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.
authors: Division of Molecular Microbiology, College of Life Sciences, University of Dundee, Dundee DD1 5EH, United Kingdom.
authors: Deborah E A
authors: DE
authors: Lockhart
authors: Division of Molecular Microbiology, College of Life Sciences, University of Dundee, Dundee DD1 5EH, United Kingdom.
authors: Alexander
authors: A
authors: Schuettelkopf
authors: Division of Molecular Microbiology, College of Life Sciences, University of Dundee, Dundee DD1 5EH, United Kingdom.
authors: David E
authors: DE
authors: Blair
authors: Division of Molecular Microbiology, College of Life Sciences, University of Dundee, Dundee DD1 5EH, United Kingdom; MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, University of Dundee, Dundee DD1 5EH, United Kingdom. Electronic address: dmfvanaalten@dundee.ac.uk.
authors: Daan M F
authors: DM
authors: van Aalten
mesh_terms: D001232:Aspergillus fumigatus / Q000201:enzymology*; D002688:Chitinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D018360:Crystallography, X-Ray; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D057166:High-Throughput Screening Assays; D020128:Inhibitory Concentration 50; D007700:Kinetics; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011487:Protein Conformation
chemical_list: D004791:Enzyme Inhibitors; D002688:Chitinases
keywords: Aspergillus fumigatus; Chitinases; High-throughput screen (HTS); Inhibitors