Evaluation of Dipeptide α-Keto-β-aldehydes as New Inhibitors of Cathepsin S

A series of dipeptidyl α-keto-β-aldehydes (glyoxals), prepared by solid-/solution-phase chemistries, were assessed for their inhibitory activity against cathepsin S, a lysosomal cysteine protease implicated in a number of important pathophysiological processes. The inhibitor Cbz-Phe-Leu-COCHO, which...

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Bibliographic Details
Published in:Biochemical and biophysical research communications 2000-08, Vol.275 (2), p.401-405
Main Authors: Walker, Brian, Lynas, John F., Meighan, Mark A., Brömme, Dieter
Format: Article
Language:English
Subjects:
Aldehydes - chemistry
Aldehydes - pharmacology
cathepsins
Cathepsins - antagonists & inhibitors
cysteine protease
Dipeptides - chemistry
Evaluation Studies as Topic
glyoxals
lysosomal enzymes
peptide-based inhibitors
Protease Inhibitors - pharmacology
synthetic inhibitor
transition state analogues
α-keto-β-aldehyde
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Summary:A series of dipeptidyl α-keto-β-aldehydes (glyoxals), prepared by solid-/solution-phase chemistries, were assessed for their inhibitory activity against cathepsin S, a lysosomal cysteine protease implicated in a number of important pathophysiological processes. The inhibitor Cbz-Phe-Leu-COCHO, which exhibits slow-binding kinetic characteristics, was found to be almost 400-fold more selective for cathepsin S (Ki = 0.185 nM) than for cathepsin B (76 nM) and is, to our knowledge, the most potent, reversible, synthetic cathepsin S inhibitor reported to date.
ISSN:0006-291X
1090-2104
DOI:10.1006/bbrc.2000.3311