| 357

Index

A. niger 149 Alternaria helianthi 148 A. versicolor 149 ALX-0018 344 Abciximab 342 ALX-0061 344 Ablynx 345 ALX-0141 344 Absorption 77 ALX-0681 344 – enhancers 78 N-amidino-YrF-MebAla-OH 176 – disadvantage of 78 2-amino-2-hydroxy-methyl-1,3- ABT-229 273 propanediol 81 ABY-002 344 (1R,2S)-1-amino-2-vinyl-cyclopropyl AC187 297, 299, 300 carboxylic acid (vinyl-ACCA)-containing Acetaminophen 298 inhibitors 29 Acetylcholine binding protein (AChBP) 128 2-amino-4-thiazolyl-group 43 Acetylcholine receptor (AChR) 328 1-aminocyclopropyl carboxylic acid Acinetobacter baumannii 64, 91, 107, 109 (ACCA) 22 Acne vulgaris, treatment of 166–67 AMPbiotech 57 Acquired immune deficiency syndrome Amphipacity 141 (AIDS) 45 Amygdala 249 Activated carbonyl inhibitors 17 a-amylases 141 Acylated ghrelin 259, 270 Amylin 256–57, 295 Acylated KTP derivative 178 – anorexigenic effect 257 Acylcarnitines 79 – humans, amylin agonism in 295–309 Adalimumab 337, 347 Amylin agonism, translational research ADAMB. See Dermorphin on 295–309 Adnectins 350 – amylin physiology, overview of 295 Adrenocorticotropic hormone (ACTH) 250 – insulin-dependent diabetes 297–99 Aesculus hippocastanum 141 –– gastric emptying and amylin Affibodies 350 agonism 298–99 Aggregation 73 –– gastric emptying and diabetes 298 Agonists 175 –– glucagon and amylin agonism 297–98 Agouti-related protein (AGRP) 252 –– post-prandial hyperglucagonemia and Agouti-signaling protein (ASIP) 252 diabetes 297 AIDS symptomatic stage 238 – obesity, translational research in 299–309 L-Alanine 317 –– amylin agonism-based translational Alcea rosea 144 research 307–9 Alexion Pharmaceuticals 343 –– clinical studies 302–3 Alfalfa antifungal peptide (alfAFP) 149 –– combination studies 304 s Aliskirin 44 –– combined amylin and leptin Alkanoylcholines 79 agonism 305–7 Aloe vera gel 78, 80 –– endogenous amylin, role of 299–300

Peptide Drug Discovery and Development: Translational Research in Academia and Industry, First Edition. Edited by Miguel Castanho and Nuno C. Santos. r 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. Published 2011 by WILEY-VCH Verlag GmbH & Co. KGaA

bindex 26 July 2011; 12:38:10 358 | Index Amylin agonism, translational research on –– patents 61–63 (continued) –– potential applications of 63–64 –– pre-clinical studies 300–302 –– spin-off creation 66–68 –– small molecule agents, and amylin –– technology transfer 64–66 agonism 304 – therapeutic potential 113–14 – pramlintide 296 Antiviral inhibitors, identification and Amylin monotherapy 301 characterization of 7 Amylin physiology, overview of 295 Apical epithelial cell membrane 74 Amylin receptor (AMY) 256 Aplastic anemia (AA) 200 Amylin-induced weight loss versus caloric Arabidopsis 148 restriction 300 Arabidopsis thaliana 150 Analgesia 172 Arcuate nucleus (ARC) 250 L-V13KL analogs 105 Area postrema (AP) 247, 257, 295 Angiocept 344 L-Arg 177 Angiotensin converting enzyme (ACE) 38 Arginine 233 Angiotensin II 38 Arginine tolerance test 297 Anionic polymers 79 L-arginine vasopressin 75 Anorexia 284 b-arrestin 273 Anorexigenic effects, of amylin 300 Astrocytes 321 Antagonists 175 ATN-103 344 d-antagonists 176 Autoimmune disorders 315 Antibiotics 166 Avastin 339 Antibodies 337–50 Azathioprine 200, 202 – fragments 341–43 Azithromycin 283 – intracellular 347–50 –– immunogenicity of engineered B cell epitopes 314 antibodies 348–49 Bacterially expressed peptides 220 –– new protein scaffolds, developing 349–50 Bacteriophage 314 – multivalent, bispecific, and Barrel-stave model 92 bifunctional fragments, engineering Basal epithelial cell membrane 74 of 345–47 Bed nucleus of the stria terminalis (BNST) 249 – single-domain antibodies 343–45 Benzoyl peroxide 166 – structure 338–41 Benzoylation 60 Antibody-dependent cellular cytotoxicity Benzyl-methoxyproline 18, 22 (ADCC) 338 Beta-barrelin 140 Anticalins 350 Bexxar 339, 346 s Anti-CD20 antibody (Rituxan ) 200 BI00201335 29, 30, 31 Antigen-presenting cells (APC) 319 Bifunctional antibodies 346 Antigens and vaccines BILA 2157 44 – peptides as 314–15 BILD 1257 35 Anti-HIV-1 therapeutics 209 BILD 1263 36 Antimicrobial peptides (AMP or AMPs) Bile salts 79 91–114, 139 BILN 2061 29 – amphipathic a-helical antimicrobial peptides BILN 2061 (ciluprevir) 28 –– antimicrobial and hemolytic activities BioBreeding rats 298 of 92–94 Biological delivery system 174 –– structure–activity relationship (SAR) Biotechnological products, from Plant studies of 94–112 AMPs 144–50 – commercialization 112–13 Biphalin 175, 176 – cyclic b-sheet antimicrobial peptides Bispecific antibodies 345–46 –– structure–activity relationship (SAR) Blood–brain barrier (BBB) 174, 321 studies of 94–112 Body mass index (BMI) 247 – marketing of 57–68 Bombesin and Gastrin-Releasing –– basic research 58–60 Peptide 257–58 –– costs for patenting 63 Bombesin receptor subtype 3 (BRS-3) 257

