Résumé :
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Communication n° 670 Introduction : Currently, there is no safe and effective medicines available to treat muscle atrophy. Proteasome inhibitors appear to be valuable candidates since they reduce the rate of proteolysis in skeletal muscle atrophy. They also block the dominant negative effect of LGMD-1C mutant and rescue wild-type caveolin-3 suggesting an interest in this pathology. Objectives : Our aim is the design, synthesis and enzymatic study of novel proteasome inhibitors acting in a reversible manner and, unlike the well-known Velcade® used in the treatment of multiple myeloma, without creating an irreversible covalent bond between the targeted enzyme and the inhibitor. A selective control of chymotrypsin-like, trypsin-like or post-acid active sites is also expected. Methods : Using rational approaches including molecular modelling, two librairies of compounds have been designed and synthesized. Their effects on chymotrypsin-, trypsin- and post-acid activities of human and rabbit proteasomes have been evaluated by spectrofluorometric measurements using Suc-LLVY-amc, Boc-LRR-amc and Z-LLE-ß-NA, respectively (amc = 7-amino-4-methylcoumarin ; NA = 2-naphtylamine) at pH 7.5 and 30 °C. Results : In the first strategy, short peptides derived from peptide sequences included in proteins known to be cleaved by proteasome have been synthesized. Pseudopeptidic links have been introduced instead of the scissile bond leading to several inhibitors of the chymotrypsin activity. In the second strategy, cyclic and linear mimics of the natural molecule TMC-95A have been obtained leading to reversible inhibitors. Conclusion : About 20 new molecules have been designed, synthesized and studied for their effects on proteasome activities. Selective inhibitions of the three active sites were observed. This encourages us to improve their efficiency by further modifications of their structure. Their bioavalaibility will be increased by introducing D- and ß-amino acids.
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