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

Deborah E. A. Lockhart, Alexander Schuettelkopf, David E. Blair, Daan M. F. van Aalten (Lead / Corresponding author)

    Research output: Contribution to journalArticle

    4 Citations (Scopus)
    119 Downloads (Pure)

    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.

    Original languageEnglish
    Pages (from-to)3282-3290
    Number of pages9
    JournalFEBS Letters
    Volume588
    Issue number17
    Early online date22 Jul 2014
    DOIs
    Publication statusPublished - 25 Aug 2014

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    Student Theses

    "Sugar Coat" Genetic & chemical validation of Aspergillus fumigatus cell wall targets

    Author: Lockhart, D. E. A., 2014

    Supervisor: Van Aalten, D. (Supervisor)

    Student thesis: Doctoral ThesisDoctor of Philosophy

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