Getting in shape: Controlling peptide bioactivity and bioavailability using conformational constraints

ACS Chemical Biology

Volumn 8, Issue 3, 2013, Pages 488-499

  Bock, Jonathan E ^a   Gavenonis, Jason ^a   Kritzer, Joshua A ^a  

^a TUFTS UNIVERSITY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ALANINE; ALKENE; ALPHA AMANITIN; CALCIUM CHANNEL BLOCKING AGENT; CYCLOSPORIN A; ENFUVIRTIDE; ENKEPHALIN; FIBRONECTIN; GABAPENTIN; GLYCINE; GROWTH HORMONE; KALATA B1; MELANOCORTIN; NATURAL PRODUCT; OXYTOCIN; PARATHYROID HORMONE RELATED PROTEIN; PHENYLALANINE; PROTEIN BCL 2; SOMATOSTATIN; SOMATOSTATIN DERIVATIVE; UNCLASSIFIED DRUG; PEPTIDE;

ACROMEGALY; ANALGESIA; APOPTOSIS; ASSAY; CELL SURFACE; CYTOPLASM; CYTOTOXICITY; DRUG ACTIVITY; DRUG BIOAVAILABILITY; DRUG DEGRADATION; DRUG DISTRIBUTION; DRUG POTENCY; DRUG SELECTIVITY; EX VIVO STUDY; HUMAN; IC 50; IN VITRO STUDY; INTESTINE ABSORPTION; NEUROPATHIC PAIN; NONHUMAN; PARALLEL ARTIFICIAL MEMBRANE PERMEABILITY ASSAY; PHARMACOKINETICS; PHYSICAL CHEMISTRY; PRESCRIPTION; PRIORITY JOURNAL; PROTEIN BINDING; PROTEIN CONFORMATION; PROTEIN DEGRADATION; PROTEIN ENGINEERING; PROTEIN MOTIF; PROTEIN STRUCTURE; REVIEW; STRUCTURE ACTIVITY RELATION; ANIMAL; CHEMICAL STRUCTURE; CHEMISTRY; METABOLISM;

ANIMALS; HUMANS; MODELS, MOLECULAR; PEPTIDES; PROTEIN CONFORMATION;

EID: 84875138812     PISSN: 15548929     EISSN: 15548937     Source Type: Journal    
DOI: 10.1021/cb300515u     Document Type: Review

References (145)

1. Lipinski, C. A., Lombardo, F., Dominy, B. W., and Feeney, P. J. (1997) Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings Adv. Drug Delivery Rev. 23, 3-25
2. Veber, D. F., Johnson, S. R., Cheng, H. Y., Smith, B. R., Ward, K. W., and Kopple, K. D. (2002) Molecular properties that influence the oral bioavailability of drug candidates J. Med. Chem. 45, 2615-2623
3. Driggers, E. M., Hale, S. P., Lee, J., and Terrett, N. K. (2008) The exploration of macrocycles for drug discovery-an underexploited structural class Nat. Rev. Drug Discovery 7, 608-624
4. Evans, B. E., Rittle, K. E., Bock, M. G., DiPardo, R. M., Freidinger, R. M., Whitter, W. L., Lundell, G. F., Veber, D. F., and Anderson, P. S. (1988) Methods for drug discovery: development of potent, selective, orally effective cholecystokinin antagonists J. Med. Chem. 31, 2235-2246
5. Duarte, C. D., Barreiro, E. J., and Fraga, C. A. M. (2007) Privileged structures: A useful concept for the rational design of new lead drug candidates Mini-Rev. Med. Chem. 7, 1108-1119
6. Scott, E. L. (1912) On the influence of intravenous injections of an extract of the pancreas on experimental pancreatic diabetes Am. J. Physiol. 29, 306-310
7. Banting, F. G., Best, C. H., Collip, J. B., MacLeod, J. J. R., and Noble, E. C. (1922) The effect of pancreatic extract (insulin) on normal rabbits Am. J. Physiol. 62, 162-176
8. Adessi, C. and Soto, C. (2002) Converting a peptide into a drug: Strategies to improve stability and bioavailability Curr. Med. Chem. 9, 963-978
9. Vagner, J., Qu, H. C., and Hruby, V. J. (2008) Peptidomimetics, a synthetic tool of drug discovery Curr. Opin. Chem. Biol. 12, 292-296
10. Wieland, T. and Faulstich, H. (1978) Amatoxins, phallotoxins, phallolysin, and antamanide-biologically-active components of poisonous amanita mushrooms CRC Crit. Rev. Biochem. 5, 185-260
11. Hallen, H. E., Luo, H., Scott-Craig, J. S., and Walton, J. D. (2007) Gene family encoding the major toxins of lethal Amanita mushrooms Proc. Natl. Acad. Sci. U.S.A. 104, 19097-19101
12. Wieland, T. and Faulstich, H. (1991) 50 years of amanitin Experientia 47, 1186-1193
13. Letschert, K., Faulstich, H., Keller, D., and Keppler, D. (2006) Molecular characterization and inhibition of amanitin uptake into human hepatocytes Toxicol. Sci. 91, 140-149
14. Lindell, T. J., Weinberg, F., Morris, P. W., Roeder, R. G., and Rutter, W. J. (1970) Specific inhibition of nuclear RNA polymerase II by alpha-amanitin Science 170, 447-449
