Novel Aza Peptide Inhibitors and Active-Site Probes of Papain-Family Cysteine Proteases

Steven H.L. Verhelst, Martin D. Witte, Shirin Arastu-Kapur, Marko Fonovic, Matthew Bogyo

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37 Citations (Scopus)
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Abstract

Recent characterization of multiple classes of functionalized azapeptides as effective covalent inhibitors of cysteine proteases prompted us to investigate O-acyl hydroxamates and their azapeptide analogues for use as activity-based probes (ABPs). We report here a new class of azaglycine-containing O-acylhydroxamates that form stable covalent adducts with target proteases. This allows them to be used as ABPs for papain family cysteine proteases. A second class of related analogues containing a novel O-acyl hydroxyurea warhead was found to function as covalent inhibitors of papain-like proteases. These inhibitors can be easily synthesized on solid support, which allows rapid optimization of compounds with improved selectivity and potency for a given target enzyme. We present here one such optimized inhibitor that showed selective inhibition of falcipain 1, a protease of the malaria-causing parasite, Plasmodium falciparum.
Original languageEnglish
Pages (from-to)943-950
Number of pages8
JournalChemBioChem
Volume7
Issue number6
DOIs
Publication statusPublished - 2006

Keywords

  • proteomics
  • inhibitors
  • drug design
  • cysteine proteases
  • activity-based probes

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