Journal
BIOLOGICAL CHEMISTRY
Volume 384, Issue 12, Pages 1613-1618Publisher
WALTER DE GRUYTER & CO
DOI: 10.1515/BC.2003.179
Keywords
Aza-asparagine; clan CD enzymes; cysteine proteases; epoxysuccinate; irreversible inhibitor; synthetic inhibitor
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Funding
- NIAID NIH HHS [AI053247] Funding Source: Medline
- NIGMS NIH HHS [GM61964, GM54401] Funding Source: Medline
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Azapeptide epoxides are a new class of irreversible cysteine protease inhibitors. Derivatives containing a P1 azaasparagine residue are specific for Schistosoma mansoni and pig kidney legumains, which are clan CD cysteine proteases. The inhibitors have secondorder rate constants of up to 10(4) M(-1)s(-1) with pig kidney legumain and IC50 values as low as 45 nM with S. mansoni legumain. The most potent epoxides contain an ester moiety with S,S stereochemistry attached to the epoxide. Interestingly, amide and amino acid derivatives of the epoxysuccinate moiety were not inhibitors of legumain, while disubstituted amide derivatives are quite potent. The inhibitors have little or no inhibitory activity with other proteases such as caspases, chymotrypsin, papain, cathepsin B, granzyme B, and various aspartyl proteases.
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