15. Schreiber, S. L. and Crabtree, G. R. (1992) The mechanism of action of cyclosporine-A and FK506 Immunol. Today 13, 136-142
16. Wenger, R. M., France, J., Bovermann, G., Walliser, L., Widmer, A., and Widmer, H. (1994) The 3D structure of a cyclosporine analog in water is nearly identical to the cyclophilin-bound cyclosporine conformation FEBS Lett. 340, 255-259
17. Altschuh, D., Vix, O., Rees, B., and Thierry, J. C. (1992) A conformation of cyclosporine-A in aqueous environment revealed by the X-ray structure of a cyclosporine-FAB complex Science 256, 92-94
18. Fesik, S. W., Gampe, R. T., Eaton, H. L., Gemmecker, G., Olejniczak, E. T., Neri, P., Holzman, T. F., Egan, D. A., Edalji, R., Simmer, R., Helfrich, R., Hochlowski, J., and Jackson, M. (1991) NMR studies of [U-C13]cyclosporin A bound to cyclophilin: bound conformation and portions of cyclosporine involved in binding Biochemistry 30, 6574-6583
19. Fesik, S. W., Neri, P., Meadows, R., Olejniczak, E. T., and Gemmecker, G. (1992) A model of the cyclophilin cyclosporine-A (CSA) complex from NMR and X-ray data suggests that CSA binds as a transition-state analog J. Am. Chem. Soc. 114, 3165-3166
20. Kallen, J., Spitzfaden, C., Zurini, M. G. M., Wider, G., Widmer, H., Wuthrich, K., and Walkinshaw, M. D. (1991) Structure of human cyclophilin and its binding-site for cyclosporine-A determined by X-ray crystallography and NMR spectroscopy Nature 353, 276-279
21. Spitzfaden, C., Weber, H. P., Braun, W., Kallen, J., Wider, G., Widmer, H., Walkinshaw, M. D., and Wuthrich, K. (1992) Cyclosporine-A-cyclophilin complex formation-a model based on X-ray and NMR data FEBS Lett. 300, 291-300
22. Kessler, H., Kock, M., Wein, T., and Gehrke, M. (1990) Reinvestigation of the conformation of cyclosporine-A in chloroform Helv. Chim. Acta 73, 1818-1832
23. Navia, M. A. and Chaturvedi, P. R. (1996) Design principles for orally bioavailable drugs Drug Discovery Today 1, 179-189
24. White, T. R., Renzelman, C. M., Rand, A. C., Rezai, T., McEwen, C. M., Gelev, V. M., Turner, R. A., Linington, R. G., Leung, S. S. F., Kalgutkar, A. S., Bauman, J. N., Zhang, Y. Z., Liras, S., Price, D. A., Mathiowetz, A. M., Jacobson, M. P., and Lokey, R. S. (2011) On-resin N-methylation of cyclic peptides for discovery of orally bioavailable scaffolds Nat. Chem. Biol. 7, 810-817
25. Rezai, T., Bock, J. E., Zhou, M. V., Kalyanaraman, C., Lokey, R. S., and Jacobson, M. P. (2006) Conformational flexibility, internal hydrogen bonding, and passive membrane permeability: Successful in silico prediction of the relative permeabilities of cyclic peptides J. Am. Chem. Soc. 128, 14073-14080
26. Chatterjee, J., Gilon, C., Hoffman, A., and Kessler, H. (2008) N-Methylation of peptides: a new perspective in medicinal chemistry Acc. Chem. Res. 41, 1331-1342
27. Veber, D. F., Freidinger, R. M., Perlow, D. S., Paleveda, W. J., Holly, F. W., Strachan, R. G., Nutt, R. F., Arison, B. H., Homnick, C., Randall, W. C., Glitzer, M. S., Saperstein, R., and Hirschmann, R. (1981) A potent cyclic hexapeptide analog of somatostatin Nature 292, 55-58
28. Veber, D. F., Holly, F. W., Nutt, R. F., Bergstrand, S. J., Brady, S. F., Hirschmann, R., Glitzer, M. S., and Saperstein, R. (1979) Highly-active cyclic and bicyclic somatostatin analogs of reduced ring size Nature 280, 512-514
29. Hruby, V. J. and Balse, P. M. (2000) Conformational and topographical considerations in designing agonist peptidomimetics from peptide leads Curr. Med. Chem. 7, 945-970
30. Hruby, V. J., Alobeidi, F., and Kazmierski, W. (1990) Emerging approaches in the molecular design of receptor-selective peptide ligands-conformational, topographical and dynamic considerations Biochem. J. 268, 249-262
31. Kessler, H. (1982) Peptide conformations 0.19. Conformation and biological-activity of cyclic-peptides Angew. Chem., Int. Ed. Engl. 21, 512-523
32. Ovadia, O., Greenberg, S., Laufer, B., Gilon, C., Hoffman, A., and Kessler, H. (2010) Improvement of drug-like properties of peptides: the somatostatin paradigm Expert Opin. Drug Discovery 5, 655-671
