title: The multivalent effect in glycosidase inhibition: probing the influence of architectural parameters with cyclodextrin-based iminosugar click clusters.
abstract: In contrast to most lectins, glycosidases may appear to be unpromising targets for multivalent binding because they display only a single active site. To explore the potential of multivalency on glycosidase inhibition, unprecedented cyclodextrin-based iminosugar conjugates have been designed and prepared. The synthesis was performed by way of Cu(I) -catalyzed azide-alkyne cycloaddition reaction under microwave activation between propargylated multivalent β-cyclodextrins and an azide-armed N-alkyl 1-deoxynojirimycin derivative. Evaluation with a panel of glycosidases of this new class of glycomimetic clusters revealed the strongest affinity enhancement observed to date for a multivalent glycosidase inhibitor, with binding enhancement up to four orders of magnitude over the corresponding monovalent ligand for α-mannosidase. These results demonstrate that the multivalency concept extends beyond carbohydrate-lectin recognition processes to glycomimetic-enzyme inhibition.
authors: Laboratoire de Synthèse Organique et Molécules Bioactives, Université de Strasbourg, et CNRS (UMR 7509), Ecole Européenne de Chimie, Polymères et Matériaux, 25 rue Becquerel, 67087 Strasbourg, France.
authors: Camille
authors: C
authors: Decroocq
authors: David
authors: D
authors: Rodríguez-Lucena
authors: Virginie
authors: V
authors: Russo
authors: Teresa
authors: T
authors: Mena Barragán
authors: Carmen
authors: C
authors: Ortiz Mellet
authors: Philippe
authors: P
authors: Compain
mesh_terms: D002384:Catalysis; D057930:Click Chemistry; D003300:Copper / Q000737:chemistry; D006026:Glycoside Hydrolases / Q000037:antagonists & inhibitors*; D050111:Imino Sugars / Q000737:chemistry*; D008958:Models, Molecular; D047392:beta-Cyclodextrins / Q000737:chemistry*
chemical_list: D050111:Imino Sugars; D047392:beta-Cyclodextrins; D003300:Copper; D006026:Glycoside Hydrolases