Please use this identifier to cite or link to this item: https://www.arca.fiocruz.br/handle/icict/23847
Title: 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
Authors: Hoekstra, William J.
Hargrove, Tatiana Y.
Wawrzak, Zdzislaw
Batista, Denise da Gama Jaen
Silva, Cristiane F. da
Nefertiti, Aline S. G.
Rachakonda, Girish
Schotzinger, Robert J.
Villalta, Fernando
Soeiro, Maria de 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 / Vanderbilt University. Center for Structural Biology. Nashville, Tennessee, USA.
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.
Keywords: Chagas Disease
Trypanosoma cruzi
VT-1161
Treatment
Murine Model
Target Enzyme CYP51
keywords: Doença de Chagas
Trypanosoma cruzi
Tratamento
Meidcamentos Antifúngicos
Issue Date: 2016
Publisher: American Society for Microbiology
Citation: HOEKSTRA, William J. et al. 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. Antimicrobial Agents and Chemotherapy, v.60, n.2, p.1058-1066, Feb. 2016.
DOI: 10.1128/AAC.02287-15
ISSN: 0066-4804
Copyright: open access
Appears in Collections:IOC - Artigos de Periódicos

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