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https://hdl.handle.net/2440/59374
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Type: | Journal article |
Title: | Calpains: Attractive targets for the development of synthetic inhibitors |
Author: | Pietsch, M. Chua, K. Abell, A. |
Citation: | Current Topics in Medicinal Chemistry, 2010; 10(3):270-293 |
Publisher: | Bentham Science Publ Ltd |
Issue Date: | 2010 |
ISSN: | 1568-0266 1873-4294 |
Statement of Responsibility: | Markus Pietsch, Krystle C.H. Chua, Andrew D. Abell |
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. |
Keywords: | β-strand conformation Calpain calpain assay calpastatin crystal structure cysteine protease macrocycles protease inhibitors |
Rights: | Copyright Bentham Science Publishers Ltd. |
DOI: | 10.2174/156802610790725489 |
Grant ID: | http://purl.org/au-research/grants/arc/DP0771901 http://purl.org/au-research/grants/arc/DP0771901 |
Published version: | http://dx.doi.org/10.2174/156802610790725489 |
Appears in Collections: | Aurora harvest Chemistry publications |
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