bindex 26 July 2011; 12:38:10 Index | 359 Bombesin-like peptides 257–58 cDNA 120–21 Botrytis cinerea 140, 148 CDR grafting 348, 349 BP015 peptide 58 CDR-grafting based humanization BP021 peptide 58 method 348 BP76 peptide 60 CECMEL11 library 58, 59 BP77 peptide 60 Cell penetrating proteins 81 BP78 peptide 60 b-cell dysregulation 295 BP100 peptide 58, 59 a-cells 297, 298 BP102 peptide 60 Centocor 342 BP103 peptide 60 Central nervous system (CNS) BP125 peptide 60 analgesia 172 BP126 peptide 60 Centrally secreted neuropeptide systems Bracelet 141 – corticotropin releasing factor 248–56 Brain derived neurotrophic factor – melanin concentrating hormone (BDNF) 322 (MCH) 249–50 Brain, neurotropic factors in – melanocortins 250–52 – neuroprotection and augmentation – neuromedin S (NMS) 254–55 of 321–23 – neuromedin U (NMU) 254–55 Breath method – neuropeptide Y (NPY) 252–54 –[13C]-octanoic acid 284 – opioids 255–56 Brief ITP primer 199–201 – QRFP 256 BRS-3 agonists 257 Cephalexin 72 Brush border membrane bound enzymes and Certolizumab pegol 339 intracellular enzymes 76 Chaperones 148 Bupropion (Contrave) 255 Chelating agents 79 Butanediamide 43 Chemical delivery system 174 Chemokine receptors 210 C34 211–13, 218, 220, 221 Chemotherapy-induced thrombocytopenia C34coil 219 (CIT) 200 C52L 220 Chitin-binding scaffolds 143 Cachexia 270 Chitosan 79, 84 Caco-2 cells 176 CHO cells 273 Calcitonin receptor (CT) Cholecystokinin (CCK) 258–59, 307 – splicing isoforms 256 Chronic intestinal pseudoobstruction 279 Campath 339 Chronic relapsing EAE (CR-EAE) 317 CaMV35S 149 Ciclooxigenase 1 179 Cancer anorexia 284 Ciclooxigenase 2 179 Candida albicans 150 CIDSAV 57 Capsicum chinense 150 Cimzia 342 Carbohydrate binding-domains 143 Circular dichroism (CD) 96, 102 Carbopol 79 Cisapride 283 Carcinoembryonic antigen (CEA) 314 Clavibacter michiganensis subsp. Carpet pore model 92 sepedonicus 148 Cathelicidins 92 Clindamycin 164 Catheter-related infections, prevention c-Mpl 189 of 165–66 13C NMR spin–lattice relaxation Cationic polymers 79 experiments 21 Cationicity 141 CNS delivery 174 Cationization 178 Cocaine-amphetamine-related transcript (CCIZN17)3 222 (CART) 252 CCK2R 258 Colletotrichum coccoides 148 CCK-AR 258 Combinatorial protein engineering 349 CCR5 210 Combined amylin and leptin agonism 305–7 CD4 210 Complementarity determining region CD4-BFFI 221–22 (CDR)1 329

bindex 26 July 2011; 12:38:10 360 | Index Complement-dependent cytotoxicity C-terminally conjugated Fc-peptide-peptide (CDC) 338 (Fc-TMP-TMP) 194 Concentration effect 179 C-termini 144 Cone snails 119–20 Curvularia spp 148 Conopeptides 119 CVID 129 Conotoxin CXCR4 210 – classification and targets 121–22 Cyclic nausea and vomiting 282 – discovery and characterization 120–21 Cyclic peptides 59 – as drug leads 128–33 Cyclic vomiting syndrome (CVS) 282 –– o-conotoxins 129–30, 130–31 Cyclic b-sheet peptides 113 –– in drug design 128–29 Cyclization 143 –– re-engineered conotoxins, in drug Cyclosporin 171, 200 design 131–33 Cyclosporin A 79, 315, 320 – folding 127 Cyclotides 140, 141, 143 – synthesis 124–27 Cysteines 141 Conotoxin-based leads, in drug Cysteine-stabilized ab motifs (CSab) 141 design 119–33 Cytochrome P450 enzyme (CYP3A4) 270 – classification and targets 121–22 Cytotoxic T-cell (CTL) 314 – cone snails 119–20 – discovery and characterization 120–21 D&D drug 183 – drug discovery, prospects for 124 [D-Ala2, N-MePhe4, Gly-ol]-enkephalin] – folding 127 (DAMGO) 255 – posttranslational modifications 122–24 [D-Pen2,D-Pen5]-enkephalin (DPDPE) 175 – structure by NMR and X-Ray 127–28 D1 analogs, biological activity of 109 – synthesis 124–27 D1(V13) and D16(K13, K16), helical net a-conotoxins 121, 129–30, 130–31 representations for 111 Conus geographus 120 D16 107–10 s Conus magus 129 Dalacin T 164 Conus marmoreus 130 DALDA. see Dermorphin Conus victoriae 130 Danazol 202 Copaxone 316, 318 DARPins 350 Copolymer 1 (Cop 1) 316 DDIVPC as an inhibitor of NS3 protease 16– – clinical studies with MS patients 317–18 18 – development of 316–27 Decapeptide angiotensin I 38 – immunological mechanisms involved in Defensin-1 (pth1) gene 148 mitigation of disease by 318–20 Defensins 92, 140, 141, 143 – immunomodulation, in CNS 320–21 Degradation – inflammatory bowel disease, effect – intracellular peptide degradation 76 on 326–27 – by luminal enzymes 76 – myelin repair and neurogenesis 323–26 – proteolytic 76 – neuroprotection and augmentation of Demyelination 324 –– neurotropic factors in brain 321–23 Denazol 200 Corticosteroids 202 Dermorphin 175, 176 Corticotropin releasing factor (CRF) 248–56, Des-acyl ghrelin 259 248–49 Dextran sulfate sodium (DSS)-induced CP32M 218 colitis 326 CP621–652 218 Diabetes Cremophor EL 79 – and gastric emptying 298 Crohn’s disease (CD) 326 – post-prandial hyperglucagonemia and 297 13C spin–lattice relaxation measurements 13 Diabetes mellitus C-terminal acid 17, 18 – type 1 295, 298 C-terminal carboxyl derivatives 18 –– peptides therapy for 327–28 C-terminal carboxylate inhibitor 18 – type 2 (T2DM) 261, 295, 298 C-terminal carboxylic acid 29 Diabetes-associated peptide (DAP) 256 C-terminal warhead 15 Diabetic gastroparesis 274, 277, 281, 284

