Rational design of glycomimetic compounds targeting the Saccharomyces cerevisiae transglycosylase Gas2

The transglycosylase Saccharomyces cerevisiae Gas2 (ScGas2) belongs to a large family of enzymes that are key players in yeast cell wall remodeling. Despite its biological importance, no studies on the synthesis of substrate-based compounds as potential inhibitors have been reported. We have synthesized a series of docking-guided glycomimetics that were evaluated by fluorescence spectroscopy and saturation-transfer difference (STD) NMR experiments, revealing that a minimum of three glucose units linked via a β-(1,3) linkage are required for achieving molecular recognition at the binding donor site. The binding mode of our compounds is further supported by STD-NMR experiments using the active site-mutants Y107Q and Y244Q. Our results are important for both understanding of ScGas2-substrate interactions and setting up the basis for future design of glycomimetics as new antifungal agents.This study was supported by the Ministerio de Economía y Competitividad (MINECO) and FEDER Program (Madrid, Spain, projects CTQ2013-44367-C2-1-P and CTQ2013-44367-C2-2-P), and the Gobierno de Aragón (Zaragoza, Spain. E. M. and J. V.G. thank MEC for FPU and FPI predoctoral grants, respectively. The ARAID Foundation (Gobierno de Aragón, Spain) is also acknowledged for financial support.Peer reviewe