33. Vale, W., Brazeau, P., Grant, G., Nussey, A., Burgus, R., Rivier, J., Ling, N., and Guillemi., R. (1972) Observations on action mode of somatostatin, hypothalamic factor inhibiting growth-hormone secretion C. R. Hebd. Seances Acad. Sci., Ser. D 275, 2913-2916
34. Freidinger, R. M., Veber, D. F., Perlow, D. S., Brooks, J. R., and Saperstein, R. (1980) Bioactive conformation of luteinizing-hormone-releasing hormone-evidence from a conformationally constrained analog Science 210, 656-658
35. Veber, D. F., Holly, F. W., Paleveda, W. J., Nutt, R. F., Bergstrand, S. J., Torchiana, M., Glitzer, M. S., Saperstein, R., and Hirschmann, R. (1978) Conformationally restricted bicyclic analogs of somatostatin Proc. Natl. Acad. Sci. U.S.A. 75, 2636-2640
36. Biron, E., Chatterjee, J., Ovadia, O., Langenegger, D., Brueggen, J., Hoyer, D., Schmid, H. A., Jelinek, R., Gilon, C., Hoffman, A., and Kessler, H. (2008) Improving oral bioavailability of peptides by multiple N-methylation: Somatostatin analogues Angew. Chem., Int. Ed. 47, 2595-2599
37. Al-Obeidi, F., Castrucci, A. M., Hadley, M. E., and Hruby, V. J. (1989) Potent and prolonged acting cyclic lactam analogues of alpha-melanotropin: design based on molecular dynamics J. Med. Chem. 32, 2555-2561
38. Doedens, L., Opperer, F., Cai, M., Beck, J. G., Dedek, M., Palmer, E., Hruby, V. J., and Kessler, H. (2010) Multiple N-methylation of MT-II backbone amide bonds leads to melanocortin receptor subtype hMC1R selectivity: pharmacological and conformational studies J. Am. Chem. Soc. 132, 8115-8128
39. Linde, Y., Ovadia, O., Safrai, E., Xiang, Z., Portillo, F. P., Shalev, D. E., Haskell-Luevano, C., Hoffman, A., and Gilon, C. (2008) Structure-activity relationship and metabolic stability studies of backbone cyclization and N-methylation of melanocortin peptides Biopolymers 90, 671-682
40. Al-Obeidi, F., Hadley, M. E., Pettitt, B. M., and Hruby, V. J. (1989) Design of a new class of superpotent cyclic.alpha.-melanotropins based on quenched dynamic simulations J. Am. Chem. Soc. 111, 3413-3416
41. Hess, S., Linde, Y., Ovadia, O., Safrai, E., Shalev, D. E., Swed, A., Halbfinger, E., Lapidot, T., Winkler, I., Gabinet, Y., Faier, A., Yarden, D., Xiang, Z., Portillo, F. P., Haskell-Luevano, C., Gilon, C., and Hoffman, A. (2008) Backbone cyclic peptidomimetic melanocortin-4 receptor agonist as a novel orally administrated drug lead for treating obesity J. Med. Chem. 51, 1026-1034
42. Pierschbacher, M. D., Hayman, E. G., and Ruoslahti, E. (1981) Location of the cell-attachment site in fibronectin with monoclonal antibodies and proteolytic fragments of the molecule Cell 26, 259-267
43. Pierschbacher, M. D. and Ruoslahti, E. (1984) Cell attachment activity of fibronectin can be duplicated by small synthetic fragments of the molecule Nature 309, 30-33
44. Aumailley, M., Gurrath, M., Muller, G., Calvete, J., Timpl, R., and Kessler, H. (1991) Arg-Gly-Asp constrained within cyclic pentapeptides-strong and selective inhibitors of cell-adhesion to vitronectin and laminin fragment-P1 FEBS Lett. 291, 50-54
45. Dechantsreiter, M. A., Planker, E., Matha, B., Lohof, E., Holzemann, G., Jonczyk, A., Goodman, S. L., and Kessler, H. (1999) N-methylated cyclic RGD peptides as highly active and selective alpha(v)beta(3) integrin antagonists J. Med. Chem. 42, 3033-3040
46. Goodman, S. L., Holzemann, G., Sulyok, G. A. G., and Kessler, H. (2002) Nanomolar small molecule inhibitors for αvβ6, αvβ5, and αvβ3 integrins J. Med. Chem. 45, 1045-1051
47. Dawson, R., Muller, L., Dehner, A., Klein, C., Kessler, H., and Buchner, J. (2003) The N-terminal domain of p53 is natively unfolded J. Mol. Biol. 332, 1131-1141
48. Mas-Moruno, C., Rechenmacher, F., and Kessler, H. (2010) Cilengitide: the first anti-angiogenic small molecule drug candidate design, synthesis and clinical evaluation Anticancer Agents Med. Chem. 10, 753-768
