Résumé :
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Inhibiting the proteasome appears as a promising therapeutic tool for the treatment of muscle pathologies, including muscle atrophy and several myopathies. We have designed new proteasome inhibitors based on the cyclic natural inhibitor TMC-95A. Several linear mimics that are more readily synthesized than the cyclic parent molecule have been developed that act in a reversible manner without creating a covalent bond with the catalytic Thr1, as do Bortezomib®, MG-132 and lactacystin. The first generation of linear mimics was further modified in order to increase the affinity towards the three types of 20S proteasome catalytic sites, the metabolic stability and the cell penetration. The molecules inhibit selectively the proteasome but neither calpain I, nor cathepsin B. Biological activity of several of these inhibitors was evaluated using cultured C2C12 myotubes expressing a mutant form of caveolin-3 (CAV3) harbouring the Limb Girdle Muscular Dystrophy 1C (LGMD-1C)-associated P104L mutation. Previous results have shown that this mutant form of CAV3 acts in a dominant negative fashion and may aggregate with the wild-type form, leading to the ubiquitination and degradation by the proteasome of both molecules. Treatment of CAV3P104L expressing myotubes with our inhibitors revealed that they were able to block the dominant negative effect of the LGMD-1C mutant by partly rescuing wild-type caveolin-3 and restoring its membrane localization. This cellular activity was stronger than that of MG 132. Additionally, the cytotoxicity of the proteasome inhibitors was evaluated on muscle and non-muscle cells and our non-covalent inhibitors displayed a lower toxicity than MG132.
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