2H N NR R N H HOR 1 R 2 3-Amino- 2H-azirine R1 RH H O R 2 H N N N OH N O O HOR1 R 2 HR 5(4H)-Oxazolone RH H O R 5NH 2 N N NR5 HOR1 R 2 H

Peptide

Azirine/oxazolone method ch-A February 20, 2008 19:49 Char Count=

41 Azirine/oxazolone method

is formally activated by the ring strain. with, for example, an amino acid ester to Upon reaction with a carboxy component, give, e.g., tripeptides with α,α-disubstituted dipeptide amides are obtained that un- amino acids in the middle position [H. dergo acid-catalyzed cyclization with 5(4H)- Heimgartner, Angew. Chem. Int. Ed. 1991, oxazolone formation, followed by reaction 30, 238]. ch-A February 20, 2008 19:49 Char Count=

42