Calpains: Attractive targets for the development of synthetic inhibitors
Date
2010
Authors
Pietsch, M.
Chua, K.
Abell, A.
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Journal article
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Current Topics in Medicinal Chemistry, 2010; 10(3):270-293
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Markus Pietsch, Krystle C.H. Chua, Andrew D. Abell
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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 P<sub>1</sub> and P<sub>3</sub> 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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Copyright Bentham Science Publishers Ltd.