title: Novel aza peptide inhibitors and active-site probes of papain-family cysteine proteases.
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.
authors.affiliation: Department of Pathology, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA 94305, USA.
authors.forename: Steven H L
authors.initials: SH
authors.lastname: Verhelst
authors.forename: Martin D
authors.initials: MD
authors.lastname: Witte
authors.forename: Shirin
authors.initials: S
authors.lastname: Arastu-Kapur
authors.forename: Marko
authors.initials: M
authors.lastname: Fonovic
authors.forename: Matthew
authors.initials: M
authors.lastname: Bogyo
mesh_terms: D000818:Animals; D001372:Aza Compounds / Q000138:chemical synthesis* / Q000737:chemistry; D001665:Binding Sites; D003546:Cysteine Endopeptidases / Q000737:chemistry*; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis*; D008099:Liver / Q000201:enzymology; D015335:Molecular Probes / Q000737:chemistry*; D015394:Molecular Structure; D010206:Papain / Q000737:chemistry*; D010455:Peptides / Q000138:chemical synthesis* / Q000737:chemistry; D051381:Rats
chemical_list: D001372:Aza Compounds; D015853:Cysteine Proteinase Inhibitors; D015335:Molecular Probes; D010455:Peptides; D003546:Cysteine Endopeptidases; C099607:falcipain; D010206:Papain