A Fragment-Based Method to Discover Irreversible Covalent Inhibitors of Cysteine Proteases | Zendy

Stefan G. Kathman | Zendy; Ziyang Xu | Zendy; Alexander V. Statsyuk | Zendy

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A Fragment-Based Method to Discover Irreversible Covalent Inhibitors of Cysteine Proteases

Author(s) -

Stefan G. Kathman,

Ziyang Xu,

Alexander V. Statsyuk

Publication year - 2014

Publication title -

journal of medicinal chemistry

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 2.01

H-Index - 261

eISSN - 1520-4804

pISSN - 0022-2623

DOI - 10.1021/jm500345q

Subject(s) - chemistry , papain , proteases , cysteine protease , cysteine proteinase inhibitors , cysteine , covalent bond , electrophile , enzyme , biochemistry , protease , combinatorial chemistry , enzyme inhibitor , stereochemistry , organic chemistry , catalysis , apoptosis , programmed cell death , caspase

A novel fragment-based drug discovery approach is reported which irreversibly tethers drug-like fragments to catalytic cysteines. We attached an electrophile to 100 fragments without significant alterations in the reactivity of the electrophile. A mass spectrometry assay discovered three nonpeptidic inhibitors of the cysteine protease papain. The identified compounds display the characteristics of irreversible inhibitors. The irreversible tethering system also displays specificity: the three identified papain inhibitors did not covalently react with UbcH7, USP08, or GST-tagged human rhinovirus 3C protease.

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