Vinyl Sulfones as Antiparasitic Agents and a Structural Basis for Drug Design

摘要

Cysteine proteases of the papain superfamily are implicated in a number of cellular processes and are important virulence factors in the pathogenesis of parasitic disease. These enzymes have therefore emerged as promising targets for antiparasitic drugs. We report the crystal structures of three major parasite cysteine proteases, cruzain, falcipain-3, and the first reported structure of rhodesain, in complex with a class of potent, small molecule, cysteine protease inhibitors, the vinyl sulfones. These data, in conjunction with comparative inhibition kinetics, provide insight into the molecular mechanisms that drive cysteine protease inhibition by vinyl sulfones, the binding specificity of these important proteases and the potential of vinyl sulfones as antiparasitic drugs. Cysteine proteases of the papain superfamily are implicated in a number of cellular processes and are important virulence factors in the pathogenesis of parasitic disease. These enzymes have therefore emerged as promising targets for antiparasitic drugs. We report the crystal structures of three major parasite cysteine proteases, cruzain, falcipain-3, and the first reported structure of rhodesain, in complex with a class of potent, small molecule, cysteine protease inhibitors, the vinyl sulfones. These data, in conjunction with comparative inhibition kinetics, provide insight into the molecular mechanisms that drive cysteine protease inhibition by vinyl sulfones, the binding specificity of these important proteases and the potential of vinyl sulfones as antiparasitic drugs. Sleeping sickness (African trypanosomiasis), caused by Trypanosoma brucei, and malaria, caused by Plasmodium falciparum, are significant, parasitic diseases of sub-Saharan Africa (1Balakrishnan I. Gillespie S.H. Zuckerman J.N. Principles and Practice of Travel Medicine. John Wiley & Sons, New York2002: 91-124Crossref Google Scholar). Chagas' disease (South American trypanosomiasis), caused by Trypanosoma cruzi, affects approximately, 16–18 million people in South and Central America. For all three of these protozoan diseases, resistance and toxicity to current therapies makes treatment increasingly problematic, and thus the development of new drugs is an important priority (2Docampo R. Moreno S.N. Parasitol Res. 2003; 90 (Suppl. 1): S10-S13Crossref PubMed Scopus (102) Google Scholar, 3Laufer M.K. Djimdé A.A. Plowe C.V. Am. J. Trop. Med. Hyg. 2007; 77: 160-169Crossref PubMed Scopus (58) Google Scholar, 4Ouellette M. Trop. Med. Int. Health. 2001; 6: 874-882Crossref PubMed Scopus (59) Google Scholar). T. cruzi, T. brucei, and P. falciparum produce an array of potential target enzymes implicated in pathogenesis and host cell invasion, including a number of essential and closely related papain-family cysteine proteases (5Caffrey C.R. Scory S. Steverding D. Curr. Drug Targets. 2000; 1: 155-162Crossref PubMed Scopus (89) Google Scholar, 6Rosenthal P.J. Int. J. Parasitol. 2004; 34: 1489-1499Crossref PubMed Scopus (292) Google Scholar). Inhibitors of cruzain and rhodesain, major cathepsin L-like papain-family cysteine proteases of T. cruzi and T. brucei rhodesiense (7Caffrey C.R. Hansell E. Lucas K.D. Brinen L.S. Alvarez Hernandez A. Cheng J. Gwaltney 2nd, S.L. Roush W.R. Stierhof Y.D. Bogyo M. Steverding D. McKerrow J.H. Mol. Biochem. Parasitol. 2001; 118: 61-73Crossref PubMed Scopus (154) Google Scholar, 8Eakin A.E. Mills A.A. Harth G. McKerrow J.H. Craik C.S. J. Biol. Chem. 1992; 267: 7411-7420Abstract Full Text PDF PubMed Google Scholar, 9Nkemgu N.J. Grande R. Hansell E. McKerrow J.H. Caffrey C.R. Steverding D. Int. J. Antimicrob. Agents. 2003; 22: 155-159Crossref PubMed Scopus (30) Google Scholar, 10Steverding D. Caffrey C.R. Sajid M. Mini. Rev. Med. Chem. 2006; 6: 1025-1032Crossref PubMed Scopus (30) Google Scholar) display considerable antitrypanosomal activity (11Engel J.C. Doyle P.S. McKerrow J.H. Medicina. 1999; 59 (Suppl. 2): 171-175PubMed Google Scholar, 12Vicik R. Hoerr V. Glaser M.