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.
Antimicrob Agents Chemother
; 60(2): 1058-66, 2016 Feb.
Article
em En
| MEDLINE
| ID: mdl-26643331
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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Piridinas
/
Tetrazóis
/
Tripanossomicidas
/
Trypanosoma cruzi
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Esterol 14-Desmetilase
/
Inibidores de 14-alfa Desmetilase
Limite:
Animals
Idioma:
En
Revista:
Antimicrob Agents Chemother
Ano de publicação:
2016
Tipo de documento:
Article
País de afiliação:
Estados Unidos