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

Deborah E. A. Lockhart; Alexander Schuettelkopf; David E. Blair; Daan M. F. van Aalten

doi:10.1016/j.febslet.2014.07.015

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

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

University of Dundee

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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 language	English
Pages (from-to)	3282-3290
Number of pages	9
Journal	FEBS Letters
Volume	588
Issue number	17
Early online date	22 Jul 2014
DOIs	https://doi.org/10.1016/j.febslet.2014.07.015
Publication status	Published - 25 Aug 2014

Bibliographical note

We wish to thank the Dundee Drug Discovery Unit for access to the diversity set library and the European Synchrotron Radiation Facility, Grenoble, for time at the beamline. This work was supported by a Grant (G0900138) and a Wellcome Trust Senior Research Fellowship (WT087590MA) to D.M.F.v.A. D.E.A.L. is the recipient of a MRC Clinical Research Training Fellowship (G1100430). The structures have been deposited in the Protein Data Bank with accession codes 4TX6 and 4TXE.

Keywords

Aspergillus fumigatus
Chitinases
Crystallography, X-Ray
Drug Evaluation, Preclinical
Enzyme Inhibitors
High-Throughput Screening Assays
Inhibitory Concentration 50
Kinetics
Models, Molecular
Molecular Sequence Data
Protein Conformation
Journal Article
Research Support, Non-U.S. Gov't

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10.1016/j.febslet.2014.07.015Licence: CC BY-NC-ND

Screening‐based discovery of Aspergillus fumigatus plant‐type chitinase inhibitors
©2015 The Authors. Published by FEBS Press and John Wiley & Sons Ltd. This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made. https://creativecommons.org/licenses/by-nc-nd/3.0/
Final published version, 1.67 MBLicence: CC BY-NC-ND

Cite this

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title = "Screening-based discovery of Aspergillus fumigatus plant-type chitinase inhibitors",

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.",

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note = "We wish to thank the Dundee Drug Discovery Unit for access to the diversity set library and the European Synchrotron Radiation Facility, Grenoble, for time at the beamline. This work was supported by a Grant (G0900138) and a Wellcome Trust Senior Research Fellowship (WT087590MA) to D.M.F.v.A. D.E.A.L. is the recipient of a MRC Clinical Research Training Fellowship (G1100430). The structures have been deposited in the Protein Data Bank with accession codes 4TX6 and 4TXE.",

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AB - 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.

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KW - Inhibitory Concentration 50

KW - Kinetics

KW - Models, Molecular

KW - Molecular Sequence Data

KW - Protein Conformation

KW - Journal Article

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JO - FEBS Letters

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ER -

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

Abstract

Bibliographical note

Keywords

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