Abstract
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 β-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 P1 and P3 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 α-keto carbonyl compounds. Inhibitors derived from the endogenous inhibitor calpastatin and examples lacking a warhead, are now known and these are also discussed.
Keywords: Calpain, cysteine protease, calpain assay, calpastatin, crystal structure, protease inhibitors, β-strand conformation, macrocycles
Current Topics in Medicinal Chemistry
Title: Calpains: Attractive Targets for the Development of Synthetic Inhibitors
Volume: 10 Issue: 3
Author(s): Markus Pietsch, Krystle C. H. Chua and Andrew D. Abell
Affiliation:
Keywords: Calpain, cysteine protease, calpain assay, calpastatin, crystal structure, protease inhibitors, β-strand conformation, macrocycles
Abstract: 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 β-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 P1 and P3 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 α-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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Pietsch Markus, Chua C. H. Krystle and Abell D. Andrew, Calpains: Attractive Targets for the Development of Synthetic Inhibitors, Current Topics in Medicinal Chemistry 2010; 10 (3) . https://dx.doi.org/10.2174/156802610790725489
DOI https://dx.doi.org/10.2174/156802610790725489 |
Print ISSN 1568-0266 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4294 |
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