The Multivalent Effect in Glycosidase Inhibition: Probing the Influence of Architectural Parameters with Cyclodextrin-based Iminosugar Click Clusters

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 CuI-catalyzed azidealkyne cycloaddition reaction under microwave activation between propargylated multivalent beta-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 a-mannosidase. These results demonstrate that the multivalency concept extends beyond carbohydratelectin recognition processes to glycomimeticenzyme inhibition.