A fragment-based method to discover irreversible covalent inhibitors of cysteine proteases

Stefan G. Kathman, Ziyang Xu, Alexander V. Statsyuk*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

97 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)4969-4974
Number of pages6
JournalJournal of Medicinal Chemistry
Volume57
Issue number11
DOIs
StatePublished - Jun 12 2014

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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