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Inhibitors against Fungal Cell Wall Remodeling Enzymes
Author(s) -
Delso Ignacio,
ValeroGonzalez Jessika,
GomollónBel Fernando,
CastroLópez Jorge,
Fang Wenxia,
Navratilova Iva,
van Aalten Daan M. F.,
Tejero Tomás,
Merino Pedro,
HurtadoGuerrero Ramon
Publication year - 2018
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201700720
Subject(s) - enzyme , cell wall , aspergillus fumigatus , chemistry , pyridinium , biochemistry , biophysics , stereochemistry , microbiology and biotechnology , biology , medicinal chemistry
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 Af Gel4 with an IC 50 value of 42 μ m .