Preclinical development of kinetin as a safe error-prone SARS-CoV-2 antiviral able to attenuate virus-induced inflammation
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Data de Publicação: | 2023 |
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/56575 |
Resumo: | Open Access: This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
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Souza, Thiago Moreno L.Pinho, Vagner D.Setim, Cristina F.Sacramento, Carolina Q.Marcon, RodrigoRodrigues, Natalia FintelmanChaves, Otavio A.Heller, MelinaTemerozo, Jairo RamosFerreira, André C.Mattos, MayaraMomo, Patrícia B.Dias, Suelen S. G.Gesto, João S. M.Dutra, Filipe PereiraViola, João P. B.Queiroz Junior, Celso MartinsGuimarães, Lays CordeiroChaves, Ian MeiraGuimarães, Pedro Pires GoulartCosta, Vivian VasconcelosTeixeira, Mauro MartinsBou-Habib, Dumith ChequerBozza, Patrícia TorresAguillón, Anderson R.Siqueira Junior, JarbasMacedo Junior, SergioAndrade, Edineia L.Fadanni, Guilherme P.Tolouei, Sara E. L.Potrich, Francine B.Santos, Adara A.Marques, Naiani F.Calixto, João B.Rabi, Jaime A.2023-01-24T13:50:56Z2023-01-24T13:50:56Z2023SOUZA, Thiago Moreno L. et al. Preclinical development of kinetin as a safe error-prone SARS-CoV-2 antiviral able to attenuate virus-induced inflammation. Nature Communications, v. 14, n. 199, p. 1-17, 2023.https://www.arca.fiocruz.br/handle/icict/5657510.1038/s41467-023-35928-zOpen Access: This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.O artigo trata do desenvolvimento de um antiviral de uso oral contra a Covid-19. A substância, batizada de MB-905, foi purificada a partir da cinetina e demonstrou-se eficaz para inibir a replicação do Sars-CoV-2 em linhagens de células humanas hepáticas e pulmonares, além de auxiliar a frear o processo inflamatório desencadeado pelo vírus.Orally available antivirals against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are necessary because of the continuous circulation of new variants that challenge immunized individuals. Because severe COVID- 19 is a virus-triggered immune and inflammatory dysfunction, molecules endowed with both antiviral and anti-inflammatory activity are highly desirable. We identified here that kinetin (MB-905) inhibits the in vitro replication of SARS-CoV-2 in human hepatic and pulmonary cell lines. On infected monocytes, MB-905 reduced virus replication, IL-6 and TNFα levels. MB-905 is converted into its triphosphate nucleotide to inhibit viral RNA synthesis and induce error-prone virus replication. Coinhibition of SARS-CoV-2 exonuclease, a proofreading enzyme that corrects erroneously incorporated nucleotides during viral RNA replication, potentiated the inhibitory effect of MB-905. MB- 905 shows good oral absorption, its metabolites are stable, achieving longlasting plasma and lung concentrations, and this drug is not mutagenic nor cardiotoxic in acute and chronic treatments. SARS-CoV-2-infected hACE-mice and hamsters treated with MB-905 show decreased viral replication, lung necrosis, hemorrhage and inflammation. Because kinetin is clinically investigated for a rare genetic disease at regimens beyond the predicted concentrations of antiviral/anti-inflammatory inhibition, our investigation suggests the opportunity for the rapid clinical development of a new antiviral substance for the treatment of COVID-19.The authors are grateful to the Hemotherapy Service of the Hospital Clementino Fraga Filho (Federal University of Rio de Janeiro, Brazil) for providing buffy coats. We thank Fiocruz and INCa for the use of the cellular and animal