bindex 26 July 2011; 12:38:10 Index | 361 DiaPep277 327 – peripherally secreted neuropeptides Diet-induced obese (DIO) prone 300 256–63 Differential line-broadening (DLB) –– amylin 256–57 method 8, 18 –– bombesin-like peptides 257–58 N,N-dimethylacetamide side chain 43 –– cholecystokinin (CCK) 258–59 N,N-dimethylamide fragment 44 –– ghrelin 259–60 Dimethylformamide (DMF) 126 –– glucagon-like peptide-1 (GLP-1) 260–61 20,60-dimethyltyrosine 176 –– leptin 261–62 DIO ovariectomized (OVX) rat model 307 –– oxyntomodulin (OXM) 262 s DioRaSSP (Diosynth Rapid Solution –– PYY3-36 and pancreatic polypeptide Synthesis of Peptides) 172 (PP) 262–63 Dipeptide isostere 45 Endogenous peptides into new Dipeptidyl peptidase-IV (DPP-IV 260 analgesics 171–84

DIPP-NH2[c] 176 Endomitoses 189 Disulfide-poor peptides 119 Endomorphin-1 (EM-1) 173 Disulfide-rich peptides 119 Endomorphin-2 (EM-2) 173 Dmt-Ticc[CH2NH]Phe-Phe-NH2 176 Endomorphins 173, 175 [Dmt1]DALDA 176 – versus typical opioids 173 Dom-0200/ART621 344 Endorphins 173 Domantis 345 Enfuvirtide 172, 211, 213–14, 216, 217, 218, Domperidone 283 220, 222–23, 232 Dorsal root ganglion (DRG) 130 Engineered Kunitz-type inhibitors 350 DP107 211 Enkephalin 173, 175, 179 DP-178. See Enfuvirtide Enterobacter species 64, 91 DPDPE. See Enkephalin Enterococcus faecalis 106 D-peptides 219 Enterococcus faecium 63 Drug candidates, peptides as 327–29 Enterocococcus faecium 91 Drug delivery enhancement, multiple Enterocytes 74 approaches for 174 Enzyme inhibition 84 s Drug discovery, prospects for 124 Epoetin alfa (Eprex ) 190 Dual-altered peptide ligand (APL) 328 Eptifibatide 172 D-V13K (D1) 106 Erbitux 339 Dyax 350 Erwinia amylovora 58, 59 Dynorphins 173 Erythromycin 270, 273, 274, 275, 279, 281, Dyslipidemia 300 282, 283 Erythropoietin receptor (EpoR) 192 Ecallantide 350 ESBA105, 344 Eculizumab 339 Escherichia coli 64, 146, 147, 148, 149 Efflux inhibitors 79 ESKAPE microorganisms 63, 91 Efflux transport systems 76–77 Estradiol 307 Electrogastrography 282 Ethylene glycol-bis(2-aminoethylether)-N,N, Encephalitogenic protein 316 N’,N’-tetraacetic acid (EGTA) 79 Endogenous amylin, role of 299–300 Eucommia ulmoides 143 Endogenous peptides and their Eukaryotic cell membrane receptors 247–63 – and antimicrobial peptides 93 – centrally secreted neuropeptide systems Eukaryotic system 146 –– corticotropin releasing factor 248–56 EX-1314 276 –– melanin concentrating hormone EX-1315 276 (MCH) 249–50 Excallantide 344 –– melanocortins 250–52 Experimental autoimmune encephalomyelitis –– neuromedin S (NMS) 254–55 (EAE) 316 –– neuromedin U (NMU) 254–55 Experimental autoimmune MG –– neuropeptide Y (NPY) 252–54 (EAMG) 328 –– opioids 255–56 Extracellular signal regulated kinase –– QRFP 256 (ERK) 261

