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The Investigational Drug VT-1129 Is a Highly Potent Inhibitor of Cryptococcus Species CYP51 but Only Weakly Inhibits the Human Enzyme

Andrew Warrilow, Josie Parker, Claire Price Orcid Logo, W. David Nes, Edward P. Garvey, William J. Hoekstra, Robert J. Schotzinger, Diane Kelly, Steven Kelly

Antimicrobial Agents and Chemotherapy, Volume: 60, Issue: 8, Pages: 4530 - 4538

Swansea University Authors: Andrew Warrilow, Josie Parker, Claire Price Orcid Logo, Diane Kelly, Steven Kelly

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DOI (Published version): 10.1128/aac.00349-16

Abstract

Cryptococcosis is a life-threatening disease often associated with HIV infection. Three Cryptococcus species CYP51 enzymes were purified and catalyzed the 14α-demethylation of lanosterol, eburicol, and obtusifoliol. The investigational agent VT-1129 bound tightly to all three CYP51 proteins (dissoci...

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Published in: Antimicrobial Agents and Chemotherapy
ISSN: 0066-4804 1098-6596
Published: American Society for Microbiology 2016
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URI: https://cronfa.swan.ac.uk/Record/cronfa64805
first_indexed 2025-01-09T20:23:29Z
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spelling 2025-01-09T12:44:11.3470678 v2 64805 2023-10-24 The Investigational Drug VT-1129 Is a Highly Potent Inhibitor of Cryptococcus Species CYP51 but Only Weakly Inhibits the Human Enzyme f066e233e8d0136c9f547b86fa43747f Andrew Warrilow Andrew Warrilow true false e563ed4e1c7db8d1e131fb78a5f8d0d5 Josie Parker Josie Parker true false 9a4e4dfa37f4318c6fa67933d4fc9a17 0000-0002-6045-4835 Claire Price Claire Price true false 5ccf81e5d5beedf32ef8d7c3d7ac6c8c Diane Kelly Diane Kelly true false b17cebaf09b4d737b9378a3581e3de93 Steven Kelly Steven Kelly true false 2023-10-24 Cryptococcosis is a life-threatening disease often associated with HIV infection. Three Cryptococcus species CYP51 enzymes were purified and catalyzed the 14α-demethylation of lanosterol, eburicol, and obtusifoliol. The investigational agent VT-1129 bound tightly to all three CYP51 proteins (dissociation constant [Kd] range, 14 to 25 nM) with affinities similar to those of fluconazole, voriconazole, itraconazole, clotrimazole, and ketoconazole (Kd range, 4 to 52 nM), whereas VT-1129 bound weakly to human CYP51 (Kd, 4.53 μM). VT-1129 was as effective as conventional triazole antifungal drugs at inhibiting cryptococcal CYP51 activity (50% inhibitory concentration [IC50] range, 0.14 to 0.20 μM), while it only weakly inhibited human CYP51 activity (IC50, ∼600 μM). Furthermore, VT-1129 weakly inhibited human CYP2C9, CYP2C19, and CYP3A4, suggesting a low drug-drug interaction potential. Finally, the cellular mode of action for VT-1129 was confirmed to be CYP51 inhibition, resulting in the depletion of ergosterol and ergosta-7-enol and the accumulation of eburicol, obtusifolione, and lanosterol/obtusifoliol in the cell membranes. Journal Article Antimicrobial Agents and Chemotherapy 60 8 4530 4538 American Society for Microbiology 0066-4804 1098-6596 Cryptococcosis, Cryptococcus, CYP51 enzymes, VT-1129 1 8 2016 2016-08-01 10.1128/aac.00349-16 http://dx.doi.org/10.1128/aac.00349-16 COLLEGE NANME COLLEGE CODE Swansea University This work was supported in part by the European Regional Development Fund/Welsh Government funded BEACON research program (Swansea University), the National Science Foundation of the United States (grant NSF-MCB-09020212 awarded to W. David Nes, Texas Tech University), and Viamet Pharmaceuticals, Inc. (Durham, NC, USA). 2025-01-09T12:44:11.3470678 2023-10-24T09:57:44.9044364 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Medicine Andrew Warrilow 1 Josie Parker 2 Claire Price 0000-0002-6045-4835 3 W. David Nes 4 Edward P. Garvey 5 William J. Hoekstra 6 Robert J. Schotzinger 7 Diane Kelly 8 Steven Kelly 9
