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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Amides / chemistry*
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Amides / pharmacology
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Binding Sites
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Crystallography, X-Ray
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Cysteine Proteases / chemistry*
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Cysteine Proteases / metabolism
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Humans
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Jurkat Cells
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Protease Inhibitors / chemical synthesis
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Protease Inhibitors / chemistry*
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Protease Inhibitors / toxicity
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Protein Structure, Tertiary
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Sulfones / chemical synthesis
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Sulfones / chemistry*
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Sulfones / pharmacology
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Sulfones / toxicity
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Trypanocidal Agents / chemical synthesis
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Trypanocidal Agents / chemistry*
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Trypanocidal Agents / toxicity
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Trypanosoma brucei brucei / drug effects
Substances
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Amides
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Protease Inhibitors
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SMDC 256047
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Sulfones
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Trypanocidal Agents
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Cysteine Proteases