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Inhibitors against fungal cell wall remodeling enzymes

DOI: 10.1002/cmdc.201700720 DOI Help

Authors: Ignacio Delso (University of Zaragoza) , Jessika Valero-Gonzalez (University of Zaragoza) , Fernando Gomollón-Bel (University of Zaragoza) , Jorge Castro-López (University of Zaragoza) , Wenxia Fang (University of Dundee) , Iva Navratilova (University of Dundee) , Daan M F Van Aalten (University of Dundee) , Tomás Tejero (University of Zaragoza) , Pedro Merino (University of Zaragoza) , Ramon Hurtado-Guerrero (University of Zaragoza)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Chemmedchem , VOL 6

State: Published (Approved)
Published: December 2017
Diamond Proposal Number(s): 10121

Abstract: 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 IC50 value of 42 μm.

Journal Keywords: Aspergillus fumigatus; carbohydrates; glycomimetics; oligosaccharides; transglycosylases

Diamond Keywords: Fungi; Enzymes

Subject Areas: Chemistry, Biology and Bio-materials, Medicine


Instruments: I02-Macromolecular Crystallography

Added On: 26/01/2018 14:43

Discipline Tags:

Pathogens Infectious Diseases Health & Wellbeing Biochemistry Chemistry Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)