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 (Lead / Corresponding author)

Research output: Contribution to journal › Article › peer-review

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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

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10.1016/j.febslet.2014.07.015

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http://www.sciencedirect.com/science/article/pii/S001457931400564X

Genetic Structural and Chemical Validation of Aspergillus Fumigatus Cell Wall Targets (Programme Grant)
van Aalten, D. (Investigator)
Medical Research Council
1/11/14 → 31/10/19
Project: Research
Sugar Coat: Validation of UDP Galactopyranose Mutase as a Potential Antifungal Target (Clinical PhD Fellowship - Deborah Lockhart)
Lockhart, D. (Investigator) & van Aalten, D. (Investigator)
Medical Research Council
5/09/11 → 4/09/14
Project: Research
Aref#d: 21559. Molecular Mechanisms of Fungal Cell Wall Assembly (Programme Grant)
van Aalten, D. (Investigator)
Medical Research Council
1/11/09 → 31/10/14
Project: Research

"Sugar Coat" Genetic & chemical validation of Aspergillus fumigatus cell wall targets
Lockhart, D. E. A. (Author), Van Aalten, D. (Supervisor), 2014
Student thesis: Doctoral Thesis › Doctor of Philosophy

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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.",

author = "Lockhart, {Deborah E. A.} and Alexander Schuettelkopf and Blair, {David E.} and {van Aalten}, {Daan M. F.}",

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PY - 2014/8/25

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DO - 10.1016/j.febslet.2014.07.015

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JO - FEBS Letters

JF - FEBS Letters

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

Abstract

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Genetic Structural and Chemical Validation of Aspergillus Fumigatus Cell Wall Targets (Programme Grant)

Sugar Coat: Validation of UDP Galactopyranose Mutase as a Potential Antifungal Target (Clinical PhD Fellowship - Deborah Lockhart)

Aref#d: 21559. Molecular Mechanisms of Fungal Cell Wall Assembly (Programme Grant)

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

Cite this

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

Abstract

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Projects

Genetic Structural and Chemical Validation of Aspergillus Fumigatus Cell Wall Targets (Programme Grant)

Sugar Coat: Validation of UDP Galactopyranose Mutase as a Potential Antifungal Target (Clinical PhD Fellowship - Deborah Lockhart)

Aref#d: 21559. Molecular Mechanisms of Fungal Cell Wall Assembly (Programme Grant)

Student theses

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

Cite this