Peptidomimetic Library

Description

ChemDiv’s library of peptidomimetics contains 36,711 compounds.

Peptidomimetics are sophisticated organic compounds specifically designed to imitate the biological activity of peptides, which are chains of amino acids playing key roles in biological processes. Unlike traditional peptides, peptidomimetics may share structural similarities to peptides but are fundamentally distinct, particularly in their side chains or molecular backbones. This differentiation is not merely structural but extends to their stability, efficacy, and potential therapeutic applications.

One of the primary benefits of peptidomimetics in drug discovery lies in their enhanced stability. Natural peptides, while potent, are often quickly degraded by enzymes in the body, limiting their therapeutic utility. Peptidomimetics, by contrast, are designed to resist enzymatic degradation, thereby extending their half-life in the biological system, and enhancing their effectiveness as drugs. Furthermore, peptidomimetics offer improved specificity and potency. By fine-tuning their molecular structure, scientists can design peptidomimetics that tightly bind to their target proteins with high specificity, minimizing off-target effects and potential side effects. This precise targeting capability makes them highly attractive for developing treatments for a wide range of diseases, from cancer to autoimmune disorders.

Another advantage is their versatility in drug design. Peptidomimetics can be engineered to mimic not only the structure but also the function of peptides, allowing for the modulation of protein-protein interactions that are often undruggable by small molecules. This opens up new avenues for therapeutic intervention, particularly in targeting complex diseases that have eluded traditional small-molecule drug discovery.

Despite their similarities in mode of action, there can sometimes be confusion in classifying a compound as a peptidomimetic or a small organic molecular mimic. This stems from their intermediate molecular masses, which sit between the low molecular weights typical of small molecules and the higher molecular weights of traditional peptides. However, this intermediate size is precisely what allows peptidomimetics to bridge the gap between small molecules and biologics, offering a unique combination of the advantages of both.

Our library of peptidomimetics represents a promising frontier in drug discovery, offering enhanced stability, specificity, and versatility over traditional small molecules and peptides. Their ability to mimic the biological activity of peptides while overcoming the limitations of natural peptides positions them as potent tools in the development of new therapeutics, promising to revolutionize treatment strategies across various therapeutic areas.

Publications

i Zubay, G. L. Biochemistry, 4th ed.; Wm. C. Brown Publishers: Dubaque, Iowa, 1998.

ii Hu, Z.; Ma, B.; Wolfson, H.; Nussinov, R. Proteins: Structure, Function, and Genetics 2000, 39, 331-342.

iii Stites, W. E. Chem. Rev. 1997, 97, 1233-1250.

iv Conte, L. L.; Chothia, C.; Janin, J. J. Mol. Biol. 1999, 285, 2177-2198.

v Ma, B.; Elkayam, T.; Wolfson, H.; Nussinov, R. PNAS 2003, 100, 5772-5777.

vi Arkin, M. R.; Wells, J. A. Nature Reviews: Drug Discovery 2004, 3, 301-317.

vii DeLano, W. L. Curr. Opin. Struc. Bio. 2002, 12, 14-20.

viii (a) Park, C.; Burgess, K. J. Comb. Chem. 2001, 3, 257-266; (b) Orner, B. P.; Ernst, J. T.; Hamilton, A. D. J. Am. Chem. Soc. 2001, 123, 5382-5383.

ix (a) Marchesini, S. Secondary Protein Structure: 3.10 helix. http://www.med.unibs.it/~marchesi/310.html (accessed 9/29/05). (b) Janes, R. W. First Year: Basic Biochemistry. http://www.qmul.ac.uk/~ugbt760/bas02new.doc (accessed 9/29/05)

x A Server for b-Turn Types Prediction. http://bioinformatics.uams.edu/raghava/betaturns/method.html (accessed 9/29/05).

xi Sipkins, D. A.; Wei, X.; Wu, J. W.; Runnels, J. M.; Cote, D.; Means, T. K.; Luster, D. A.; Scadden, D. T.; Lin, C. P. Nature 2005, 435, 969-974.

xii Y. Lavrovsky, Y.A. Ivanenkov, K.V. Balakin, A.V. Ivachtchenko. CXCR4 receptor as a promising target for oncolytic drugs. Mini-Reviews in Medicinal Chemistry, 2008, 8, 1075-1087.