49. Schottelius, M., Laufer, B., Kessler, H., and Wester, H.-J. r. (2009) Ligands for mapping αvβ3-integrin expression in vivo Acc. Chem. Res. 42, 969-980
50. Chatterjee, J., Laufer, B., and Kessler, H. (2012) Synthesis of N-methylated cyclic peptides Nat. Protoc. 7, 432-444
51. Wilson, R. M., Stockdill, J. L., Wu, X. Y., Li, X. C., Vadola, P. A., Park, P. K., Wang, P., and Danishefsky, S. J. (2012) A fascinating journey into history: exploration of the world of isonitriles en route to complex amides Angew. Chem., Int. Ed. 51, 2834-2848
52. Biron, E. and Kessler, H. (2005) Convenient synthesis of N-methylamino acids compatible with Fmoc solid-phase peptide synthesis J. Org. Chem. 70, 5183-5189
53. King, G. F. (2011) Venoms as a platform for human drugs: translating toxins into therapeutics Expert Opin. Biol. Ther. 11, 1469-1484
54. Lewis, R. J. and Garcia, M. L. (2003) Therapeutic potential of venom peptides Nat. Rev. Drug Discovery 2, 790-802
55. Craik, D. J., Cemazar, M., and Daly, N. L. (2006) The cyclotides and related macrocyclic peptides as scaffolds in drug design Curr. Opin. Drug Discovery Dev. 9, 251-260
56. Clark, R. J., Jensen, J., Nevin, S. T., Callaghan, B. P., Adams, D. J., and Craik, D. J. (2010) The engineering of an orally active conotoxin for the treatment of neuropathic pain Angew. Chem., Int. Ed. 49, 6545-6548
57. Getz, J. A., Rice, J. J., and Daugherty, P. S. (2011) Protease-resistant peptide ligands from a knottin scaffold library ACS Chem. Biol. 6, 837-844
58. Clark, R. J., Akcan, M., Kaas, Q., Daly, N. L., and Craik, D. J. (2012) Cyclization of conotoxins to improve their biopharmaceutical properties Toxicon 59, 446-455
59. Tam, J. P., Lu, Y. A., Yang, J. L., and Chiu, K. W. (1999) An unusual structural motif of antimicrobial peptides containing end-to-end macrocycle and cystine-knot disulfides Proc. Natl. Acad. Sci. U.S.A. 96, 8913-8918
60. Garcia, A. E., Tai, K. P., Puttamadappa, S. S., Shekhtman, A., Ouellette, A. J., and Camarero, J. A. (2011) Biosynthesis and antimicrobial evaluation of backbone-cyclized alpha-defensins Biochemistry 50, 10508-10519
61. Lehrer, R. I., Cole, A. M., and Selsted, M. E. (2012) Theta-defensins: cyclic peptides with endless potential J. Biol. Chem. 287, 27014-27019
62. Maksimov, M. O., Pan, S. J., and Link, A. J. (2012) Lasso peptides: structure, function, biosynthesis, and engineering Nat. Prod. Rep. 29, 996-1006
63. Wong, C. T. T., Rowlands, D. K., Wong, C. H., Lo, T. W. C., Nguyen, G. K. T., Li, H. Y., and Tam, J. P. (2012) Orally active peptidic bradykinin B-1 receptor antagonists engineered from a cyclotide scaffold for inflammatory pain treatment Angew. Chem., Int. Ed. 51, 5620-5624
64. Craik, D. J., Daly, N. L., Mulvenna, J., Plan, M. R., and Trabi, M. (2004) Discovery, structure and biological activities of the cyclotides Curr. Protein Pept. Sci. 5, 297-315
65. Gran, L. (1973) Effect of a polypeptide isolated from kalata-kalata (Oldenlandia-affinis DC) on estrogen dominated uterus Acta Pharmacol. Toxicol. (Copenhagen) 33, 400-408
66. Halai, R., Caaghan, B., Daly, N. L., Clark, R. J., Adams, D. J., and Craik, D. J. (2011) Effects of cyclization on stability, structure, and activity of alpha-conotoxin RgIA at the alpha 9 alpha 10 nicotinic acetylcholine receptor and GABA(B) receptor J. Med. Chem. 54, 6984-6992
67. Carstens, B. B., Clark, R. J., Daly, N. L., Harvey, P. J., Kaas, Q., and Craik, D. J. (2011) Engineering of conotoxins for the treatment of pain Curr. Pharm. Des. 17, 4242-4253
68. Henchey, L. K., Jochim, A. L., and Arora, P. S. (2008) Contemporary strategies for the stabilization of peptides in the alpha-helical conformation Curr. Opin. Chem. Biol. 12, 692-697
69. Verdine, G. L. and Hilinski, G. J. (2012) Stapled peptides for intracellular drug targets, in Methods in Enzymology: Protein Engineering for Therapeutics, Vol 203, Pt B (Wittrup, K. D. and Verdine, G. L., Eds.), pp 3-33, Elsevier Academic Press Inc., San Diego.
