title: The Investigational Drug VT-1129 Is a Highly Potent Inhibitor of Cryptococcus Species CYP51 but Only Weakly Inhibits the Human Enzyme.
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.
authors.affiliation: Centre for Cytochrome P450 Biodiversity, Institute of Life Science, Swansea University Medical School, Swansea, Wales, United Kingdom.
authors.forename: Andrew G S
authors.initials: AG
authors.lastname: Warrilow
authors.affiliation: Centre for Cytochrome P450 Biodiversity, Institute of Life Science, Swansea University Medical School, Swansea, Wales, United Kingdom.
authors.forename: Josie E
authors.initials: JE
authors.lastname: Parker
authors.affiliation: Centre for Cytochrome P450 Biodiversity, Institute of Life Science, Swansea University Medical School, Swansea, Wales, United Kingdom.
authors.forename: Claire L
authors.initials: CL
authors.lastname: Price
authors.affiliation: Center for Chemical Biology, Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, Texas, USA.
authors.forename: W David
authors.initials: WD
authors.lastname: Nes
authors.affiliation: Viamet Pharmaceuticals, Inc., Durham, North Carolina, USA.
authors.forename: Edward P
authors.initials: EP
authors.lastname: Garvey
authors.affiliation: Viamet Pharmaceuticals, Inc., Durham, North Carolina, USA.
authors.forename: William J
authors.initials: WJ
authors.lastname: Hoekstra
authors.affiliation: Viamet Pharmaceuticals, Inc., Durham, North Carolina, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Schotzinger
authors.affiliation: Centre for Cytochrome P450 Biodiversity, Institute of Life Science, Swansea University Medical School, Swansea, Wales, United Kingdom.
authors.forename: Diane E
authors.initials: DE
authors.lastname: Kelly
authors.affiliation: Centre for Cytochrome P450 Biodiversity, Institute of Life Science, Swansea University Medical School, Swansea, Wales, United Kingdom s.l.kelly@swansea.ac.uk.
authors.forename: Steven L
authors.initials: SL
authors.lastname: Kelly
mesh_terms: D000935:Antifungal Agents / Q000009:adverse effects / Q000494:pharmacology*; D003022:Clotrimazole / Q000009:adverse effects / Q000494:pharmacology; D003454:Cryptococcus / Q000187:drug effects* / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D004875:Ergosterol / Q000378:metabolism; D015725:Fluconazole / Q000009:adverse effects / Q000494:pharmacology; D006801:Humans; D017964:Itraconazole / Q000009:adverse effects / Q000494:pharmacology; D007654:Ketoconazole / Q000009:adverse effects / Q000494:pharmacology; D007810:Lanosterol / Q000031:analogs & derivatives / Q000378:metabolism; D011725:Pyridines / Q000009:adverse effects* / Q000494:pharmacology*; D058886:Sterol 14-Demethylase / Q000378:metabolism*; D013777:Tetrazoles / Q000009:adverse effects* / Q000494:pharmacology*; D065819:Voriconazole / Q000009:adverse effects / Q000494:pharmacology
chemical_list: D000935:Antifungal Agents; D011725:Pyridines; D013777:Tetrazoles; C000612857:VT-1129; D007810:Lanosterol; D017964:Itraconazole; C014520:ebericol; D015725:Fluconazole; D058886:Sterol 14-Demethylase; D003022:Clotrimazole; D065819:Voriconazole; D007654:Ketoconazole; D004875:Ergosterol