bindex 26 July 2011; 12:38:10 362 | Index Fatty acids 79 Gastrointestinal tract, strategies to overcome Fatty Zucker rats 298 barriers of 77–84 Fire blight 59 – absorption enhancing agents 77–78 FK-506 peptide 315, 320 –– chemical and physical modifications Flexible apo receptor 14 78–81 Fluoren-9-ylmethoxycarbonyl (Fmoc) 126 –– targeting receptors and transporters Fluorescein isothiocyanate labeled dextran 82–83 (FD-4) 74 –– targeting specific regions of the Fluorescence spectroscopy 179 gastrointestinal tract 81–82 Fluoroketone 12 – enzyme inhibition 84 Food intake and body weight – formulation strategies 83–84 – clinical studies 302–3 – mucoadhesive systems 84 – endogenous amylin, role of 299–300 – particulate carrier systems 83–84 – pre-clinical studies 300–302 Gastrointestinal transit time and site-specific Fo¨rster resonance energy transfer absorption 77 (FRET) 236 Gastroparesis 283 Functional dyspepsia (FD) 282–83, 282 Gastroparesis Cardinal Symptom Index 277 Fusarium graminearum 149 Gastroparesis, meaning of 279 Fusarium moniliforme 148 Gastroparesis, patients with 279–84 Fusarium oxysporum 140 – anorexia and decreased appetite 284 Fusarium oxysporum f. sp. vasinfectum 148 – cyclic nausea and vomiting 282 Fusarium solani 149 – diabetic gastroparesis 281 Fusion inhibitor peptides, of HIV 215–22 – functional dyspepsia (FD) 282–83 – bacterially expressed peptides 220 – gastro-esophageal reflux disease – helicity increase and binding to gp41 216–19 (GERD) 283–84 – isomeric peptides and resistance to – migraine 282 proteolysis 219–20 – Parkinson’s disease 281–82 – peptides modification by derivatization with Gaviscon 283 lipids/proteins 220–22 Genentech 342 FusoGen Pharmaceuticals Inc. 215 GERD 283 Fuzeon. See Enfuvirtide Ghrelin 259–60, 270, 271, 276–77, 284 – assays relevant to non-GI activity 276–77 G protein-coupled receptors (GPCR) 249, 269 – assays relevant to the therapeutic Gastric emptying 297 mechanism of action 276 – and amylin agonism 298–99 – clinical development of 284–85 – and diabetes 298 – clinical potential of 270–71 Gastric emptying, delayed Ghrelin and motilin, similarities and – critically ill patients with 279 differences between 269–70 Gastric MMCs 270 Ghrelin mRNA 269 Gastro-esophageal reflux disease Ghrelin O-acyltransferase (GOAT) 259 (GERD) 278, 283–84 Ghrelin receptor 269 Gastrointestinal (GI) motility 269 Ghrelin receptor agonists 276, 285 Gastrointestinal tract 72 Ghrelin system 269 Gastrointestinal tract, biochemical barriers Ghrelin, forms of 270 of 75–76 Glatiramer acetate (GA) 316, 318 – brush border membrane bound enzymes GlaxoSmithKline 346 and intracellular enzymes 76 GLP-1. See Glucagon-like peptide-1 (GLP-1) – luminal enzymes 76 Glucagon, and amylin agonism 297–98 Gastrointestinal tract, physical barriers Glucagon-like peptide-1 (GLP-1) 260–61, 260 of 73–75 – GLP-1 receptor (GLP-1R) 260 – paracellular pathway 75 Glucose-stimulated insulin secretion – transcellular pathway 73–74 (GSIS) 258 –– apical epithelial cell membrane 74 Glutamic acid 233 –– basal epithelial cell membrane 74 L-glutamic acid 313, 317 –– unstirred water layer 73–74 Glutathione S-transferase (GST) 148

bindex 26 July 2011; 12:38:10 Index | 363 Glycocalyx 73, 74 HIV. See Human immunodeficiency virus Glycosylation 175 (HIV) GM-109 275 HIV protease inhibitors 45–47 Golimumab 339, 347 HIV-1 gp120-CD4 binding 210, 211 – fusion inhibitor 232 gp120-coreceptors binding inhibitors 211 HIV-1 gp41 232 gp41 210, 215, 216–19 HIV35 216 GPR38 269 Hoffmann-La Roche, Inc. 211 G-protein receptor kinases 273 Hollyhock 144 Graft against host (GVH) 320 Hordeum vulgareum 141 Gramicidin S (GS) 95–96, 95, 103 Host defense peptide 92 Gram-negative bacteria 58, 63 Humalog 172 Gram-positive bacteria 58, 63, 106 Human anti-chimeric antibody Growth hormone secretagogue receptor (HACA) 337 type-1a (GHS-R1a) 259 Human anti-human antibodies Growth hormone secretagogues 276 (HAHAs) 337 GS12 (cyclo-(VKLKYdPKVKLYdP) 96 Human anti-mouse antibodies GS14 (cyclo-(VKLKVYdPLKVKLYdP) 95–96 (HAMAs) 337, 348 GS14K4 (cyclo-(VKLKdVYdPLKVKLYdP) 96 Human cytomegalovirus (HCMV) GSK962040 274 protease 7–15 Guinea-pigs 276 – antiviral inhibitors, identification and characterization of 7 H2 receptor antagonists (H2RAs) 283 – determining structures of ligands bound HCMV protease. See Human cytomegalovirus to 8–10 (HCMV) protease – ligand adaptations upon binding 12–14 HCV. See Hepatitis C virus – optimized peptidyl segment 10–12 Heat-shock proteins (HSP) 327 – SAR studies 10 HeLa 150 – strategic summary 14–15 a-helical peptides 113 Human immunodeficiency virus (HIV) 140, a-helices 144 209, 314 Hemagglutinin (HA) 79 – drug-resistance and combination Hepatitis C virus (HCV) 15–32 therapy 222–23 – as an antiviral target 15 – entry and inhibition 210–11 – BI00201335 29–32 – HIV-1 envelope protein 209–10 – DDIVPC as an inhibitor of NS3 – HIV-1 fusion inhibitors 211–15 protease 16–18 – HIV-1 infection 231 – knowledge building 18–21 – HIV protease inhibitors 45–47 – macrocyclization 25–29 – HIV-1 – NS3 serine protease 16 –– fusion inhibitor 232 – N-terminal truncation and improved P1, P2 – HIV-1 gp41 232 and P5 substituents 22–25 – new fusion inhibitor peptides, – “sensemaking” and knowledge building creating 215–22 phase 18 Human leukocyte elastase (HLE) 18 Her2/neu 315 Humanized antibodies 337, 338 Herceptin 339 Humira 339 Heroin 174 Hydrofluoric acid (HF) 126 Herpes simplex virus 32–38 Hydrophilicity of peptide drugs 73 – ribonucleotide reductase inhibitors 32–38 Hyperglycemia 279 Heterologous plant antimicrobial defensins, Hyperinsulinemia 295, 300 production of 147 Hypermotility 298 Hevein-like AMPs 140 Hypoglycemic override mechanism 298 Hexyl insulin mono-conjugate 2 (HIM2) 81 High fat diet (HFD) 259 IBS 283 Hippocampal neurogenesis 308 Ibuprofen (IBP) 178, 179, 181

