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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

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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...

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Published in: Journal of Medicinal Chemistry
ISSN: 0022-2623 1520-4804
Published: American Chemical Society (ACS) 2024
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URI: https://cronfa.swan.ac.uk/Record/cronfa67193
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spelling v2 67193 2024-07-26 Identification of Potent and Selective Inhibitors of <i>Acanthamoeba</i>: Structural Insights into Sterol 14α-Demethylase as a Key Drug Target 1dc64e55c2c28d107ef7c3db984cccd2 0000-0001-5446-2997 David Lamb David Lamb true false b17cebaf09b4d737b9378a3581e3de93 Steven Kelly Steven Kelly true false 2024-07-26 MEDS 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 Journal Article Journal of Medicinal Chemistry 67 9 7443 7457 American Chemical Society (ACS) 0022-2623 1520-4804 amoeba; repurposing, cytochrome P450; crystal structure; 9 5 2024 2024-05-09 10.1021/acs.jmedchem.4c00303 COLLEGE NANME Medical School COLLEGE CODE MEDS Swansea University Another institution paid the OA fee MRC and NIH 2024-08-29T13:53:21.3038516 2024-07-26T12:50:16.0033494 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Biomedical Science Tatiana Y. Hargrove 1 David Lamb 0000-0001-5446-2997 2 Zdzislaw Wawrzak 3 Marcus Hull 4 Steven Kelly 5 F. Peter Guengerich 0000-0002-7458-3048 6 Galina I. Lepesheva 0000-0002-6975-1131 7 67193__31175__f8778cda346e42a7971acba5baf59913.pdf 67193.VoR.pdf 2024-08-29T13:50:56.1968709 Output 11458748 application/pdf Version of Record true © 2024 The Authors. This article is licensed under CC-BY 4.0. true eng https://creativecommons.org/licenses/by/4.0/
title Identification of Potent and Selective Inhibitors of <i>Acanthamoeba</i>: Structural Insights into Sterol 14α-Demethylase as a Key Drug Target
spellingShingle Identification of Potent and Selective Inhibitors of <i>Acanthamoeba</i>: Structural Insights into Sterol 14α-Demethylase as a Key Drug Target
David Lamb
Steven Kelly
title_short Identification of Potent and Selective Inhibitors of <i>Acanthamoeba</i>: Structural Insights into Sterol 14α-Demethylase as a Key Drug Target
title_full Identification of Potent and Selective Inhibitors of <i>Acanthamoeba</i>: Structural Insights into Sterol 14α-Demethylase as a Key Drug Target
title_fullStr Identification of Potent and Selective Inhibitors of <i>Acanthamoeba</i>: Structural Insights into Sterol 14α-Demethylase as a Key Drug Target
title_full_unstemmed Identification of Potent and Selective Inhibitors of <i>Acanthamoeba</i>: Structural Insights into Sterol 14α-Demethylase as a Key Drug Target
title_sort Identification of Potent and Selective Inhibitors of <i>Acanthamoeba</i>: Structural Insights into Sterol 14α-Demethylase as a Key Drug Target
author_id_str_mv 1dc64e55c2c28d107ef7c3db984cccd2
b17cebaf09b4d737b9378a3581e3de93
author_id_fullname_str_mv 1dc64e55c2c28d107ef7c3db984cccd2_***_David Lamb
b17cebaf09b4d737b9378a3581e3de93_***_Steven Kelly
author David Lamb
Steven Kelly
author2 Tatiana Y. Hargrove
David Lamb
Zdzislaw Wawrzak
Marcus Hull
Steven Kelly
F. Peter Guengerich
Galina I. Lepesheva
format Journal article
container_title Journal of Medicinal Chemistry
container_volume 67
container_issue 9
container_start_page 7443
publishDate 2024
institution Swansea University
issn 0022-2623
1520-4804
doi_str_mv 10.1021/acs.jmedchem.4c00303
publisher American Chemical Society (ACS)
college_str Faculty of Medicine, Health and Life Sciences
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hierarchy_top_id facultyofmedicinehealthandlifesciences
hierarchy_top_title Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id facultyofmedicinehealthandlifesciences
hierarchy_parent_title Faculty of Medicine, Health and Life Sciences
department_str Swansea University Medical School - Biomedical Science{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Biomedical Science
document_store_str 1
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description 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
published_date 2024-05-09T13:53:19Z
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