SYBIO = Design and synthesis of bioactive glycomimetics, from square sugars to sweet giants!
The research projects of SYBIO combine the development of new synthetic methodologies and the design of natural-like heterocycles (mainly carbohydrate mimics) of biological and therapeutic interest. The overall aim is to develop efficient synthetic access to original glycomimetics in order to accelerate the discovery of potent inhibitors of carbohydrate-processing enzymes and then target diseases, such as lysosomal diseases or cystic fibrosis (mucoviscidosis), which involve glycosidases or/and glycosyltransferases. To explore unfrequented regions of chemical and intellectual property spaces, we have recently synthesized unprecedented four-membered carbasugars (square sugars) and spiranic iminosugars. As organic chemists, we were attracted by the number of synthetic challenges that such structures represent with several contiguous asymmetric centres, small cycles and a high density of functional groups. Recent studies in our lab have also led to the discovery of a strong multivalent effect in glycosidase inhibition. Thus, cyclopeptoid platforms displaying up to 48 copies of an iminosugar inhibitor has been found to be up to 170,000 fold more potent than the corresponding monovalent model. These sweet giants were synthesized efficiently by click chemistry using a dendrimer approach. Application to glycosidase of therapeutic interest in the field of cystic fibrosis has led to the first description of a multivalent effect for correcting protein folding defects in cells and should find applications for the treatment of a number of protein folding disorders. Based on fruitful collaborations with biochemists, analytical chemists and structural biologists, we are currently exploring the molecular basis of the affinity increase observed to rationalize the outstandingly large inhibitory multivalent effect disclosed.
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