bindex 26 July 2011; 12:38:10 364 | Index

Ibuprofen-KTP-amide (IKTP-NH2) 178, Kalbitor/DX-88 350 179, 181 Klebsiella pneumoniae 64, 91 IFN-g 321 Knottins 140 IFN-b 315 KTP-amide (KTP-NH2) 178, 179, 181 IgNAR 343 KTP-K-palmitoyl 178 IL-10 320, 321 Kyotorphin (KTP) 177 IL-4 320 Kyotorphin derivatives 171–84 Immune thrombocytopenic purpura (ITP) 189 – academia and pharmaceutical Immunogenicity 338 industry 183–84 Immunoglobulin G (IgG) 340, 341 – BBB permeability, with peptide–membrane Immunoglobulins 192 partition studies 179 Immunomodulators – central nervous system analgesic – peptides as 315–16 peptides 172–73 Immunomodulatory peptides, additional – delivering analgesic peptides to brain – as drug candidates 327–29 174–75 Impatiens 140 – endogenous dipeptide, potential of Inclusion bodies (IBs) 147 177–78 Incomplete Freund’s adjuvant (IFA) 316 – endogenous opioid system 173–74 Indolicidin 159, 160 – future drug candidates, peptides as “Induced fit” model 7 171–72 Inflammation 270 – new KTP derivatives 178–79 Inflammatory bowel disease (IBD) 326 – new opioid-derived peptides, development – Copolymer 1 (Cop 1) effect on of 175–77 326–27 – partition to membrane and enhanced Influenza virus 314 analgesic activity 179–83 Insulin 75, 171, 295 Insulin monotherapy 295 b-lactam antibiotics 72 Insulin therapy 279 Lacy mutants 147 Insulin-dependent diabetes, translational Lansoprazole 283 research in 297–99 Large unilamellar vesicles (LUVs) 179 – amylin agonism and gastric emptying Lateral septum 249 298–99 Leptin 261–62, 300, 305, 307 – amylin agonism and glucagon 297–98 [Leu13]-motilin 275 – gastric emptying and diabetes 298 Leucin encephalin 75 – post-prandial hyperglucagonemia and Licensing 64–66, 65 diabetes 297 Ligand adaptations upon binding 12–14 Integrilin (eptifibatide) 172 Lipid-transfer proteins 140 Interferon (IFN) 315 Lipophilicity 178, 183 – IFN-a 30 Liposomes 83 Intestinal epithelium, transport pathways LIPPSO 57 across 72–73 Liquid chromatography-mass spectrometry Intrabodies. See Intracellular antibodies (LC-MS) 121 Intracellular antibodies 347–50 Liquid chromatography-tandem mass Intracerebroventricular (icv) 260 spectrometry (LC-MS/MS) 238 Intranasal delivery system 172 L-Lysine 317 IQN17 219 Lower esophageal sphincter (LES) 278 Islet amyloid polypeptide (IAPP) 256 Lucentis 339 Isotretinoin therapy 166 Luminal enzymes 76 Lytic enzymes 177 Janus-kinase 2 (Jak2) 261 Januvia (sitagliptin) 261 M. cochincinensis 143 Macrocyclic inhibitor 25 Kalata B8 143 Macrocyclization 25–29, 25, 26 Kalata-B1 143 Macrolides 271

