No Cover Image

Journal article 141 views 13 downloads

Identification of Potent and Selective Inhibitors of <i>Acanthamoeba</i>: Structural Insights into Sterol 14α-Demethylase as a Key Drug Target

Tatiana Y. Hargrove, David Lamb Orcid Logo, Zdzislaw Wawrzak, Marcus Hull, Steven Kelly, F. Peter Guengerich Orcid Logo, Galina I. Lepesheva Orcid Logo

Journal of Medicinal Chemistry, Volume: 67, Issue: 9, Pages: 7443 - 7457

Swansea University Authors: David Lamb Orcid Logo, Steven Kelly

  • 67193.VoR.pdf

    PDF | Version of Record

    © 2024 The Authors. This article is licensed under CC-BY 4.0.

    Download (10.93MB)

Check full text

DOI (Published version): 10.1021/acs.jmedchem.4c00303

Abstract

Acanthamoeba are free-living pathogenic protozoa that cause blinding keratitis, disseminated infection, and granulomatous amebic encephalitis,which is generally fatal. The development of efficient and safe drugs is a critical unmet need. Acanthamoeba sterol 14α-demethylase (CYP51) is an essential en...

Full description

Published in: Journal of Medicinal Chemistry
ISSN: 0022-2623 1520-4804
Published: American Chemical Society (ACS) 2024
Online Access: Check full text

URI: https://cronfa.swan.ac.uk/Record/cronfa67193
Tags: Add Tag
No Tags, Be the first to tag this record!
Abstract: Acanthamoeba are free-living pathogenic protozoa that cause blinding keratitis, disseminated infection, and granulomatous amebic encephalitis,which is generally fatal. The development of efficient and safe drugs is a critical unmet need. Acanthamoeba sterol 14α-demethylase (CYP51) is an essential enzyme of the sterol biosynthetic pathway. Repurposing antifungal azoles for amoebic infections has been reported, but their inhibitory effects on Acanthamoeba CYP51 enzymatic activity have not been studied. Here, we report catalytic properties, inhibition, and structural characterization of CYP51 from Acanthamoeba castellanii. The enzyme displays a 100-fold substrate preference for obtusifoliolover lanosterol, supporting the plant-like cycloartenol-based pathway in thepathogen. The strongest inhibition was observed with voriconazole (1 h IC50 0.45μM), VT1598 (0.25 μM), and VT1161 (0.20 μM). The crystal structures of A. castellanii CYP51 with bound VT1161 (2.24 Å) and without an inhibitor (1.95 Å), presented here, can be used in the development of azole-based scaffolds to achieve optimal amoebicidal effectiveness
Keywords: amoeba; repurposing, cytochrome P450; crystal structure;
College: Faculty of Medicine, Health and Life Sciences
Funders: MRC and NIH
Issue: 9
Start Page: 7443
End Page: 7457

Similar Items