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.; 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.

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

Detalhes bibliográficos
Autor(a) principal:	Hoekstra, William J.
Data de Publicação:	2015
Outros Autores:	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.
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.

Metadados do item

id	CRUZ_9c879273836fe8ffee1e3354575e0851
oai_identifier_str	oai:www.arca.fiocruz.br:icict/29637
network_acronym_str	CRUZ
network_name_str	Repositório Institucional da FIOCRUZ (ARCA)
repository_id_str	2135
spelling	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 texttext/plain54477https://www.arca.fiocruz.br/bitstream/icict/29637/3/marianazare_soeiro_etal_IOC_2015.pdf.txt70723e5bccc88611e2c0fd35fb2c753dMD53icict/296372018-10-19 02:00:59.312oai:www.arca.fiocruz.br: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ório InstitucionalPUBhttps://www.arca.fiocruz.br/oai/requestrepositorio.arca@fiocruz.bropendoar:21352018-10-19T05:00:59Repositório Institucional da FIOCRUZ (ARCA) - Fundação Oswaldo Cruz (FIOCRUZ)false
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
language	eng
dc.rights.driver.fl_str_mv	info:eu-repo/semantics/openAccess
eu_rights_str_mv	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
instname_str	Fundação Oswaldo Cruz (FIOCRUZ)
instacron_str	FIOCRUZ
institution	FIOCRUZ
reponame_str	Repositório Institucional da FIOCRUZ (ARCA)
collection	Repositório Institucional da FIOCRUZ (ARCA)
bitstream.url.fl_str_mv	https://www.arca.fiocruz.br/bitstream/icict/29637/1/license.txt https://www.arca.fiocruz.br/bitstream/icict/29637/2/marianazare_soeiro_etal_IOC_2015.pdf https://www.arca.fiocruz.br/bitstream/icict/29637/3/marianazare_soeiro_etal_IOC_2015.pdf.txt
bitstream.checksum.fl_str_mv	5a560609d32a3863062d77ff32785d58 9b5ff1419ae11b3d3015760bd97ec6d1 70723e5bccc88611e2c0fd35fb2c753d
bitstream.checksumAlgorithm.fl_str_mv	MD5 MD5 MD5
repository.name.fl_str_mv	Repositório Institucional da FIOCRUZ (ARCA) - Fundação Oswaldo Cruz (FIOCRUZ)
repository.mail.fl_str_mv	repositorio.arca@fiocruz.br
_version_	1798324964117446656

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

Registros relacionados