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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]

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