biosafety level 3 platforms, respectively. Thanks are also due to the animal biosafety level 3 laboratory at UFMG (Laboratório Institucional de Pesquisa, LIPq); Centro de Laboratórios Multiusuários, CELAM; Laboratório de Biossegurança Nível 3, NB3-ICB. The authors also acknowledge Patricia Machado Rodrigues e Silva Martins and Tatiana Paula Teixeira Ferreira from Fiocruz for the microphotograph analysis. We thank Dr. Ester Sabino and Brazil-UK Center for Arbovirus Discovery Diagnosis Genomics and Epidemiology (CADDE) Genomic Network - Instituto de Medicina Tropical, for donating the P1 VoC. National Institutes of Science and Technology Program (INCT) on Diseases of Neglected Populations (INCT-IDPN, # 465313/2014-0), on Innovation in Medicines and Identification of New Therapeutics Targets (INCT-INOVAMED), on Neuroimmunomodulation (INCT/NIM) and on Dengue and Host-microorganism Interaction (INCT dengue). Universidade Federal de Minas Gerais (UFMG). All authors thank Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, Finance Code 403543/ 2020-7), Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ, Finance Code E-26/210.775/2021), Minas Gerais Foundation for Science (FAPEMIG), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) and Empresa Brasileira de Pesquisa e Inovação Industrial (Embrapii; finance code 015/2020). TMLS, JBC, and JR acknowledge the Rede Virus and Dr. Marcelo M. Morales from Ministry of Science, Technology, and Innovation (MCTI).Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Imunofarmacologia. Rio de Janeiro, RJ, Brasil / Fundação Oswaldo Cruz. Centro de Desenvolvimento Tecnológico em Saúde. Rio de Janeiro, RJ, Brasil.Microbiológica Química e Farmacêutica Doutor Nicanor. Rio de Janeiro, RJ, Brasil.Instituto Nacional de Ciência e Tecnologia sobre Inovação em Medicamentos e Identificação de Novas Terapêuticas. Centro de Inovação e Ensaios Pré-clínicos. Florianópolis, SC, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Imunofarmacologia. Rio de Janeiro, RJ, Brasil / Fundação Oswaldo Cruz. Centro de Desenvolvimento Tecnológico em Saúde. Rio de Janeiro, RJ, Brasil.Instituto Nacional de Ciência e Tecnologia sobre Inovação em Medicamentos e Identificação de Novas Terapêuticas. Centro de Inovação e Ensaios Pré-clínicos. Florianópolis, SC, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Imunofarmacologia. Rio de Janeiro, RJ, Brasil / Fundação Oswaldo Cruz. Centro de Desenvolvimento Tecnológico em Saúde. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Imunofarmacologia. Rio de Janeiro, RJ, Brasil / Fundação Oswaldo Cruz. Centro de Desenvolvimento Tecnológico em Saúde. Rio de Janeiro, RJ, Brasil.Instituto Nacional de Ciência e Tecnologia sobre Inovação em Medicamentos e Identificação de Novas Terapêuticas. Centro de Inovação e Ensaios Pré-clínicos. Florianópolis, SC, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Imunofarmacologia. Rio de Janeiro, RJ, Brasil / Instituto Nacional de Ciência e Tecnologia em Neuroimunomodulação. Rio de Janeiro, RJ, Brasil / Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Imunofarmacologia. Rio de Janeiro, RJ, Brasil / Fundação Oswaldo Cruz. Centro de Desenvolvimento Tecnológico em Saúde. Rio de Janeiro, RJ, Brasil / Universidade Iguaçu. Nova Iguaçu, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Imunofarmacologia. Rio de Janeiro, RJ, Brasil / Fundação Oswaldo Cruz. Centro de Desenvolvimento Tecnológico em Saúde. Rio de Janeiro, RJ, Brasil.Microbiológica Química e Farmacêutica Doutor Nicanor. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Imunofarmacologia. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Imunofarmacologia. Rio de Janeiro, RJ, Brasil / Fundação Oswaldo Cruz. Centro de Desenvolvimento Tecnológico em Saúde. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Imunofarmacologia. Rio de Janeiro, RJ, Brasil.Instituto Nacional do Câncer. Programa de Imunologia e Biologia Tumoral. Rio de Janeiro, RJ, Brasil.Universidade Federal de Minas Gerais. Instituto de Ciências Biológicas. Centro de Pesquisa e Desenvolvimento de Fármacos. Belo Horizonte, MG, Brasil.Universidade Federal de Minas Gerais. Instituto de Ciências Biológicas. Departamento de Fisiologia e Biofísica. Belo Horizonte, MG, Brasil.Universidade Federal de Minas Gerais. Instituto de Ciências Biológicas. Centro de Pesquisa e Desenvolvimento de Fármacos. Belo Horizonte, MG, Brasil.Universidade Federal de Minas Gerais. Instituto de Ciências Biológicas. Centro de Pesquisa e Desenvolvimento de Fármacos. Belo Horizonte, MG, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Pesquisa sobre o Timo. Rio de Janeiro, RJ, Brasil / Instituto Nacional de Ciência e Tecnologia em Neuroimunomodulação. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Imunofarmacologia. Rio de Janeiro, RJ, Brasil.Microbiológica Química e Farmacêutica Doutor Nicanor. Rio de Janeiro, RJ, Brasil.Instituto Nacional de Ciência e Tecnologia sobre Inovação em Medicamentos e Identificação de Novas Terapêuticas. Centro de Inovação e Ensaios Pré-clínicos. Florianópolis, SC, Brasil.Instituto Nacional de Ciência e Tecnologia sobre Inovação em Medicamentos e Identificação de Novas Terapêuticas. Centro de Inovação e Ensaios Pré-clínicos. Florianópolis, SC, Brasil.Instituto Nacional de Ciência e Tecnologia sobre Inovação em Medicamentos e Identificação de Novas Terapêuticas. Centro de Inovação e Ensaios Pré-clínicos. Florianópolis, SC, Brasil.Instituto Nacional de Ciência e Tecnologia sobre Inovação em Medicamentos e Identificação de Novas Terapêuticas. Centro de Inovação e Ensaios Pré-clínicos. Florianópolis, SC, Brasil.Instituto Nacional de Ciência e Tecnologia sobre Inovação em Medicamentos e Identificação de Novas Terapêuticas. Centro de Inovação e Ensaios Pré-clínicos. Florianópolis, SC, Brasil.Instituto Nacional de Ciência e Tecnologia sobre Inovação em Medicamentos e Identificação de Novas Terapêuticas. Centro de Inovação e Ensaios Pré-clínicos. Florianópolis, SC, Brasil.Instituto Nacional de Ciência e Tecnologia sobre Inovação em Medicamentos e Identificação de Novas Terapêuticas. Centro de Inovação e Ensaios Pré-clínicos. Florianópolis, SC, Brasil.Instituto Nacional de Ciência e Tecnologia sobre Inovação em Medicamentos e Identificação de Novas Terapêuticas. Centro de Inovação e Ensaios Pré-clínicos. Florianópolis, SC, Brasil.Instituto Nacional de Ciência e Tecnologia sobre Inovação em Medicamentos e Identificação de Novas Terapêuticas. Centro de Inovação e Ensaios Pré-clínicos. Florianópolis, SC, Brasil.Microbiológica Química e Farmacêutica Doutor Nicanor. Rio de Janeiro, RJ, Brasil.engNatureCOVID-19SARS-CoV-2Antiviral AgentsKinetinCOVID-19SARS-CoV-2AntiviralMB-905Virus-induced inflammationKinetinCOVID-19SARS-CoV-2Antiviral AgentsKinetinPreclinical development of kinetin as a safe error-prone SARS-CoV-2 antiviral able to attenuate virus-induced inflammationinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleinfo: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/56575/1/license.txt5a560609d32a3863062d77ff32785d58MD51ORIGINALPreclinical_SARS_COV_2.pdfPreclinical_SARS_COV_2.pdfapplication/pdf4815817https://www.arca.fiocruz.br/bitstream/icict/56575/3/Preclinical_SARS_COV_2.pdf932d3795588aedeb833874d842022e48MD53icict/565752023-09-04 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dc.title.en_US.fl_str_mv |