70. Satterthwait, A. C., Arrhenius, T., Hagopian, R. A., Zavala, F., Nussenzweig, V., and Lerner, R. A. (1988) Conformational restriction of peptidyl immunogens with covalent replacements for the hydrogen bond Vaccine 6, 99-103
71. Osapay, G. and Taylor, J. W. (1992) Multicyclic polypeptide model compounds 0.2. Synthesis and conformational properties of a highly alpha-helical uncosapeptide constrained by 3 side-chain to side-chain lactam bridges J. Am. Chem. Soc. 114, 6966-6973
72. Osapay, G. and Taylor, J. W. (1990) Multicyclic polypeptide model compounds 0.1. Synthesis of a tricyclic amphiphilic alpha-helical peptide using an oxime resin, segment-condensation approach J. Am. Chem. Soc. 112, 6046-6051
73. Felix, A. M., Heimer, E. P., Wang, C. T., Lambros, T. J., Fournier, A., Mowles, T. F., Maines, S., Campbell, R. M., Wegrzynski, B. B., Toome, V., Fry, D., and Madison, V. S. (1988) Synthesis, biological-activity and conformational-analysis of cyclic GRF analogs Int. J. Pept. Protein Res. 32, 441-454
74. Henchey, L. K., Jochim, A. L., and Arora, P. S. (2008) Contemporary strategies for the stabilization of peptides in the α-helical conformation Curr. Opin. Chem. Biol. 12, 692-697
75. Taylor, J. W. (2002) The synthesis and study of side-chain lactam-bridged peptides Biopolymers 66, 49-75
76. Ghadiri, M. R. and Choi, C. (1990) Secondary structure nucleation in peptides-transition-metal ion stabilized alpha-helices J. Am. Chem. Soc. 112, 1630-1632
77. Lieberman, M. and Sasaki, T. (1991) Iron(II) organizes a synthetic peptide into 3-helix bundles J. Am. Chem. Soc. 113, 1470-1471
78. Estieu-Gionnet, K. and Guichard, G. (2011) Stabilized helical peptides: overview of the technologies and therapeutic promises Expert Opin. Drug Discovery 6, 937-963
79. Condon, S. M., Morize, I., Darnbrough, S., Burns, C. J., Miller, B. E., Uhl, J., Burke, K., Jariwala, N., Locke, K., Krolikowski, P. H., Kumar, N. V., and Labaudiniere, R. F. (2000) The bioactive conformation of human parathyroid hormone. Structural evidence for the extended helix postulate J. Am. Chem. Soc. 122, 3007-3014
80. Chorev, M., Roubini, E., McKee, R. L., Gibbons, S. W., Goldman, M. E., Caulfield, M. P., and Rosenblatt, M. (1991) Cyclic parathyroid hormone-related protein antagonists: lysine 13 to aspartic acid 17 [i to (i+ 4)] side chain to side chain lactamization Biochemistry 30, 5968-5974
81. Barbier, J. R., Neugebauer, W., Morley, P., Ross, V., Soska, M., Whitfield, J. F., and Willick, G. (1997) Bioactivities and secondary structures of constrained analogues of human parathyroid hormone: Cyclic lactams of the receptor binding region J. Med. Chem. 40, 1373-1380
82. Morley, P., Whitfield, J. F., Willick, G. E., Ross, V., MacLean, S., Barbier, J. R., Isaacs, R. J., and Andreassen, T. T. (2001) The effect of monocyclic and bicyclic analogs of human parathyroid hormone (hPTH)-(1-31)NH2 on bone formation and mechanical strength in ovariectomized rats Calcif. Tissue Int. 68, 95-101
83. Charoenchai, L., Wang, H., Wang, J. B., and Aldrich, J. V. (2008) High affinity conformationally constrained nociceptin/orphanin FQ(1-13) amide analogues J. Med. Chem. 51, 4385-4387
84. Ambo, A., Hamazaki, N., Yamada, Y., Nakata, E., and Sasaki, Y. (2001) structure-activity studies on nociceptin analogues: ORL1 receptor binding and biological activity of cyclic disulfide-containing analogues of nociceptin peptides J. Med. Chem. 44, 4015-4018
85. Cascales, L., Henriques, S. T., Kerr, M. C., Huang, Y.-H., Sweet, M. J., Daly, N. L., and Craik, D. J. (2011) Identification and characterization of a new family of cell-penetrating peptides J. Biol. Chem. 286, 36932-36943
86. Snyder, E. L. and Dowdy, S. F. (2004) Cell penetrating peptides in drug delivery Pharm. Res. 21, 389-393
87. Wender, P. A., Galliher, W. C., Goun, E. A., Jones, L. R., and Pillow, T. H. (2008) The design of guanidinium-rich transporters and their internalization mechanisms Adv. Drug Delivery Rev. 60, 452-472
88. Cronican, J. J., Thompson, D. B., Beier, K. T., McNaughton, B. R., Cepko, C. L., and Liu, D. R. (2010) Potent delivery of functional proteins into mammalian cells in vitro and in vivo using a supercharged protein ACS Chem. Biol. 5, 747-752
