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Screening‐based discovery of Aspergillus fumigatus plant‐type chitinase inhibitors
Author(s) -
Lockhart Deborah E.A.,
Schuettelkopf Alexander,
Blair David E.,
van Aalten Daan M.F.
Publication year - 2014
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/j.febslet.2014.07.015
Subject(s) - aspergillus fumigatus , chitinase , aspergillus , high throughput screening , drug discovery , biology , plant disease , microbiology and biotechnology , antifungal , chemical library , enzyme , biochemistry , chemistry , small molecule
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 ( Af ChiA1) 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.