Pietsch, M.Chua, K.Abell, A.2010-07-082010-07-082010Current Topics in Medicinal Chemistry, 2010; 10(3):270-2931568-02661873-4294http://hdl.handle.net/2440/59374The 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.enCopyright Bentham Science Publishers Ltd.β-strand conformationCalpaincalpain assaycalpastatincrystal structurecysteine proteasemacrocyclesprotease inhibitorsJournal article002009510810.2174/1568026107907254890002744305000042-s2.0-7794946951135967Abell, A. [0000-0002-0604-2629]