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)

Research output: Contribution to journalArticle

2 Citations (Scopus)
4 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

Fingerprint

Chitinases
Aspergillus fumigatus
Aspergillus
Screening
Arsenals
X ray crystallography
X Ray Crystallography
Virulence
Throughput
Molecules
Kinetics
Growth
Pharmaceutical Preparations
Therapeutics

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

Cite this

Lockhart, D. E. A., Schuettelkopf, A., Blair, D. E., & van Aalten, D. M. F. (2014). Screening-based discovery of Aspergillus fumigatus plant-type chitinase inhibitors. FEBS Letters, 588(17), 3282-3290. https://doi.org/10.1016/j.febslet.2014.07.015

Screening-based discovery of Aspergillus fumigatus plant-type chitinase inhibitors. / Lockhart, Deborah E. A.; Schuettelkopf, Alexander; Blair, David E.; van Aalten, Daan M. F. (Corresponding Author).

In: FEBS Letters, Vol. 588, No. 17, 25.08.2014, p. 3282-3290.

Research output: Contribution to journalArticle

Lockhart, DEA, Schuettelkopf, A, Blair, DE & van Aalten, DMF 2014, 'Screening-based discovery of Aspergillus fumigatus plant-type chitinase inhibitors', FEBS Letters, vol. 588, no. 17, pp. 3282-3290. https://doi.org/10.1016/j.febslet.2014.07.015
Lockhart, Deborah E. A. ; Schuettelkopf, Alexander ; Blair, David E. ; van Aalten, Daan M. F. / Screening-based discovery of Aspergillus fumigatus plant-type chitinase inhibitors. In: FEBS Letters. 2014 ; Vol. 588, No. 17. pp. 3282-3290.
@article{06974c8d99fd4e5d937450d8bd9bacd7,
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.",
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",
author = "Lockhart, {Deborah E. A.} and Alexander Schuettelkopf and Blair, {David E.} and {van Aalten}, {Daan M. F.}",
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.",
year = "2014",
month = "8",
day = "25",
doi = "10.1016/j.febslet.2014.07.015",
language = "English",
volume = "588",
pages = "3282--3290",
journal = "FEBS Letters",
issn = "0014-5793",
publisher = "Elsevier",
number = "17",

}

TY - JOUR

T1 - Screening-based discovery of Aspergillus fumigatus plant-type chitinase inhibitors

AU - Lockhart, Deborah E. A.

AU - Schuettelkopf, Alexander

AU - Blair, David E.

AU - van Aalten, Daan M. F.

N1 - 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.

PY - 2014/8/25

Y1 - 2014/8/25

N2 - 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.

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.

KW - Aspergillus fumigatus

KW - Chitinases

KW - Crystallography, X-Ray

KW - Drug Evaluation, Preclinical

KW - Enzyme Inhibitors

KW - High-Throughput Screening Assays

KW - Inhibitory Concentration 50

KW - Kinetics

KW - Models, Molecular

KW - Molecular Sequence Data

KW - Protein Conformation

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1016/j.febslet.2014.07.015

DO - 10.1016/j.febslet.2014.07.015

M3 - Article

VL - 588

SP - 3282

EP - 3290

JO - FEBS Letters

JF - FEBS Letters

SN - 0014-5793

IS - 17

ER -