The investigational drug VT-1129 is a highly potent inhibitor of Cryptococcus species CYP51 but only weakly inhibits the human enzyme

Andrew G.S. Warrilow, Josie E. Parker, Claire L. Price, W. David Nes, Edward P. Garvey, William J. Hoekstra, Robert J. Schotzinger, Diane E. Kelly, Steven L. Kelly

Research output: Contribution to journalArticle

24 Scopus citations

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.

Original languageEnglish
Pages (from-to)4530-4538
Number of pages9
JournalAntimicrobial Agents and Chemotherapy
Volume60
Issue number8
DOIs
StatePublished - Aug 2016

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    Warrilow, A. G. S., Parker, J. E., Price, C. L., Nes, W. D., Garvey, E. P., Hoekstra, W. J., Schotzinger, R. J., Kelly, D. E., & Kelly, S. L. (2016). The investigational drug VT-1129 is a highly potent inhibitor of Cryptococcus species CYP51 but only weakly inhibits the human enzyme. Antimicrobial Agents and Chemotherapy, 60(8), 4530-4538. https://doi.org/10.1128/AAC.00349-16