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

✍ Scribed by Steven H. L. Verhelst; Martin D. Witte; Shirin Arastu-Kapur; Marko Fonovic; Matthew Bogyo

• Book ID: 101819123
• Publisher: John Wiley and Sons
• Year: 2006
• Tongue: English
• Weight: 300 KB
• Volume: 7
• Category: Article
• ISSN: 1439-4227
• DOI: 10.1002/cbic.200600001

✦ Synopsis

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.