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

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...

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Bibliographic Details
Published in:Chembiochem : a European journal of chemical biology 2006-06, Vol.7 (6), p.943-950
Main Authors: Verhelst, Steven H.L, Witte, Martin D, Arastu-Kapur, Shirin, Fonovic, Marko, Bogyo, Matthew
Format: Article
Language:English
Subjects:
activity-based probes
Animals
Aza Compounds - chemical synthesis
Aza Compounds - chemistry
Binding Sites
Cysteine Endopeptidases - chemistry
cysteine proteases
Cysteine Proteinase Inhibitors - chemical synthesis
drug design
inhibitors
Liver - enzymology
Molecular Probes - chemistry
Molecular Structure
Papain - chemistry
Peptides - chemical synthesis
Peptides - chemistry
Plasmodium falciparum
proteomics
Rats
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Summary: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.
ISSN:1439-4227
1439-7633
1439-4227
DOI:10.1002/cbic.200600001