bindex 26 July 2011; 12:38:10 Index | 365 MAGE 315 – assays relevant to possible non-GI Maltose-binding protein (MBP) 148 activity 275–76 Mammalian and microbial cellular – assays relevant to the therapeutic membranes, AMP selectivity mechanism of action 271–75 between 93–94 – clinical development of 284–85 Mammalian cell culture 149 – clinical potential of 270–71 MAR study 150 Motilin receptor 269 Mass spectrometry (MS) 120–21 Motilin receptor agonist 274 MBI 226. See Omiganan pentahydrochloride Motilin receptor agonist GSK962040 284 MC3 receptor 250 Motilin receptor antagonist 275 MC4 receptor 252 MP0112 344 MCHR1 249 M-site peptide 9 MCHR2 250 MT103 344 Median preoptic nucleus 249 MT110 344 Medicago sativa 149 MUC-1 315 Megakaryocytes 189 Mucoadhesive systems 84 Megestrol 284 Multiple sclerosis (MS) 316 Megestrol acetate 284 – Copolymer 1 (Cop 1) in 317–18 Melanin concentrating hormone – polypeptide immunomodulator drug, for (MCH) 249–50 treatment of 316–27 Melanocortins 250–52 Multiple system atrophy (MSA) 281 a-melanocyte stimulating hormone (a- Muramyl dipetide (MDP) 315 MSH) 250 Murine monoclonal antibodies 348 Melittin 80 MVIIA 129 Membrane transduction peptides. See Cell MX-594AN. See Omiganan penetrating proteins pentahydrochloride Membrane translocating sequences. See Cell Myasthenia gravis (MG) penetrating proteins – peptides therapy for 328 Met-enkephalin 177 Myelin basic protein (MBP) 316 Methicillin-resistant Staphylococcus aureus Myelin oligodendrocyte glycoprotein (MRSA) 163 (MOG) 316 Methotrexate 338 Myelin proteolipid protein (PLP) 316 N-methyl-2-pyridylethyl-substituent 44 Myelin repair and neurogenesis 323–26 Methyl ketones 12 Mylotarg 339, 346 Methylotrophic yeast 148 Myrosinase-binding proteins type 1 Metoclopramide 279, 282, 283 (MBP-1) 140 Metreleptin 257, 299, 304, 306 Microbial fermentation 149 N. crassa 149 Migraine 282 N36 211, 215, 216, 217 Migrating motor complex (MMC) 269 Naloxone 175, 177 Mitemcinal 274, 281, 284, 285 Naltrexone 255 Mitogen-activated protein (MAP) 255 Naphthyl-methoxyproline 22 Mo¨bius 141 Napin 143 Molecular size, of peptide drugs 73 Nasogastric feeding 279 Monoclonal antibodies 338 National Institutes of Health 183 Monoclonal human IgG 316 Neonatal Fc receptor (FcRn) 192 Morphiceptin 75 Neosporin 91 Morphine 173, 176 Neuromedin S (NMS) 254–55 Mosapride 283 Neuromedin U (NMU) 254–55 Motilide mitemcinal 284 Neuronal nicotinic acetylcholine receptor Motilides 271 (nAChR) 121, 129 Motilin 269, 270, 271–76, 273, 274 Neuronal noradrenaline transporter – and ghrelin, similarities and differences (NET) 130 between 269–70 Neuronal progenitor cells (NPCs) 323

bindex 26 July 2011; 12:38:10 366 | Index Neuropeptide Y (NPY) 252–54 Oligodendrocyte progenitor cells Neuropeptides 247 (OPCs) 323 Neuropsychiatric disease, treatment of Omiganan pentahydrochloride 159–67 – amylin agonism in 307 – clinical studies 165–67 Neurotrophin (NT) 323 – for topical indications 159–60 Nicotiana alata 140, 141 – minimal inhibitory concentrations Nitric oxide (NO) synthase 177 (MIC) 162 [Nle13]-motilin 274 – preclinical efficacy studies 163–64 NMR ROESY experiment 21 – preclinical toxicology studies 164–65 NMUR1 254 – spectrum of activity 163 NMUR2 254 – structure and mechanism of action 160–63 s Nobex Corporation 81 Omiganan-induced killing 162 NOESY (nuclear Overhauser OmigardTM 160 spectroscopy) 11, 17, 18 Onglyza (Saxagliptin) 261 – transferred NOESY model 25 Opioid-like drugs 183 Non-acylated ghrelin 270 m-opiod receptor (MOR) 173, 176 Non-encephalitogenic protein 316 d-opioid receptor 176 Non-enzymatic degradation of k-opioid receptors 176 peptides 73 Opioids 255–56 Non-polar face and polar face substituted Opium 173 peptide analogs, antimicrobial activity Optimized peptidyl segment 10–12 and hemolytic activity of 101 Oral peptide drug delivery 71–85 Non-structural (NS) proteins 15 – challenges associated with 72–77 Nonylphenoxypoly-oxyethylene 79 –– efflux transport systems 76–77 Normoglycemia 298 –– gastrointestinal tract, biochemical barriers N-peptide inhibitors 211 of 75–76 NS3 protease inhibitors 29 –– gastrointestinal tract, physical barriers NS3 serine protease 16 of 73–75 NSAIDS (non-steroidal anti-inflammatory –– gastrointestinal transit time and site- drugs) 183 specific absorption 77 N-terminal cleavage products 16, 17 –– transport pathways across intestinal N-terminal truncation and improved epithelium 72–73 P1, P2 and P5 substituents –– unfavorable physicochemical 22–25 properties 73 N-terminus, modifications at 34 – gastrointestinal tract, strategies to overcome Nuclear magnetic resonance (NMR) 6, barriers of 77–84 7, 8, 127 –– absorption enhancing agents 77–78 –– chemical and physical Obesity 247 modifications 78–81 Obesity, translational research in 299–309 –– formulation strategies 83–84 – amylin agonism and small molecule –– targeting receptors and agents 304 transporters 82–83 – amylin agonism-based translational –– targeting specific regions of the research 307–9 gastrointestinal tract 81–82 – combination studies 304 Ornamental tobacco 140 – combined amylin and leptin Oxyntomodulin (OXM) 260, 262 agonism 305–7 Oxytocin 171 – food intake and body weight –– clinical studies 302–3 P. guajava 144 –– endogenous amylin, role of 299–300 P. personata 148 –– pre-clinical studies 300–302 P1 ACCA group 22 Obineptide 263 P2–P3 butanediamide inhibitors 43 Octapeptide angiotensin II 38 P2–P3 butanediamide renin inhibitors 44 OKT3 339 Paclitaxel–peptide conjugates 172