xiii (a) K.V. Balakin, Y.A. Ivanenkov, et al. Regulators of Chemokine Receptor Activity as Promising Anticancer Therapeutics. Current Cancer Drug Targets, 2008, 8, 299-340; (b) AMD3100: CXCR4 Chemokine Receptor Antagonist. http://www.sigmaaldrich.com/img/assets/13760/amd3100.pdf (accessed 9/29/05).

xiv Li, L.; Thomas, R. M.; Suzuki, H.; De Brabander, J. K.; Wang, X.; Harran, P. G. Science 2004, 305, 1471-1474.

xv Montalto, M. C.; Collard, C. D.; Buras, J. A.; Reenstra, W. R.; McClaine, R.; Gies, D. R.; Rother, R. P.; Stahl, G. L. J. Immunol. 2001, 166, 4148-4153.

xvi (a) Cochran, A. G. Chemistry & Biology. 2000, 7, R85-R94; (b) Berman, A. E.; Kozlova, N. I.; Morozevich, G. E. Biochemistry (Moscow) 2003, 68, 1284-1299; (c) Newham, P.; Humphries, M. J. Molecular Medicine Today 1996, 96, 304-313.

xvii D’Alessio, P.; Moutet, M.; Coudrier, E.; Darquenne, S.; Chaudiere, J. Free Radical Biology & Medicine 1998, 24, 979-987.

xviii Gadek, T. R.; Burdick, D. J.; McDowell, R. S.; Stanley, M. S.; Marsters, J. C., Jr.; Paris, K. J.; Oare, D. A.; Reynolds, M. E.; Ladner, C.; Zioncheck, K. A.; Lee, W. P.; Gribling, P.; Dennis, M. S.; Skelton, N. J.; Tumas, D. B.; Clark, K. R.; Keating, S. M.; Beresini, M. H.; Tilley, J. W.; Presta, L. G.; Bodary, S. C. Science 2002, 295, 1086-1089.

xix Hippenmeyer, P. J.; Ruminski, R. P.; Rico, J. G.; Sharon, H.; Lu, D.; Griggs, D. W. Anitviral Research 2002, 55, 169-178.

xx (a) Lee, H. B.; Zaccaro, M. C.; Pattarawarapan, M.; Roy, S.; Saragovi, H. U.; Burgess, K. J. Org. Chem. 2004, 69, 701-713; (b) Reyes, S. J.; Burgess, K. Tetrahedron: Asymmetry 2005, 16, 1061-1069; (c) Maliartchouk, S.; Feng, Y.; Ivanisevic, L.; Debeir, T.; Cuello, A. C.; Burgess, K.; Saragovi, H. U. Mol. Pharm. 2000, 57, 385-391; (d) Ogbu, C. O.; Qabar, M. N.; Boatman, P. D.; Urban, J.; Meara, J. P.; Ferguson, M. D.; Tulinsky, J.; Lum, C.; Babu, S.; Blaskovich, M. A.; Nakanishi, H.;

Ruan, F.; Cao, B.; Minarik, R.; Little, T.; Nelson, S.; Nguyen, M.; Gall, A.; Kahn, M. Bioorg. Med. Chem. Lett. 1998, 8, 2321; (e) Fink, B. E.; Kym, P. R.; Katzenellenbogen, J. A. J. Am. Chem. Soc. 1998, 120, 4334; (f) Johannesson, P.; Lindeberg, G.; Tong, W.; Gogoll, A.; Karlen, A.; Hallberg, A. J. Med. Chem. 1999, 42, 601; (g) Golebiowski, A.; Klopfenstein, S. R.; Chen, J. J.; Shao, X. Tet. Lett. 2000, 41, 4841-4844; (e) Pfeifer, M. E.; Moehle, K.; Linden, A.; Robinson, J. Helv. Chim. Acta 2000, 83, 444.

xxi (a) Pattarawarapan, M.; Burgess, K. J. Med. Chem. 2003, 46, 5277-5291; (b) Maliartchouk, S.; Feng, Y.; Ivanisevic, L.; Debeir, T.; Cuello, A. C.; Burgess, K.; Saragovi, H. U. Mol. Pharm. 2000, 57, 385-391.

