Understanding multivalent effects in glycosidase inhibition using C-glycoside click clusters as molecular probes

Abstract

The synthesis of the first examples of multivalent C-glycosides based on C₆₀-fullerene or β-cyclodextrin cores by way of Cu(I)-catalyzed azide–alkyne cycloadditions is reported. These compounds were designed as molecular probes to understand the mechanisms underlying the outstanding multivalent effects observed in glycosidase inhibition. The inhibition results obtained support a multivalent-binding model based on two scenarios both involving nonspecific interactions and varying by the presence or the absence of active site specific interactions. The magnitude of the multivalent effect obtained depends on the identity of the glycosidase involved and more specifically on the accessibility of its catalytic active site. Large inhibitory multivalent effects can be obtained when both glycosidase active sites and non-catalytic sites at the protein surface are involved in binding events. On the other hand, nonspecific interactions alone are not sufficient to achieve relative affinity enhancements exceeding a simple statistical effect (i.e., a relative inhibition potency not better than one on a valence-corrected basis).