89. Liu, T., Liu, Y., Kao, H. Y., and Pei, D. H. (2010) Membrane permeable cyclic peptidyl inhibitors against human peptidylprolyl isomerase Pin1 J. Med. Chem. 53, 2494-2501
90. McNaughton, B. R., Cronican, J. J., Thompson, D. B., and Liu, D. R. (2009) Mammalian cell penetration, siRNA transfection, and DNA transfection by supercharged proteins Proc. Natl. Acad. Sci. U.S.A. 106, 6111-6116
91. Appelbaum, J. S., LaRochelle, J. R., Smith, B. A., Balkin, D. M., Holub, J. M., and Schepartz, A. (2012) Arginine topology controls escape of minimally cationic proteins from early endosomes to the cytoplasm Chem. Biol. 19, 819-830
92. Blackwell, H. E. and Grubbs, R. H. (1998) Highly efficient synthesis of covalently cross-linked peptide helices by ring-closing metathesis Angew. Chem., Int. Ed. 37, 3281-3284
93. Schafmeister, C. E., Po, J., and Verdine, G. L. (2000) An all-hydrocarbon cross-linking system for enhancing the helicity and metabolic stability of peptides J. Am. Chem. Soc. 122, 5891-5892
94. Miller, S. J., Blackwell, H. E., and Grubbs, R. H. (1996) Application of ring-closing metathesis to the synthesis of rigidified amino acids and peptides J. Am. Chem. Soc. 118, 9606-9614
95. Walensky, L. D., Kung, A. L., Escher, I., Malia, T. J., Barbuto, S., Wright, R. D., Wagner, G., Verdine, G. L., and Korsmeyer, S. J. (2004) Activation of Apoptosis in vivo by a hydrocarbon-stapled BH3 helix Science 305, 1466-1470
96. LaBelle, J. L., Katz, S. G., Bird, G. H., Gavathiotis, E., Stewart, M. L., Lawrence, C., Fisher, J. K., Godes, M., Pitter, K., Kung, A. L., and Walensky, L. D. (2012) A stapled BIM peptide overcomes apoptotic resistance in hematologic cancers J. Clin. Invest. 122, 2018-2031
97. Phillips, C., Roberts, L. R., Schade, M., Bazin, R., Bent, A., Davies, N. L., Moore, R., Pannifer, A. D., Pickford, A. R., Prior, S. H., Read, C. M., Scott, A., Brown, D. G., Xu, B., and Irving, S. L. (2011) Design and structure of stapled peptides binding to estrogen receptors J. Am. Chem. Soc. 133, 9696-9699
98. Moellering, R. E., Cornejo, M., Davis, T. N., Del Bianco, C., Aster, J. C., Blacklow, S. C., Kung, A. L., Gilliland, D. G., Verdine, G. L., and Bradner, J. E. (2009) Direct inhibition of the NOTCH transcription factor complex Nature 462, 182-U157
99. Bernal, F., Tyler, A. F., Korsmeyer, S. J., Walensky, L. D., and Verdine, G. L. (2007) Reactivation of the p53 tumor suppressor pathway by a stapled p53 peptide J. Am. Chem. Soc. 129, 2456-2457
100. Stewart, M. L., Fire, E., Keating, A. E., and Walensky, L. D. (2010) The MCL-1 BH3 helix is an exclusive MCL-1 inhibitor and apoptosis sensitizer Nat. Chem. Biol. 6, 595-601
101. Walensky, L. D., Pitter, K., Morash, J., Oh, K. J., Barbuto, S., Fisher, J., Smith, E., Verdine, G. L., and Korsmeyer, S. J. (2006) A stapled BID BH3 helix directly binds and activates BAX Mol. Cell 24, 199-210
102. Bird, G. H., Madani, N., Perry, A. F., Princiotto, A. M., Supko, J. G., He, X. Y., Gavathiotis, E., Sodroski, J. G., and Walensky, L. D. (2010) Hydrocarbon double-stapling remedies the proteolytic instability of a lengthy peptide therapeutic Proc. Natl. Acad. Sci. U.S.A. 107, 14093-14098
103. Guo, Z. J., Mohanty, U., Noehre, J., Sawyer, T. K., Sherman, W., and Krilov, G. (2010) Probing the alpha-helical structural stability of stapled p53 peptides: molecular dynamics simulations and analysis Chem. Biol. Drug Des. 75, 348-359
104. Kutchukian, P. S., Yang, J. S., Verdine, G. L., and Shakhnovich, E. I. (2009) All-atom model for stabilization of alpha-helical structure in peptides by hydrocarbon staples J. Am. Chem. Soc. 131, 4622-4627
105. Wang, D., Chen, K., Kulp, J. L., and Arora, P. S. (2006) Evaluation of biologically relevant short α-helices stabilized by a main-chain hydrogen-bond surrogate J. Am. Chem. Soc. 128, 9248-9256
106. Chapman, R. N., Dimartino, G., and Arora, P. S. (2004) A highly stable short α-helix constrained by a main-chain hydrogen-bond surrogate J. Am. Chem. Soc. 126, 12252-12253
107. Bao, J., Dong, X. Y., Zhang, J. Z. H., and Arora, P. S. (2009) Dynamical binding of hydrogen-bond surrogate derived Bak helices to antiapoptotic protein Bcl-x L J. Phys. Chem. B 113, 3565-3571
