Journal
CURRENT TOPICS IN MEDICINAL CHEMISTRY
Volume 10, Issue 3, Pages 270-293Publisher
BENTHAM SCIENCE PUBL LTD
DOI: 10.2174/156802610790725489
Keywords
Calpain; cysteine protease; calpain assay; calpastatin; crystal structure; protease inhibitors; beta-strand conformation; macrocycles
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Funding
- ARC [DP0771901]
- German Academic Exchange Service
- Australian Federal Government
- NIH [P41 RR-01081]
- Australian Research Council [DP0771901] Funding Source: Australian Research Council
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The physiological roles of calpains are discussed, as are the associated pathological disorders that result from their over-activation. We also present practical information for establishing functional inhibition assays and an overview of X-ray crystal structures of calpain-inhibitor complexes to aid inhibitor design. These structures reveal the expected extended strand conformation for the inhibitor backbone, a geometry that has been engineered into inhibitors with the introduction of either an N-terminal heterocycle or a macrocycle that links the P-1 and P-3 residues. The structure and function of all the main classes of inhibitors are reviewed, with most examples being classified according to the nature of the C-terminal reactive warhead group that reacts with the active site cysteine of calpains. These inhibitor classes include epoxysuccinate derivatives, aldehydes, aldehyde prodrugs (hemiacetals) and keto carbonyl compounds. Inhibitors derived from the endogenous inhibitor calpastatin and examples lacking a warhead, are now known and these are also discussed.
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