Please use this identifier to cite or link to this item: https://www.arca.fiocruz.br/handle/icict/29637
Title: 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 of the potent clinical candidate VT-1161
Authors: Hoekstra, William J.
Hargrove, Tatiana Y,
Wawrzak, Zdzislaw
Batista, Denis D. G
Silva, Cristiane F. da
Nefertiti, Aline S. G.
Rachakonda, Girish
Schotzinger, Robert J.
Villalta, Fernando
Soeiro, Maria Nazaré C.
Lepesheva, Galina I.
Affilliation: Viamet Pharmaceuticals, Inc.. Durham, North Carolina, USA.
Vanderbilt University School of Medicine. Department of Biochemistry. Nashville, Tennessee, USA.
Northwestern University. Life Science Collaborative Access Team. Synchrotron Research Center. Argonne, Illinois, USA.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ. Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ. Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ. Brasil.
Meharry Medical College. Department of Microbiology and Immunology. Nashville, Tennessee, USA.
Viamet Pharmaceuticals, Inc.. Durham, North Carolina, USA.
Meharry Medical College. Department of Microbiology and Immunology. Nashville, Tennessee, USA.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ. Brasil.
Vanderbilt University School of Medicine. Department of Biochemistry. Nashville, Tennessee, USA / Center for Structural Biology Vanderbilt University. Nashville, Tenessee, USA.
Abstract: A novel antifungal drug candidate, 1-tetrazole 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 (the 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 high antiparasitic efficiency in cellular experiments against amastigotes of the Tulahuen strain of T. cruzi (EC50=2.5 nM) and was active in vivo, causing >99.8% of peak parasitemia suppression 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. Structural characterization of T. cruzi CYP51 in complex with VT-1161 provides insights into the molecular basis for the compound inhibitory potency and paves the way for further rational development of this novel, tetrazole-based inhibitory chemotype, both for antiprotozoan, and for antifungal chemotherapy
Keywords: Chagas Disease
Trypanosoma cruzi
VT-1161
sterol 14α-demethylase (CYP51)
inhibition
X-ray structure
structure-based drug design
keywords: Doença de Chagas
Trypanosoma cruzi
inibição
Estrutura de raios-x
design de drogas baseado em estrutura
Issue Date: 2015
Publisher: American Society for Microbiology
Citation: HOEKSTRA, William J. et al. 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 of the potent clinical candidate VT-1161. Antimicrob. Agents Chemother. On line Oct. 2018.
DOI: 10.1128/AAC.02287-15
ISSN: 0066-4804
Copyright: open access
Appears in Collections:IOC - Artigos de Periódicos

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