Résumé :
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Communication n° 28 Calpain I and II are ubiquitous calcium-dependent cytosolic cystein proteases that cleave intracellular substrates such as cytoskeletal and myofibrillar proteins. Activation of calpains in dystrophin-deficient muscle cells with increased levels of cytosolic calcium leads to the release of myofibrillar proteins from the sarcomeres, disorganization of the membrane cytoskeleton, general protein breakdown and necrosis of the muscle cells. Evidence that pharmacological blockade of calpain I and II with calpain inhibitors would block the pathogenesis of DMD stems from the observation that overexpression of calpastatin prevents muscle necrosis in dystrophic mice. Consequently, small-molecule calpain inhibitors offer a promising strategy for the treatment of Duchenne and Becker muscular dystrophy. However, no calpain inhibitor is currently on the market and available for application in DMD. Starting from known calpain inhibitor lead compounds, we have launched a lead optimization program involving state of the art medicinal chemistry and in vitro and in vivo test for profiling of compounds. So far we have synthesized and tested more than 800 small-molecule calpain inhibitors for calpain inhibition in cell-free assays and in cultured muscle cells. Moreover, we have already identified several compounds that improve quantitative histological parameters in the mdx mouse-model for DMD, indicating that this approach may lead to drug candidates for DMD treatment in a foreseeable future.
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