| Author | Hoekstra, William J. | |
| Author | Hargrove, Tatiana Y. | |
| Author | Wawrzak, Zdzislaw | |
| Author | Batista, Denise da Gama Jaen | |
| Author | Silva, Cristiane F. da | |
| Author | Nefertiti, Aline S. G. | |
| Author | Rachakonda, Girish | |
| Author | Schotzinger, Robert J. | |
| Author | Villalta, Fernando | |
| Author | Soeiro, Maria de Nazaré C. | |
| Author | Lepesheva, Galina I. | |
| Access date | 2018-01-02T16:44:44Z | |
| Available date | 2018-01-02T16:44:44Z | |
| Document date | 2016 | |
| 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. | pt_BR |
| ISSN | 0066-4804 | pt_BR |
| URI | https://www.arca.fiocruz.br/handle/icict/23847 | |
| Language | eng | pt_BR |
| Publisher | American Society for Microbiology | pt_BR |
| Rights | open access | |
| Subject in Portuguese | Doença de Chagas | pt_BR |
| Subject in Portuguese | Trypanosoma cruzi | pt_BR |
| Subject in Portuguese | Tratamento | pt_BR |
| Subject in Portuguese | Meidcamentos Antifúngicos | pt_BR |
| 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 | pt_BR |
| Type | Article | |
| DOI | 10.1128/AAC.02287-15 | |
| 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. | pt_BR |
| Affilliation | Viamet Pharmaceuticals, Inc.. Durham, North Carolina, USA.; | pt_BR |
| Affilliation | Vanderbilt University School of Medicine. Department of Biochemistry. Nashville, Tennessee, USA. | pt_BR |
| Affilliation | Northwestern University. Life Science Collaborative Access Team. Synchrotron Research Center. Argonne, Illinois, USA. | pt_BR |
| Affilliation | Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular Rio de Janeiro, RJ. Brasil. | pt_BR |
| Affilliation | Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular Rio de Janeiro, RJ. Brasil. | pt_BR |
| Affilliation | Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular Rio de Janeiro, RJ. Brasil. | pt_BR |
| Affilliation | Meharry Medical College. Department of Microbiology and Immunology. Nashville, Tennessee, USA. | pt_BR |
| Affilliation | Viamet Pharmaceuticals, Inc.. Durham, North Carolina, USA.; | pt_BR |
| Affilliation | Meharry Medical College. Department of Microbiology and Immunology. Nashville, Tennessee, USA. | pt_BR |
| Affilliation | Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular Rio de Janeiro, RJ. Brasil. | pt_BR |
| Affilliation | Vanderbilt University School of Medicine. Department of Biochemistry. Nashville, Tennessee, USA / Vanderbilt University. Center for Structural Biology. Nashville, Tennessee, USA. | pt_BR |
| Subject | Chagas Disease | pt_BR |
| Subject | Trypanosoma cruzi | pt_BR |
| Subject | VT-1161 | pt_BR |
| Subject | Treatment | pt_BR |
| Subject | Murine Model | pt_BR |
| Subject | Target Enzyme CYP51 | pt_BR |
| e-ISSN | 1098-6596 | |
| xmlui.metadata.dc.subject.ods | 03 Saúde e Bem-Estar | |