108. Wang, D., Lu, M., and Arora, P. S. (2008) Inhibition of HIV-1 fusion by hydrogen-bond-surrogate-based alpha helices Angew. Chem., Int. Ed. 47, 1879-1882
109. Patgiri, A., Yadav, K. K., Arora, P. S., and Bar-Sagi, D. (2011) An orthosteric inhibitor of the Ras-Sos interaction Nat. Chem. Biol. 7, 585-587
110. Henchey, L. K., Porter, J. R., Ghosh, I., and Arora, P. S. (2010) High specificity in protein recognition by hydrogen-bond-surrogate alpha-helices: selective inhibition of the p53/MDM2 complex ChemBioChem 11, 2104-2107
111. Henchey, L. K., Kushal, S., Dubey, R., Chapman, R. N., Olenyuk, B. Z., and Arora, P. S. (2010) Inhibition of hypoxia inducible factor 1-transcription coactivator interaction by a hydrogen bond surrogate alpha-helix J. Am. Chem. Soc. 132, 941-943
112. Harrison, R. S., Shepherd, N. E., Hoang, H. N., Ruiz-Gómez, G., Hill, T. A., Driver, R. W., Desai, V. S., Young, P. R., Abbenante, G., and Fairlie, D. P. (2010) Downsizing human, bacterial, and viral proteins to short water-stable alpha helices that maintain biological potency Proc. Natl. Acad. Sci. U.S.A. 107, 11686-11691
113. Kawamoto, S. A., Coleska, A., Ran, X., Yi, H., Yang, C. Y., and Wang, S. M. (2012) Design of triazole-stapled BCL9 alpha-helical peptides to target the beta-catenin/B-cell CLL/lymphoma 9 (BCL9) protein-protein interaction J. Med. Chem. 55, 1137-1146
114. Scrima, M., Le Chevalier-Isaad, A., Rovero, P., Papini, A. M., Chorev, M., and D'Ursi, A. M. (2010) Cu-I-catalyzed azide-alkyne intramolecular i-to-(i+4) side-chain-to-side-chain cyclization promotes the formation of helix-like secondary structures Eur. J. Org. Chem. 446-457
115. Cantel, S., Isaad, A. L. C., Scrima, M., Levy, J. J., DiMarchi, R. D., Rovero, P., Halperin, J. A., D'Ursi, A. M., Papini, A. M., and Chorev, M. (2008) Synthesis and conformational analysis of a cyclic peptide obtained via i to i+4 intramolecular side-chain to side-chain azide-Alkyne 1,3-dipolar cycloaddition J. Org. Chem. 73, 5663-5674
116. Madden, M. M., Muppidi, A., Li, Z. Y., Li, X. L., Chen, J. D., and Lin, Q. (2011) Synthesis of cell-permeable stapled peptide dual inhibitors of the p53-Mdm2/Mdmx interactions via photoinduced cycloaddition Bioorg. Med. Chem. Lett. 21, 1472-1475
117. Madden, M. M., Vera, C. I. R., Song, W. J., and Lin, Q. (2009) Facile synthesis of stapled, structurally reinforced peptide helices via a photoinduced intramolecular 1,3-dipolar cycloaddition reaction Chem. Commun. 5588-5590
118. Kundu, R., Cushing, P. R., Popp, B. V., Zhao, Y., Madden, D. R., and Ball, Z. T. (2012) Hybrid organic-inorganic inhibitors of a PDZ interaction that regulates the endocytic fate of CFTR Angew. Chem., Int. Ed. 51, 7217-7220
119. Zaykov, A. N. and Ball, Z. T. (2011) A general synthesis of dirhodium metallopeptides as MDM2 ligands Chem. Commun. 47, 10927-10927
120. Angelini, A., Cendron, L., Chen, S., Touati, J., Winter, G., Zanotti, G., and Heinis, C. (2012) Bicyclic peptide inhibitor reveals large contact interface with a protease target ACS Chem. Biol. 7, 817-821
121. Heinis, C., Rutherford, T., Freund, S., and Winter, G. (2009) Phage-encoded combinatorial chemical libraries based on bicyclic peptides Nat. Chem. Biol. 5, 502-507
122. Quartararo, J. S., Wu, P., and Kritzer, J. A. (2012) Peptide bicycles that inhibit the Grb2 SH2 domain ChemBioChem 13, 1490-1496
123. Hidalgo, I. J., Raub, T. J., and Borchardt, R. T. (1989) Characterization of the human-colon carcinoma cell-line (Caco-2) as a model system for intestinal epithelial permeability Gastroenterology 96, 736-749
124. Artursson, P. and Borchardt, R. T. (1997) Intestinal drug absorption and metabolism in cell cultures: Caco-2 and beyond Pharm. Res. 14, 1655-1658
125. Pauletti, G. M., Okumu, F. W., and Borchardt, R. T. (1997) Effect of size and charge on the passive diffusion of peptides across Caco-2 cell monolayers via the paracellular pathway Pharm. Res. 14, 164-168
126. Okumu, F. W., Pauletti, G. M., VanderVelde, D. G., Siahaan, T. J., and Borchardt, R. T. (1997) Effect of restricted conformational flexibility on the permeation of model hexapeptides across Caco-2 cell monolayers Pharm. Res. 14, 169-175
