title: The clinical candidate VT-1161 is a highly potent inhibitor of Candida albicans CYP51 but fails to bind the human enzyme.
abstract: The binding and cytochrome P45051 (CYP51) inhibition properties of a novel antifungal compound, VT-1161, against purified recombinant Candida albicans CYP51 (ERG11) and Homo sapiens CYP51 were compared with those of clotrimazole, fluconazole, itraconazole, and voriconazole. VT-1161 produced a type II binding spectrum with Candida albicans CYP51, characteristic of heme iron coordination. The binding affinity of VT-1161 for Candida albicans CYP51 was high (dissociation constant [Kd], ≤ 39 nM) and similar to that of the pharmaceutical azole antifungals (Kd, ≤ 50 nM). In stark contrast, VT-1161 at concentrations up to 86 μM did not perturb the spectrum of recombinant human CYP51, whereas all the pharmaceutical azoles bound to human CYP51. In reconstitution assays, VT-1161 inhibited Candida albicans CYP51 activity in a tight-binding fashion with a potency similar to that of the pharmaceutical azoles but failed to inhibit the human enzyme at the highest concentration tested (50 μM). In addition, VT-1161 (MIC = 0.002 μg ml(-1)) had a more pronounced fungal sterol disruption profile (increased levels of methylated sterols and decreased levels of ergosterol) than the known CYP51 inhibitor voriconazole (MIC = 0.004 μg ml(-1)). Furthermore, VT-1161 weakly inhibited human CYP2C9, CYP2C19, and CYP3A4, suggesting a low drug-drug interaction potential. In summary, VT-1161 potently inhibited Candida albicans CYP51 and culture growth but did not inhibit human CYP51, demonstrating a >2,000-fold selectivity. This degree of potency and selectivity strongly supports the potential utility of VT-1161 in the treatment of Candida infections.
authors.affiliation: Centre for Cytochrome P450 Biodiversity, Institute of Life Science, College of Medicine, Swansea University, Swansea, Wales, United Kingdom.
authors.forename: A G S
authors.initials: AG
authors.lastname: Warrilow
authors.affiliation: Centre for Cytochrome P450 Biodiversity, Institute of Life Science, College of Medicine, Swansea University, Swansea, Wales, United Kingdom.
authors.forename: C M
authors.initials: CM
authors.lastname: Hull
authors.affiliation: Centre for Cytochrome P450 Biodiversity, Institute of Life Science, College of Medicine, Swansea University, Swansea, Wales, United Kingdom.
authors.forename: J E
authors.initials: JE
authors.lastname: Parker
authors.affiliation: Viamet Pharmaceuticals, Inc., Durham, North Carolina, USA.
authors.forename: E P
authors.initials: EP
authors.lastname: Garvey
authors.affiliation: Viamet Pharmaceuticals, Inc., Durham, North Carolina, USA.
authors.forename: W J
authors.initials: WJ
authors.lastname: Hoekstra
authors.affiliation: Viamet Pharmaceuticals, Inc., Durham, North Carolina, USA.
authors.forename: W R
authors.initials: WR
authors.lastname: Moore
authors.affiliation: Viamet Pharmaceuticals, Inc., Durham, North Carolina, USA.
authors.forename: R J
authors.initials: RJ
authors.lastname: Schotzinger
authors.affiliation: Centre for Cytochrome P450 Biodiversity, Institute of Life Science, College of Medicine, Swansea University, Swansea, Wales, United Kingdom d.kelly@swansea.ac.uk s.l.kelly@swansea.ac.uk.
authors.forename: D E
authors.initials: DE
authors.lastname: Kelly
authors.affiliation: Centre for Cytochrome P450 Biodiversity, Institute of Life Science, College of Medicine, Swansea University, Swansea, Wales, United Kingdom d.kelly@swansea.ac.uk s.l.kelly@swansea.ac.uk.
authors.forename: S L
authors.initials: SL
authors.lastname: Kelly
mesh_terms: D058888:14-alpha Demethylase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry*; D000935:Antifungal Agents / Q000138:chemical synthesis / Q000737:chemistry*; D001665:Binding Sites; D002176:Candida albicans / Q000737:chemistry* / Q000201:enzymology; D065731:Cytochrome P-450 CYP2C19 / Q000737:chemistry; D065729:Cytochrome P-450 CYP2C9 / Q000737:chemistry; D051544:Cytochrome P-450 CYP3A / Q000737:chemistry; D057075:Enzyme Assays; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D005656:Fungal Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D015870:Gene Expression; D006801:Humans; D011485:Protein Binding; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry*; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics; D013045:Species Specificity; D058886:Sterol 14-Demethylase / Q000737:chemistry* / Q000235:genetics; D013777:Tetrazoles / Q000138:chemical synthesis / Q000737:chemistry*; D065819:Voriconazole / Q000737:chemistry
chemical_list: D058888:14-alpha Demethylase Inhibitors; D000935:Antifungal Agents; D005656:Fungal Proteins; D011725:Pyridines; D011994:Recombinant Proteins; D013777:Tetrazoles; C000599187:VT-1161; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D051544:Cytochrome P-450 CYP3A; D058886:Sterol 14-Demethylase; C510163:CYP3A4 protein, human; D065819:Voriconazole