Novel non-peptidic vinylsulfones targeting the S2 and S3 subsites of parasite cysteine proteases

  • Bioorg Med Chem Lett. 2009 Nov 1;19(21):6218-21. doi: 10.1016/j.bmcl.2009.08.098.
Clifford Bryant  1 ,  Iain D Kerr ,  Moumita Debnath ,  Kenny K H Ang ,  Joseline Ratnam ,  Rafaela S Ferreira ,  Priyadarshini Jaishankar ,  DongMei Zhao ,  Michelle R Arkin ,  James H McKerrow ,  Linda S Brinen ,  Adam R Renslo
Affiliations
  • 1. Small Molecule Discovery Center, University of California, San Francisco, CA 94158, USA.
PMID: 19773167 DOI: 10.1016/j.bmcl.2009.08.098
Abstract

We describe here the identification of non-peptidic vinylsulfones that inhibit Parasite cysteine proteases in vitro and inhibit the growth of Trypanosoma brucei brucei parasites in culture. A high resolution (1.75 A) co-crystal structure of 8a bound to cruzain reveals how the non-peptidic P2/P3 moiety in such analogs bind the S2 and S3 subsites of the protease, effectively recapitulating important binding interactions present in more traditional peptide-based Protease Inhibitors and natural substrates.