xxii (a) Orner, B. P.; Ernst, J. T.; Hamilton, A. D. J. Am. Chem. Soc. 2001, 123, 5382-5383; (b) (36) Kutzki, O.; Park, H. S.; Ernst, J. T.; Orner, B. P.; Hamilton, A. D. J. Am. Chem. Soc. 2002, 124, 11838-11839; (c) Ernst, J. T.; Becerril, J.; Park, H. S.; Yin, H.; Hamilton, A. D. Angew. Chem. Int. Ed. 2003, 42, 535-539; (d) Yin, H.; Lee, G.; Sedey, K. A.; Rodriguez, J. M.; Wang, H.-G.; Sebti, S. M.; Hamilton, A. D. J. Am. Chem. Soc. 2005, 127, 5463-5468; (e) Yin, H.; Lee, G.; Kutzki, O.; Park, H. S.; Orner, B. P.; Ernst, J. T.; Wang, H.-G.; Sebti, S. M.; Hamilton, A. D. J. Am. Chem. Soc. 2005, 127, 10191-10196; (f) Jacoby, E. Bioorg. Med. Chem. Lett. 2002, 12, 891-893; (g) Horwell, D. C.; Howson, W.; Nolan, W. P.; Ratcliffe, G. S.; Rees, D. C.; Willems, H. Tetrahedron 1995, 51, 203-216.

xxiii Shepherd, N. E.; Abbenante, G.; Fairlie, D. P. Angew. Chem. Int. Ed. 2004, 43, 2687-2690.

xxiv (a) Calvo, J. C.; Choconta, K. C.; Diaz, D.; Orozco, O.; Bravo, M. M.; Espejo, F.; Salazar, L. M.; Guzman, F.; Patarroyo, M. E. J. Med. Chem. 2003, 46, 5389-5394; (b) Peczuh, M. W.; Hamilton, A. D. Chem. Rev. 2000, 100, 2479-2494; (c) Asada, S.; Choi, Y.; Uesugi, M. J. Am. Chem. Soc. 2003, 125, 4992-4993.

xxv Peczuh, M. W.; Hamilton, A. D. Chem. Rev. 2000, 100, 2479-2494.

xxvi Fairlie, D. P.; West, M. L.; Wong, A. K. Curr. Med. Chem. 1998, 5, 29-62.

xxvii (a) Marrone, T. J.; Briggs, J. M.; McCammon, J. A. Annu. Rev. Pharmacol. Toxicol. 1997, 37, 71-90; (b) Joseph-McCarthy, D. Pharmacology & Therapeutics 1999, 84, 179-191.

xxviii McConkey, B. J.; Sobolev, V.; Edelman M. Curr. Sci. 2002, 83, 845-856.

xxix (a) Affinity, December 1998. Molecular Simulations, Inc.: San Diego, 1998. (b) Janin, J. Protein Science 2005, 14, 278-283.

xxx (a) Marrone, T. J.; Briggs, J. M.; McCammon, J. A. Annu. Rev. Pharmacol. Toxicol. 1997, 37, 71-90; (b) Joseph-McCarthy, D. Pharmacology & Therapeutics 1999, 84, 179-191; (c) McConkey, B. J.; Sobolev, V.; Edelman M. Curr. Sci. 2002, 83, 845-856.

xxxi Ajay, W.; Walters, P.; Murcko, M. J. Med. Chem. 1998, 41, 3314.

xxxii (a) Pattarawarapan, M.; Burgess, K. J. Med. Chem. 2003, 46, 5277-5291; (b) Ito, M.; Sakai, N.; Ito, K.; Mizobe, F.; Hanada, K. J. Antibiotics 1999, 52, 224-230; (c) Owolabi, J. B.; Rizkalla, G.; Tehim, A.; Ross, G. M.; Riopelle, R. J. J. Pharm.Expt. Ther. 1999, 289, 1271-1276; (d) Labie, C.; Lafon, C.; Marmouget, C.; Saubusse, P.; Fournier, J. British J. Pharm.1999, 127, 139-144; (d) LeSauteur, L.; Cheung, N. K. V.; Lisbona, R.; Saragovi, H. U. Nature Biotech. 1996, 14, 1120-1122.

xxxiii Nicolaou, K. C.; Snyder, S. A. Classics in Total Synthesis II. Wiley-VCH: Weinheim, Germany, 2003, pp. 365-378.

xxxiv (a) Christopher P. Carron, Debra M. Meyer, Jodi A. Pegg, V. Wayne Engleman, Maureen A. Nickols, Steven L. Settle, William F. Westlin, Peter G. Ruminski, and G. Allen Nickols. Cancer Research, 1998, 58, 1930-1935; (b) C P Carron, D M Meyer, V W Engleman, J G Rico, P G Ruminski, R L Ornberg, W F Westlin and G A Nickols. Journal of Endocrinology (2000) 165, 587–598.