127. Knipp, G. T., Vander Velde, D. G., Siahaan, T. J., and Borchardt, R. T. (1997) The effect of beta-turn structure on the passive diffusion of peptides across Caco-2 cell monolayers Pharm. Res. 14, 1332-1340
128. Burton, P. S., Conradi, R. A., Ho, N. F. H., Hilgers, A. R., and Borchardt, R. T. (1996) How structural features influence the biomembrane permeability of peptides J. Pharm. Sci. 85, 1336-1340
129. Kim, D. C., Burton, P. S., and Borchardt, R. T. (1993) A correlation between the permeability characteristics of a series of peptides using an in vitro cell culture model (Caco-2) and those using an in situ perfused rat ileum model of the intestinal mucosa Pharm. Res. 10, 1710-1714
130. Hess, S., Ovadia, O., Shalev, D. E., Senderovich, H., Qadri, B., Yehezkel, T., Salitra, Y., Sheynis, T., Jelinek, R., Gilon, C., and Hoffman, A. (2007) Effect of structural and conformation modifications, including backbone cyclization, of hydrophilic hexapeptides on their intestinal permeability and enzymatic stability J. Med. Chem. 50, 6201-6211
131. Kansy, M., Senner, F., and Gubernator, K. (1998) Physicochemical high throughput screening: Parallel artificial membrane permeation assay in the description of passive absorption processes J. Med. Chem. 41, 1007-1010
132. Knipp, G. T., Ho, N. F., Barsuhn, C. L., and Borchardt, R. T. (1997) Paracellular diffusion in Caco-2 cell monolayers: effect of perturbation on the transport of hydrophilic compounds that vary in charge and size J. Pharm. Sci. 86, 1105-1110
133. Pauletti, G. M., Jeffrey, A., Siahaan, T. J., Gangwar, S., and Borchardt, R. T. (1997) Improvement of oral peptide bioavailability: Peptidomimetics and prodrug strategies Adv. Drug Delivery Rev. 27, 235-256
134. Ovadia, O., Greenberg, S., Chatterjee, J., Laufer, B., Opperer, F., Kessler, H., Gilon, C., and Hoffman, A. (2011) The effect of multiple N-methylation on intestinal permeability of cyclic hexapeptides Mol. Pharm. 8, 479-487
135. Beck, J. G., Chatterjee, J., Laufer, B., Kiran, M. U., Frank, A. O., Neubauer, S., Ovadia, O., Greenberg, S., Gilon, C., Hoffman, A., and Kessler, H. (2012) Intestinal permeability of cyclic peptides: common key backbone motifs identified J. Am. Chem. Soc. 134, 12125-12133
136. Rezai, T., Yu, B., Millhauser, G. L., Jacobson, M. P., and Lokey, R. S. (2006) Testing the conformational hypothesis of passive membrane permeability using synthetic cyclic peptide diastereomers J. Am. Chem. Soc. 128, 2510-2511
137. Egan, W. J., Merz, K. M., and Baldwin, J. J. (2000) Prediction of drug absorption using multivariate statistics J. Med. Chem. 43, 3867-3877
138. Refsgaard, H. H. F., Jensen, B. F., Brockhoff, P. B., Guldbrandt, M., and Christensen, M. S. (2005) In silico prediction of membrane permeability from calculated molecular parameters J. Med. Chem. 48, 805-811
139. Bemporad, D., Essex, J. W., and Luttmann, C. (2004) Permeation of small molecules through a lipid bilayer: a computer simulation study J. Phys. Chem. B 108, 4875-4884
140. Ekins, S., Waller, C. L., Swaan, P. W., Cruciani, G., Wrighton, S. A., and Wikel, J. H. (2000) Progress in predicting human ADME parameters in silico J. Pharmacol. Toxicol. Methods 44, 251-272
141. Marrink, S. J. and Berendsen, H. J. C. (1996) Permeation process of small molecules across lipid membranes studied by molecular dynamics simulations J. Phys. Chem. 100, 16729-16738
142. Leung, S. S. F., Mijalkovic, J., Borrelli, K., and Jacobson, M. P. (2012) Testing Physical models of passive membrane permeation J. Chem. Inf. Model. 52, 1621-1636
143. Rand, A. C., Leung, S. S. F., Eng, H., Rotter, C. J., Sharma, R., Kalgutkar, A. S., Zhang, Y., Varma, M. V., Farley, K. A., Khunte, B., Limberakis, C., Price, D. A., Liras, S., Mathiowetz, A. M., Jacobson, M. P., and Lokey, R. S. (2012) Optimizing PK properties of cyclic peptides: the effect of side chain substitutions on permeability and clearance MedChemComm 3, 1282-1289
144. Nemerov, H. (1958) Trees, in Mirrors and Windows, University of Chicago Press, Chicago.
145. Satkunanathan, N., Livett, B., Gayler, K., Sandall, D., Down, J., and Khalil, Z. (2005) Alpha-conotoxin Vc1.1 alleviates neuropathic pain and accelerates functional recovery of injured neurones Brain Res. 1059, 149-158