Azapeptides as inhibitors and active site titrants for cysteine proteinases

Journal of Medicinal Chemistry
R Xing, R P Hanzlik

Abstract

Ester and amide derivatives of alpha-azaglycine (carbazic acid, H2NNHCOOH), alpha-azaalanine, and alpha-azaphenylalanine (i.e., Ac-l-Phe-NHN(R)CO-X, where X = H, CH3, or CH2Ph, respectively) were synthesized and evaluated as inhibitors of the cysteine proteinases papain and cathepsin B. The ester derivatives inactivated papain and cathepsin B at rates which increased dramatically with leaving group hydrophobicity and electronegativity. For example, with 8 (R = H, X = OPh) the apparent second-order rate constant for papain inactivation was 67 600 M-1 s-1. Amide and P1-thioamide derivatives do not inactivate papain, nor are they substrates; instead they are weak competitive inhibitors (0.2 mM < Ki < 4 mM). Inactivation of papain involves carbamoylation of the enzyme, as demonstrated by electrospray mass spectrometry. Active site titration indicated a 1:1 stoichiometry for the inactivation of papain with 8, and both inactivated papain and cathepsin B are highly resistant to reactivation by dialysis (t1/2 > 24 h at 4 degrees C). Azaalanine derivatives Ac-L-Phe-NHN(CH3)CO-X inactivate papain ca. 400- 900-fold more slowly than their azaglycine analogues, consistent with the planar configuration at Nalpha of the P1 residue and the ver...Continue Reading

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Citations

Feb 22, 2002·Medicinal Research Reviews·Benjamin J McFarland, Craig Beeson
Mar 31, 1999·Bioorganic & Medicinal Chemistry Letters·S VenkatramanR P Hanzlik
Aug 3, 2011·Future Medicinal Chemistry·Caroline ProulxWilliam D Lubell
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