Journal article 12 views
The Investigational Drug VT-1129 Is a Highly Potent Inhibitor of Cryptococcus Species CYP51 but Only Weakly Inhibits the Human Enzyme
,
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 , Diane Kelly, Steven Kelly
Full text not available from this repository: check for access using links below.
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...
| Published in: | Antimicrobial Agents and Chemotherapy |
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| ISSN: | 0066-4804 1098-6596 |
| Published: |
American Society for Microbiology
2016
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| Online Access: |
Check full text
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| URI: | https://cronfa.swan.ac.uk/Record/cronfa64805 |
| 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 (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. |
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| Keywords: |
Cryptococcosis, Cryptococcus, CYP51 enzymes, VT-1129 |
| College: |
Faculty of Medicine, Health and Life Sciences |
| Funders: |
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). |
| Issue: |
8 |
| Start Page: |
4530 |
| End Page: |
4538 |