The design of potent hydrazones and disulfides as cathepsin S inhibitors
2003; Elsevier BV; Volume: 11; Issue: 5 Linguagem: Inglês
10.1016/s0968-0896(02)00468-6
ISSN1464-3391
AutoresCharles L. Cywin, Raymond A. Firestone, Daniel W. McNeil, Christine A. Grygon, Kathryn M Crane, Della White, P Kinkade, Jerry L. Hopkins, Walter Davidson, Mark E. Labadia, Jessi Wildeson, Maurice M. Morelock, Jeffrey D. Peterson, Ernest Raymond, Maryanne L. Brown, Denice M. Spero,
Tópico(s)Natural product bioactivities and synthesis
ResumoThe design and synthesis of dipeptidyl disulfides and dipeptidyl benzoylhydrazones as selective inhibitors of the cysteine protease Cathepsin S are described. These inhibitors were expected to form a slowly reversible covalent adduct of the active site cysteine of Cathepsin S. Formation of the initial adduct was confirmed by mass spectral analysis. The nature and mechanism of these adducts was explored. Kinetic analysis of the benzoyl hydrazones indicate that these inhibitors are acting as irreversible inhibitors of Cathepsin S. Additionally, the benzoylhydrazones were shown to be potent inhibitors of Cathepsin S processing of Class II associated invariant peptide both in vitro and in vivo.
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