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

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.

SUBMITTER: Bryant C

PROVIDER: S-EPMC3760505 | biostudies-literature | 2009 Nov

REPOSITORIES: biostudies-literature

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

Bryant Clifford C Kerr Iain D ID Debnath Moumita M Ang Kenny K H KK Ratnam Joseline J Ferreira Rafaela S RS Jaishankar Priyadarshini P Zhao DongMei D Arkin Michelle R MR McKerrow James H JH Brinen Linda S LS Renslo Adam R AR

Bioorganic & medicinal chemistry letters 20090903 21

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 subs ...[more]

PMID: 19773167

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