Glucose based inhibitors of glycogen phosphorylase : toward a multivalent and dynamic approach ; Inhibiteurs glucosidiques de la glycogène phosphorylase : vers une approche multivalente et dynamique

Glycogen Phosphorylase (GP) is an enzyme which is involved in the glycogenolysis of glycogen and which therefore enters into the process of releasing free glucose into the blood. In patients with type 2 diabetes, GP is therefore a therapeutic target for the regulation of blood sugar. The catalytic site of GP is the target of glucose analogues. Thus, many glucosidic inhibitors have been synthesized in our laboratory and have shown very good activity against GP. In this project, we have considered new inhibitors by employing two distinct strategies: (1) the design and synthesis of multivalent compounds, and (2) the use of dynamic combinatorial chemistry (CCD) for the rapid identification of new inhibitors of GP. Multivalency, widely studied for lectin-carbohydrate interactions, is not widely used with enzymes. We designed a multivalent glycocluster by in silico study followed by multi-step synthesis. The first biological evaluations of these platforms did not show the presence of a multivalent effect, but we are currently awaiting more results to make a final decision on our study. CCD uses molecular building blocks that self-assemble via reversible bonds to generate a library of compounds at thermodynamic equilibrium. We applied this principle with a modified glucose to obtain a library of glucosidic compounds. The introduction into these equilibrating libraries of GP allows the ranking of the various ligands candidates in the library according to their affinity for GP. The synthesis and biological evaluation of these compounds individually allowed us to verify the classification obtained by CCD. ; La Glycogène Phosphorylase (GP) est une enzyme qui intervient dans la glycogénolyse du glycogène et qui entre donc dans le processus de libération de glucose libre dans le sang. Chez les patients atteints du diabète de type 2, la GP est donc une cible thérapeutique pour la régulation de la glycémie. Le site catalytique de la GP est la cible des analogues du glucose. Ainsi, de nombreux inhibiteurs glucosidiques ont été ...