Inhibitors against Fungal Cell Wall Remodeling Enzymes

Ignacio Delso (Lead / Corresponding author), Jessika Valero-Gonzalez, Fernando Gomollón-Bel, Jorge Castro-López, Wenxia Fang, Iva Navratilova, Daan M.F. van Aalten, Tomás Tejero, Pedro Merino (Lead / Corresponding author), Ramon Hurtado-Guerrero

Research output: Contribution to journalArticlepeer-review

6 Citations (Scopus)
348 Downloads (Pure)


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.

Original languageEnglish
Pages (from-to)128-132
Number of pages5
Issue number2
Early online date12 Dec 2017
Publication statusPublished - 22 Jan 2018


  • Aspergillus fumigatus
  • carbohydrates
  • glycomimetics
  • oligosaccharides
  • transglycosylases
  • Cell Wall/enzymology
  • Surface Plasmon Resonance
  • Triazoles/chemistry
  • Catalytic Domain
  • Aspergillus fumigatus/enzymology
  • Crystallography, X-Ray
  • Fungal Proteins/antagonists & inhibitors
  • Molecular Dynamics Simulation
  • Saccharomyces cerevisiae/enzymology
  • Glucan 1,3-beta-Glucosidase/antagonists & inhibitors
  • Ligands
  • Enzyme Inhibitors/chemistry
  • Kinetics

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology, Toxicology and Pharmaceutics(all)
  • Organic Chemistry


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