Inhibitors against Fungal Cell Wall Remodeling Enzymes

Fungal β-1,3-glucan glucanosyltransferases are glucan-remodeling enzymes that play important roles in cell wall integrity, and are essential for the viability of pathogenic fungi and yeasts. As such, they are considered possible drug targets, although inhibitors of this class of enzymes have not yet been reported. Herein we report a multidisciplinary approach based on a structure-guided design using a highly conserved transglycosylase from Sacharomyces cerevisiae, that leads to carbohydrate derivatives with high affinity for Aspergillus fumigatus Gel4. We demonstrate by X-ray crystallography that the compounds bind in the active site of Gas2/Gel4 and interact with the catalytic machinery. The topological analysis of noncovalent interactions demonstrates that the combination of a triazole with positively charged aromatic moieties are important for optimal interactions with Gas2/Gel4 through unusual pyridinium cation–π and face-to-face π–π interactions. The lead compound is capable of inhibiting AfGel4 with an IC value of 42 μm.This work was supported by Spanish MINECO Contracts (CTQ2016‐76155‐R to P.M., and BFU2016‐75633‐P to R.H.‐G.), and an MRC Programme Grant (M004139) to D.M.F.v.A. We also acknowledge the Government of Aragón (Spain) (Bioorganic Chemistry group E‐10 and Protein Targets group B‐89) for financial support. The European Commission is gratefully acknowledged (BioStruct‐X grant agreement no. 283570 and BIOSTRUCTX_5186).Peer Reviewe