bindex 26 July 2011; 12:38:10 Index | 367 Palinavir 45, 46 – leptin 261–62 1-Palmitoyl-2-oleyol-sn-glycero-3- – oxyntomodulin (OXM) 262 phosphocoline (POPC) 179 – PYY3-36 and pancreatic polypeptide Palmitoyl-DL-carnitine chloride 79 (PP) 262–63 Pancreatic polypeptide (PP) 253, 262 Permeation enhancers 77, 78 Pan-drug resistant microbes 91 Petunia 140 Panitumumab 339 Petunia hybrida 140 Paracellular transport 75 Pexelizumab 343 Parasympathetic nervous system (PNS) 249 Pfizer 343 Parkinson’s disease 281–82 Pg-AMP1 144 Particle replication in non-wetting templates P-glycoprotein-like mechanisms 76 (PRINT) technique 83, 84 Phage-display screening 3 Particulate carrier systems 83–84 Pharmacodynamics (PD) 194–99 Patenting 65 Pharmacokinetics (PK) 194–99 Patents 61–63 Phenol red 298 Pathogenesis-related (PR) proteins 140 Phenols 145 PC-1505, 221 Phentermine 299, 304 PCT level 62 Phentermine hydrochloride 304 PCT patent 62 Phospatidylinositol-3 kinase (PI-3K) 260 PDC1 protein 149 Phosphatidylcholine (PC) 236 Pegasparaginase 194 Phosphatidylserine (PS) 183 s PEG-epoetin beta (Mircera ) 190 Physicochemical properties of peptide s Pegfilgrastim (Neulasta ) 190, 194, 197 drugs 73 Peg-interferon 194 Phytoconstituents 80 PEGylated recombinant human Phytophthora parasitica f. sp.nicotianae 148 megakaryocyte growth and development Pichia pastoris 148, 149 factor (PEG-rHuMGDF) 190 Pisum sativum 141 PEGylation 81, 347 Pisum sativum defensin1 (rPsd1) 149 PepT1 82 Plant antimicrobial peptides 139–50 PepT2 82 – biotechnological products produced Peptibodies 192 from 144–50 Peptide fusion inhibitors and respective gp41 – diversity of 139–40 domains 214 – structural folds in 140–44 Peptide mimics 3 Poly(acrylic acid) 84 Peptide sequencing 120–21 Poly(acrylic acid) derivatives 79 Peptide stability to proteolytic digestion by Polyalanine 314 trypsin 106 Polyclonal human IgG (IVIG) 316 Peptide YY (PYY) 253 Poly-DL-alanine 313 Peptide–membrane partition studies, BBB Polyethylene glycol (PEG) 81, 172, 346 permeability with 179 Poly-L-lysine 313 Peptides transformation to Polylysine 313 peptidomimetics 5–7 Polymers 79 Peptidomimetics 3 Polymyxins 91 – peptides transformation to 5–7 Polypeptide immunomodulator Peptidyl segment, optimized 10–12 – drug for multiple sclerosis 316–27 Peptidyl-activated carbonyl inhibitors 14 Polyploid cells 189 Peripheral blood lymphocytes (PBL) 328 Polysorbate 80 79 Peripheral hyperinsulinemia 71 POPG (1-palmitoyl-2-oleyl-sn-glycero-3- Peripherally secreted neuropeptides (phosphor-rac-(1-glycerol)) 179 – amylin 256–57 Post-infectious gastroparesis 279 – bombesin-like peptides 257–58 Post-prandial hyperglucagonemia 297, 298 – cholecystokinin (CCK) 258–59 – and diabetes 297 – ghrelin 259–60 Post-transcriptional gene silencing – glucagon-like peptide-1 (GLP-1) 260–61 (PTGS) 150

bindex 26 July 2011; 12:38:10 368 | Index Posttranslational modification (PTM) 122–24 ReoPro 339 Prader–Willi syndrome 259, 262 Retinoids 166 Pramlintide 257, 296, 298, 302, 304, 306 Reverse transcriptase 209 – weight lowering effects of 303 Reversed-phase high performance liquid Pramlintide/metreleptin 306 chromatography (RP-HPLC) 96–98, 99, Proboscis 119 100 Prodrug strategies for peptide drugs 80 Rhizoctonia solani 148 Prodynorphin (PDYN) 255 rHuTPO 190 Proenkephalin (PENK) 255 Ribavirin 30 Prohormone convertase 1 (PC1) 260 Ribonucleotide reductase (RR) 32 Prohormone convertase 2 (PC2) 260 Ribonucleotide reductase inhibitors 32–38 Prokaryotic membranes Risk Evaluation and Mitigation Strategy – and antimicrobial peptides 93 (REMS) 203 Prokaryotic system 146 Rituxan 339 Prokinetics 283 Rituximab 338 Pro-opiomelanocortin (POMC) 250, Rodents, amylin agonism in 295–309 s 252, 255 Romiplostim (Nplate ) 189–205 Propionicacterium acnes 162, 164 – brief ITP primer 199–201 Protease inhibitors 209 –– diagnosis and treatment 199–200 Protein and antibody scaffolds 344 –– thrombopoietin and ITP 200–201 Protein folding 127 – clinical data 201–3 Protein kinase C 273 – design and development 203–5 Protein transduction domains. See Cell – discovery and optimization of 192–94 penetrating proteins – pharmacodynamics and Proteinases 141 pharmacokinetics 194–99 Proteomics 171 – thrombopoietin and c-Mpl 189–92 Proton pump inhibitors (PPIs) 283 Rosacea, treatment of 166 PRS-050 344 R-site peptide 9 Pseudomonas aeruginosa 91, 106, 107, 109 rTvD1 peptide 148 Pseudomonas aeuroginosa 64 Pseudomonas syringae 59 Saccharomyces cerevisiae 80 PTGS-MAR 150 2S albumins 143 PubMed 172 SAR studies 10 PYY3-36 and pancreatic polypeptide SBI-087 343, 344 (PP) 262–63 SC34 216–17 SC34EK 216–17, 217 QRFP 256 “Sensemaking” phase 3, 5 Quinones 145 Serine proteases 10 “Sham” feeding 300 Radioablation treatment 283 Shepherins 140 Radio-labeled nutrients 298 Sibutramine 299, 304 Ranibizumab 342 Sibutramine hydrochloride 304 Raphanus sativus 141 Sifuvirtide 215, 222, 223, 231–41 Raptiva 339 – efficiency by biomembrane selectivity Receptor activity modifying protein 236–37 (RAMP) 256 – high potency of 234–35 Re-engineered conotoxins, in drug – limited drug resistance 235–36 design 131–33 – monotherapy, stratification of 238–39 Remicade 339 – pharmacokinetics with long half-life 237– Renin 38–44 38 – aspartyl protease renin as a – structure-based drug design of 232–34 target 38–44 Signal transducer and activator of – inhibitors 42, 75 transcription-3 (STAT3) 261 Renin-angiotensin 38 Simulect 339

