Nucleoside diphosphate sugar analogues that target glycosyltransferases

Abstract

Glycosyltransferases (GTs) are enzymes that transfer carbohydrates to a range of substrates and they play a fundamental role in the recognition processes associated with several diseases. The design of glycomimetics of nucleoside diphosphate (NDP) sugars—the natural substrates that act as inhibitors or modulators of GTs—is not only necessary for the development of glycan-based therapeutic drugs, but is also a crucial tool for understanding their mechanisms of action. Whilst a large number of inhibitors that consist of modifications of the carbohydrate unit and the pyrophosphate linkage have been designed, less attention has been paid to modifications at the ribose moiety and the nucleobase. However, in recent years, promising results have been obtained through such variations, which were prompted by the initial interest in the photolabeling of enzymes to study their structure. In this Focus Review, we survey recent progress in the synthesis of NDP-sugar analogues that are modified at the ribose moiety or at the heterocyclic base.