The Clinical Candidate VT-1161 Is a Highly Potent Inhibitor of Candida albicans CYP51 but Fails To Bind the Human Enzyme
Open accessAbstract
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 [ K d ], ≤39 nM) and similar to that of the pharmaceutical azole antifungals ( K d , ≤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.
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Oteseconazole belongs to the tetrazole class, a new generation of oral lanosterol 14α-demethylase inhibitors with higher specificity for fungal CYP51 and theoretically less cross-inhibition of mammalian CYP enzymes, leading to fewer drug-drug interactions and adverse effects.
“Oteseconazole (VT-1161), developed by Mycovia Pharmaceuticals, belongs to the tetrazole class, a new generation of oral lanosterol 14⍺-demethylase inhibitors which boast higher specificity for fungal CYP51 and therefore theoretically less cross-inhibition of mammalian CYP enzymes leading to fewer drug–drug interactions and adverse effects [42].”
From Investigational Agents for the Treatment of Resistant Yeasts and Molds (2021) · cites this paper as [42]
Repeated use of fluconazole increases risk for the development of resistant strains.
“Repeated use of fluconazole also increases risk for the development of resistant strains.13,18,26”
From Clinical challenges in diagnosis and treatment of recurrent vulvovaginal candidiasis (2022) · cites this paper as [26]
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- Authors
- Warrilow, A. G. S., Hull, C. M., Parker, J. E., Garvey, E. P., Hoekstra, W. J., Moore, W. R., Schotzinger, R. J., Kelly, D. E., & Kelly, S. L.
- Affiliations
- Swansea University (GB)
- Viamet Pharmaceuticals (United States) (US)
- Venue
- Antimicrobial Agents and Chemotherapy
- Publisher
- American Society for Microbiology
- Published
- 2014-12
- Volume
- 58
- Issue
- 12
- Pages
- 7121-7127
- ISSN
- 0066-4804 (ISSN-L)
- 1098-6596
- PMC
- PMC4249504
- OpenAlex
- W1984612322
- Cited by
- 173
- References
- 41
- Citations by year
- 2026: 11 · 2025: 15 · 2024: 18 · 2023: 20 · 2022: 14 · 2021: 21 · 2020: 14 · 2019: 10 · 2018: 12 · 2017: 16 · 2016: 14 · 2015: 8
- FWCI
- 8.90
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Antimicrobial Agents and Chemotherapy (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Swansea University
- Engineering and Physical Sciences Research Council
- Topics
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Life Sciences › Agricultural and Biological Sciences › Ecology, Evolution, Behavior and Systematics › Fungal Plant Pathogen Control
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Keywords
- Candida albicans, CYP51, ERG11, cytochrome P450 inhibition, azole antifungals, enzyme selectivity, drug-drug interactions, CYP2C9, CYP2C19, CYP3A4, ergosterol, heme iron coordination, antifungal agents
- MeSH terms
- Antifungal Agents, Binding Sites, Candida albicans, Escherichia coli, Fungal Proteins, Humans, Protein Binding, Pyridines, Recombinant Proteins, Species Specificity, Tetrazoles, Gene Expression, Cytochrome P-450 CYP3A, Enzyme Assays, Sterol 14-Demethylase, 14-alpha Demethylase Inhibitors, Cytochrome P-450 CYP2C9, Cytochrome P-450 CYP2C19, Voriconazole
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