title The Investigational Drug VT-1129 Is a Highly Potent Inhibitor of Cryptococcus Species CYP51 but Only Weakly Inhibits the Human Enzyme
spellingShingle The Investigational Drug VT-1129 Is a Highly Potent Inhibitor of Cryptococcus Species CYP51 but Only Weakly Inhibits the Human Enzyme
Andrew Warrilow
Josie Parker
Claire Price
Diane Kelly
Steven Kelly
title_short The Investigational Drug VT-1129 Is a Highly Potent Inhibitor of Cryptococcus Species CYP51 but Only Weakly Inhibits the Human Enzyme
title_full The Investigational Drug VT-1129 Is a Highly Potent Inhibitor of Cryptococcus Species CYP51 but Only Weakly Inhibits the Human Enzyme
title_fullStr The Investigational Drug VT-1129 Is a Highly Potent Inhibitor of Cryptococcus Species CYP51 but Only Weakly Inhibits the Human Enzyme
title_full_unstemmed The Investigational Drug VT-1129 Is a Highly Potent Inhibitor of Cryptococcus Species CYP51 but Only Weakly Inhibits the Human Enzyme
title_sort The Investigational Drug VT-1129 Is a Highly Potent Inhibitor of Cryptococcus Species CYP51 but Only Weakly Inhibits the Human Enzyme
author_id_str_mv f066e233e8d0136c9f547b86fa43747f
e563ed4e1c7db8d1e131fb78a5f8d0d5
9a4e4dfa37f4318c6fa67933d4fc9a17
5ccf81e5d5beedf32ef8d7c3d7ac6c8c
b17cebaf09b4d737b9378a3581e3de93
author_id_fullname_str_mv f066e233e8d0136c9f547b86fa43747f_***_Andrew Warrilow
e563ed4e1c7db8d1e131fb78a5f8d0d5_***_Josie Parker
9a4e4dfa37f4318c6fa67933d4fc9a17_***_Claire Price
5ccf81e5d5beedf32ef8d7c3d7ac6c8c_***_Diane Kelly
b17cebaf09b4d737b9378a3581e3de93_***_Steven Kelly
author Andrew Warrilow
Josie Parker
Claire Price
Diane Kelly
Steven Kelly
author2 Andrew Warrilow
Josie Parker
Claire Price
W. David Nes
Edward P. Garvey
William J. Hoekstra
Robert J. Schotzinger
Diane Kelly
Steven Kelly
format Journal article
container_title Antimicrobial Agents and Chemotherapy
container_volume 60
container_issue 8
container_start_page 4530
publishDate 2016
institution Swansea University
issn 0066-4804
1098-6596
doi_str_mv 10.1128/aac.00349-16
publisher American Society for Microbiology
college_str Faculty of Medicine, Health and Life Sciences
hierarchytype
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 - Medicine{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Medicine
url http://dx.doi.org/10.1128/aac.00349-16
document_store_str 0
active_str 0
description Cryptococcosis is a life-threatening disease often associated with HIV infection. Three Cryptococcus species CYP51 enzymes were purified and catalyzed the 14α-demethylation of lanosterol, eburicol, and obtusifoliol. The investigational agent VT-1129 bound tightly to all three CYP51 proteins (dissociation constant [Kd] range, 14 to 25 nM) with affinities similar to those of fluconazole, voriconazole, itraconazole, clotrimazole, and ketoconazole (Kd range, 4 to 52 nM), whereas VT-1129 bound weakly to human CYP51 (Kd, 4.53 μM). VT-1129 was as effective as conventional triazole antifungal drugs at inhibiting cryptococcal CYP51 activity (50% inhibitory concentration [IC50] range, 0.14 to 0.20 μM), while it only weakly inhibited human CYP51 activity (IC50, ∼600 μM). Furthermore, VT-1129 weakly inhibited human CYP2C9, CYP2C19, and CYP3A4, suggesting a low drug-drug interaction potential. Finally, the cellular mode of action for VT-1129 was confirmed to be CYP51 inhibition, resulting in the depletion of ergosterol and ergosta-7-enol and the accumulation of eburicol, obtusifolione, and lanosterol/obtusifoliol in the cell membranes.
published_date 2016-08-01T14:34:45Z
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score 11.247077

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