| Author | Hoekstra, William J. | |
| Author | Hargrove, Tatiana Y, | |
| Author | Wawrzak, Zdzislaw | |
| Author | Batista, Denis D. G | |
| Author | Silva, Cristiane F. da | |
| Author | Nefertiti, Aline S. G. | |
| Author | Rachakonda, Girish | |
| Author | Schotzinger, Robert J. | |
| Author | Villalta, Fernando | |
| Author | Soeiro, Maria Nazaré C. | |
| Author | Lepesheva, Galina I. | |
| Access date | 2018-10-18T17:50:07Z | |
| Available date | 2018-10-18T17:50:07Z | |
| Document date | 2015 | |
| 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. | pt_BR |
| ISSN | 0066-4804 | pt_BR |
| URI | https://www.arca.fiocruz.br/handle/icict/29637 | |
| 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 | inibição | pt_BR |
| Subject in Portuguese | Estrutura de raios-x | pt_BR |
| Subject in Portuguese | design de drogas baseado em estrutura | pt_BR |
| 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 | pt_BR |
| Type | Article | |
| DOI | 10.1128/AAC.02287-15 | |
| 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 | 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 / Center for Structural Biology Vanderbilt University. Nashville, Tenessee, USA. | pt_BR |
| Subject | Chagas Disease | pt_BR |
| Subject | Trypanosoma cruzi | pt_BR |
| Subject | VT-1161 | pt_BR |
| Subject | sterol 14α-demethylase (CYP51) | pt_BR |
| Subject | inhibition | pt_BR |
| Subject | X-ray structure | pt_BR |
| Subject | structure-based drug design | pt_BR |
| e-ISSN | 1098-6596 | |
| xmlui.metadata.dc.subject.ods | 03 Saúde e Bem-Estar | |