bindex 26 July 2011; 12:38:10 Index | 369 Single-domain antibodies 343–45 Technology transfer Sinomenine 78, 80 – in marketing antimicrobial peptides 64–66 Small molecule agents, and amylin Technophage 345 agonism 304 Tekturna 44 SME (small and medium-sized enterprise) 68 Tephrosia villosa 148 Snakin-1 (sn1) 148 Terpenoids 145 Snakins 140 1,2,3,4-tetrahydroisoquinoline-3-carboxylic Sodium caprate 79 acid 176 Sodium caprylate 79 Tetrapeptides 22 Sodium cholate 79 TGF-b 321, 327 Sodium deoxycholate 79 Th1 cytokines 320 Sodium dodecylsulfate 79 Th2 cells 320 Sodium laurate 79 T-helper (Th) 320 Sodium taurocholate 79 Therapeutic antibodies 337, 338 Solid phase peptide synthesis (SPPS) 124 Therapeutic monoclonal antibodies, in Specificity determinants 94, 100, 104 United States 339 Spin-off creation 64–68 g-thionins 141 Spp-100 44 Thioredoxin (Trx) 148 Staphylococcus aureus 63, 91, 106 Threonine 233 Staphylococcus aureus, effect of omiganan Thrombopoietin (TPO) 190 treatment on 161 – and c-Mpl 189–92 Staphylococcus epidermidis 106 Tifuvirtide 211 Streptomyces 315 Tipranavir 46, 47 Streptozotocin-treated rats 298 Tissue localization and plant species Structural folds, in plant AMPs 140–44 distribution Structure–activity relationship (SAR) 29, 34 – in plant AMPs 139–40 Substrate peptides, mapping essential TNF-specific antibodies 347 elements of 8–10 Toll-like receptor (TLR)-2 327 Sulfhydryl ()SH) group 81 Toroidal pore model 92 Suncus murinus 274 Tosylation 60 Suppressor of cytokine signaling-3 Transcytosis 82 (SOCS-3) 261 Transdermal delivery system 172 Suprachiasmatic nucleus (SCN) 254 Transferred NOESY model 25 Supraoptic nucleus (SON) 260 Transforming growth factor (TGF) 320 Surfactants 79 Transforming growth factor-b (TGF-b) 328 Sympathetic nervous system (SNS) 249 Trifluoroacetic acid (TFA) 126 Synagis 339 Trifluoroethanol (TFE) 102 Synthetic C-peptides 211 Trifluoromethylketone analogs 17 Synthetic N-peptides 211 Trifluoromethylketone N-peptide 18 Systemic lupus erythematosus (SLE) 328 Trimeris, Inc. 211, 221 – peptides therapy for 328–29 Trinitrobenzene sulfonic acid (TNBS)- induced colitis 326 T-1144 223 Triticum aestivum 141 T-1249 211, 214–15, 223 “Trojan horse” technology 174 T-20. See Enfuvirtide Trojan peptides. See Cell penetrating proteins T-2410 218 Trp/Phe 173 T-651 221 TRU-015 343 Tachygastria 282 Trubion Pharmaceuticals 343 Tachyphylaxis 271, 273 Tuftsin 315 Tandem mass spectrometry (MS/MS) 120 Tumor-associated antigens (TAA) 315 Tannins 145 TvD1 148 t-Butoxycarbonyl (Boc) 126 L-Tyrosine 313, 317 T-cell epitopes 314 Tysabri 339 TechnoAntibodies 345 TZP-101 276, 277, 284

bindex 26 July 2011; 12:38:10 370 | Index Ubiquitin 148 Verticillium dahliae 149 UBQ 149 Vicilin-like AMPs 140 UCB 342 Vigna radiata 141 UL80 gene 7 Vigna unguiculata 148 Ulimorelin 284 Vincristine 200 Unstirred water layer 73–74 Voltage-gated calcium channel (VGCC) 121 Urocortins 249 Voltage-gated potassium channel (VGKC) 121 V13 96, 98, 103 Voltage-gated sodium channel (VGSC) 121 – with D-Ala (V13AD) 104 VrD1 141 V13K 98, 99, 103 VuD1 148 – D enantiomer of 106 V13L 110 “Warhead” strategy 10 V681 96 Whole leaf 80 Vagotomy 276 World Health Organization 171 Valorization 64–66 Wyeth 346 Vancomycin 171 – vancomycin-resistant Staphylococcus aureus Xanthomonas vesicatoria 59 (VRSA) 163 Xenopus oocytes 130 Variable heavy chains (VHH), of Xolair 339 antibodies 343 X-ray crystallographic analyses 7 Varicella zoster virus (VSV) RR 38 Vc1.1 130 Zenapax 339 Ventromedial hypothalamus (VMH) 250 Zevalin 339, 346 Verapamil 79 Zonula occludens toxin (ZOT) 78, 79

bindex 26 July 2011; 12:38:11