ArticleAntimicrobial agents and chemotherapy2016
Clinical Candidate VT-1161's Antiparasitic Effect In Vitro, Activity in a Murine Model of Chagas Disease, and Structural Characterization in Complex with the Target Enzyme CYP51 from Trypanosoma cruzi.
Article in Antimicrobial agents and chemotherapy, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed.
- Identification of Potent and Selective Inhibitors ofJournal of medicinal chemistry · 2024Article
- Review on Experimental Treatment Strategies AgainstJournal of experimental pharmacology · 2021Review
- Azole derivatives with naphthalene showing potent antifungal effects against planktonic and biofilm forms of Candida spp.: an in vitro and in silico study.International microbiology : the official journal of the Spanish Society for Microbiology · 2021Article
- Advances in preclinical approaches to Chagas disease drug discovery.Expert opinion on drug discovery · 2019Review
- Repurposing of terconazole as an antiHeliyon · 2019Article
- Successful Aspects of the Coadministration of Sterol 14α-Demethylase Inhibitor VFV and Benznidazole in Experimental Mouse Models of Chagas Disease Caused by the Drug-Resistant Strain of Trypanosoma cruzi.ACS infectious diseases · 2019Article
- Azole Resistance Reduces Susceptibility to the Tetrazole Antifungal VT-1161.Antimicrobial agents and chemotherapy · 2019Article
- CYP51 as drug targets for fungi and protozoan parasites: past, present and future.Parasitology · 2018Review
- Crystal Structures of Full-Length Lanosterol 14α-Demethylases of Prominent Fungal Pathogens Candida albicans and Candida glabrata Provide Tools for Antifungal Discovery.Antimicrobial agents and chemotherapy · 2018Article
- Discovery and Genetic Validation of Chemotherapeutic Targets for Chagas' Disease.Frontiers in cellular and infection microbiology · 2018Review
- Crystal Structure of the New Investigational Drug Candidate VT-1598 in Complex with Aspergillus fumigatus Sterol 14α-Demethylase Provides Insights into Its Broad-Spectrum Antifungal Activity.Antimicrobial agents and chemotherapy · 2017Article
- Structural analyses ofThe Journal of biological chemistry · 2017Article
- Chagas disease research and development: Is there light at the end of the tunnel?Computational and structural biotechnology journal · 2017Review
- Triazole resistance mediated by mutations of a conserved active site tyrosine in fungal lanosterol 14α-demethylase.Scientific reports · 2016Article
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11 authors.
Funding
Abstract
A novel antifungal drug candidate, the 1-tetrazole-based agent VT-1161 [(R)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-{5-[4-(2,2,2-trifluoroethoxy)phenyl]pyridin-2-yl}propan-2-ol], which is currently in two phase 2b antifungal clinical trials, was found to be a tight-binding ligand (apparent dissociation constant [Kd], 24 nM) and a potent inhibitor of cytochrome P450 sterol 14α-demethylase (CYP51) from the protozoan pathogen Trypanosoma cruzi. Moreover, VT-1161 revealed a high level of antiparasitic activity against amastigotes of the Tulahuen strain of T. cruzi in cellular experiments (50% effective concentration, 2.5 nM) and was active in vivo, causing >99.8% suppression of peak parasitemia in a mouse model of infection with the naturally drug-resistant Y strain of the parasite. The data strongly support the potential utility of VT-1161 in the treatment of Chagas disease. The structural characterization of T. cruzi CYP51 in complex with VT-1161 provides insights into the molecular basis for the compound's inhibitory potency and paves the way for the further rational development of this novel, tetrazole-based inhibitory chemotype both for antiprotozoan chemotherapy and for antifungal chemotherapy.
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