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
Autor(a) principal: | |
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Data de Publicação: | 2015 |
Outros Autores: | , , , , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Institucional da FIOCRUZ (ARCA) |
Texto Completo: | https://www.arca.fiocruz.br/handle/icict/29637 |
Resumo: | Viamet Pharmaceuticals, Inc.. Durham, North Carolina, USA. |
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Hoekstra, William J.Hargrove, Tatiana Y,Wawrzak, ZdzislawBatista, Denis D. GSilva, Cristiane F. daNefertiti, Aline S. G.Rachakonda, GirishSchotzinger, Robert J.Villalta, FernandoSoeiro, Maria Nazaré C.Lepesheva, Galina I.2018-10-18T17:50:07Z2018-10-18T17:50:07Z2015HOEKSTRA, 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. 2018.0066-4804https://www.arca.fiocruz.br/handle/icict/2963710.1128/AAC.02287-151098-6596engAmerican Society for MicrobiologyDoença de ChagasTrypanosoma cruziinibiçãoEstrutura de raios-xdesign de drogas baseado em estruturaChagas DiseaseTrypanosoma cruziVT-1161sterol 14α-demethylase (CYP51)inhibitionX-ray structurestructure-based drug designAntiparasitic 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-1161info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleViamet 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.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 chemotherapyinfo:eu-repo/semantics/openAccessreponame:Repositório Institucional da FIOCRUZ (ARCA)instname:Fundação Oswaldo Cruz (FIOCRUZ)instacron:FIOCRUZLICENSElicense.txtlicense.txttext/plain; charset=utf-82991https://www.arca.fiocruz.br/bitstream/icict/29637/1/license.txt5a560609d32a3863062d77ff32785d58MD51ORIGINALmarianazare_soeiro_etal_IOC_2015.pdfmarianazare_soeiro_etal_IOC_2015.pdfapplication/pdf6580780https://www.arca.fiocruz.br/bitstream/icict/29637/2/marianazare_soeiro_etal_IOC_2015.pdf9b5ff1419ae11b3d3015760bd97ec6d1MD52TEXTmarianazare_soeiro_etal_IOC_2015.pdf.txtmarianazare_soeiro_etal_IOC_2015.pdf.txtExtracted 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dc.title.pt_BR.fl_str_mv |
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 |
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 |
spellingShingle |
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 Hoekstra, William J. Doença de Chagas Trypanosoma cruzi inibição Estrutura de raios-x design de drogas baseado em estrutura Chagas Disease Trypanosoma cruzi VT-1161 sterol 14α-demethylase (CYP51) inhibition X-ray structure structure-based drug design |
title_short |
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 |
title_full |
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 |
title_fullStr |
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 |
title_full_unstemmed |
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 |
title_sort |
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 |
author |
Hoekstra, William J. |
author_facet |
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. |
author_role |
author |
author2 |
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. |
author2_role |
author author author author author author author author author author |
dc.contributor.author.fl_str_mv |
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. |
dc.subject.other.pt_BR.fl_str_mv |
Doença de Chagas Trypanosoma cruzi inibição Estrutura de raios-x design de drogas baseado em estrutura |
topic |
Doença de Chagas Trypanosoma cruzi inibição Estrutura de raios-x design de drogas baseado em estrutura Chagas Disease Trypanosoma cruzi VT-1161 sterol 14α-demethylase (CYP51) inhibition X-ray structure structure-based drug design |
dc.subject.en.pt_BR.fl_str_mv |
Chagas Disease Trypanosoma cruzi VT-1161 sterol 14α-demethylase (CYP51) inhibition X-ray structure structure-based drug design |
description |
Viamet Pharmaceuticals, Inc.. Durham, North Carolina, USA. |
publishDate |
2015 |
dc.date.issued.fl_str_mv |
2015 |
dc.date.accessioned.fl_str_mv |
2018-10-18T17:50:07Z |
dc.date.available.fl_str_mv |
2018-10-18T17:50:07Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.citation.fl_str_mv |
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. |
dc.identifier.uri.fl_str_mv |
https://www.arca.fiocruz.br/handle/icict/29637 |
dc.identifier.issn.pt_BR.fl_str_mv |
0066-4804 |
dc.identifier.doi.none.fl_str_mv |
10.1128/AAC.02287-15 |
dc.identifier.eissn.none.fl_str_mv |
1098-6596 |
identifier_str_mv |
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. 0066-4804 10.1128/AAC.02287-15 1098-6596 |
url |
https://www.arca.fiocruz.br/handle/icict/29637 |
dc.language.iso.fl_str_mv |
eng |
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eng |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
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openAccess |
dc.publisher.none.fl_str_mv |
American Society for Microbiology |
publisher.none.fl_str_mv |
American Society for Microbiology |
dc.source.none.fl_str_mv |
reponame:Repositório Institucional da FIOCRUZ (ARCA) instname:Fundação Oswaldo Cruz (FIOCRUZ) instacron:FIOCRUZ |
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