Screening-based discovery of Aspergillus fumigatus plant-type chitinase inhibitors

FEBS Lett. 2014 Aug 25;588(17):3282-90. doi: 10.1016/j.febslet.2014.07.015. Epub 2014 Jul 22.

Abstract

A limited therapeutic arsenal against increasing clinical disease due to Aspergillus spp. necessitates urgent characterisation of new antifungal targets. Here we describe the discovery of novel, low micromolar chemical inhibitors of Aspergillus fumigatus family 18 plant-type chitinase A1 (AfChiA1) by high-throughput screening (HTS). Analysis of the binding mode by X-ray crystallography confirmed competitive inhibition and kinetic studies revealed two compounds with selectivity towards fungal plant-type chitinases. These inhibitors provide new chemical tools to probe the effects of chitinase inhibition on A. fumigatus growth and virulence, presenting attractive starting points for the development of further potent drug-like molecules.

Keywords: Aspergillus fumigatus; Chitinases; High-throughput screen (HTS); Inhibitors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aspergillus fumigatus / enzymology*
  • Chitinases / antagonists & inhibitors*
  • Chitinases / chemistry
  • Crystallography, X-Ray
  • Drug Evaluation, Preclinical
  • Enzyme Inhibitors / pharmacology*
  • High-Throughput Screening Assays
  • Inhibitory Concentration 50
  • Kinetics
  • Models, Molecular
  • Molecular Sequence Data
  • Protein Conformation

Substances

  • Enzyme Inhibitors
  • Chitinases

Associated data

  • PDB/4TX6
  • PIR/4TXE