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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
Author
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.
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.
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