Preclinical development of kinetin as a safe error-prone SARS-CoV-2 antiviral able to attenuate virus-induced inflammation |
title |
Preclinical development of kinetin as a safe error-prone SARS-CoV-2 antiviral able to attenuate virus-induced inflammation |
spellingShingle |
Preclinical development of kinetin as a safe error-prone SARS-CoV-2 antiviral able to attenuate virus-induced inflammation Souza, Thiago Moreno L. COVID-19 SARS-CoV-2 Antiviral Agents Kinetin COVID-19 SARS-CoV-2 Antiviral MB-905 Virus-induced inflammation Kinetin COVID-19 SARS-CoV-2 Antiviral Agents Kinetin |
title_short |
Preclinical development of kinetin as a safe error-prone SARS-CoV-2 antiviral able to attenuate virus-induced inflammation |
title_full |
Preclinical development of kinetin as a safe error-prone SARS-CoV-2 antiviral able to attenuate virus-induced inflammation |
title_fullStr |
Preclinical development of kinetin as a safe error-prone SARS-CoV-2 antiviral able to attenuate virus-induced inflammation |
title_full_unstemmed |
Preclinical development of kinetin as a safe error-prone SARS-CoV-2 antiviral able to attenuate virus-induced inflammation |
title_sort |
Preclinical development of kinetin as a safe error-prone SARS-CoV-2 antiviral able to attenuate virus-induced inflammation |
author |
Souza, Thiago Moreno L. |
author_facet |
Souza, Thiago Moreno L. Pinho, Vagner D. Setim, Cristina F. Sacramento, Carolina Q. Marcon, Rodrigo Rodrigues, Natalia Fintelman Chaves, Otavio A. Heller, Melina Temerozo, Jairo Ramos Ferreira, André C. Mattos, Mayara Momo, Patrícia B. Dias, Suelen S. G. Gesto, João S. M. Dutra, Filipe Pereira Viola, João P. B. Queiroz Junior, Celso Martins Guimarães, Lays Cordeiro Chaves, Ian Meira Guimarães, Pedro Pires Goulart Costa, Vivian Vasconcelos Teixeira, Mauro Martins Bou-Habib, Dumith Chequer Bozza, Patrícia Torres Aguillón, Anderson R. Siqueira Junior, Jarbas Macedo Junior, Sergio Andrade, Edineia L. Fadanni, Guilherme P. Tolouei, Sara E. L. Potrich, Francine B. Santos, Adara A. Marques, Naiani F. Calixto, João B. Rabi, Jaime A. |
author_role |
author |
author2 |
Pinho, Vagner D. Setim, Cristina F. Sacramento, Carolina Q. Marcon, Rodrigo Rodrigues, Natalia Fintelman Chaves, Otavio A. Heller, Melina Temerozo, Jairo Ramos Ferreira, André C. Mattos, Mayara Momo, Patrícia B. Dias, Suelen S. G. Gesto, João S. M. Dutra, Filipe Pereira Viola, João P. B. Queiroz Junior, Celso Martins Guimarães, Lays Cordeiro Chaves, Ian Meira Guimarães, Pedro Pires Goulart Costa, Vivian Vasconcelos Teixeira, Mauro Martins Bou-Habib, Dumith Chequer Bozza, Patrícia Torres Aguillón, Anderson R. Siqueira Junior, Jarbas Macedo Junior, Sergio Andrade, Edineia L. Fadanni, Guilherme P. Tolouei, Sara E. L. Potrich, Francine B. Santos, Adara A. Marques, Naiani F. Calixto, João B. Rabi, Jaime A. |
author2_role |
author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author |
dc.contributor.author.fl_str_mv |
Souza, Thiago Moreno L. Pinho, Vagner D. Setim, Cristina F. Sacramento, Carolina Q. Marcon, Rodrigo Rodrigues, Natalia Fintelman Chaves, Otavio A. Heller, Melina Temerozo, Jairo Ramos Ferreira, André C. Mattos, Mayara Momo, Patrícia B. Dias, Suelen S. G. Gesto, João S. M. Dutra, Filipe Pereira Viola, João P. B. Queiroz Junior, Celso Martins Guimarães, Lays Cordeiro Chaves, Ian Meira Guimarães, Pedro Pires Goulart Costa, Vivian Vasconcelos Teixeira, Mauro Martins Bou-Habib, Dumith Chequer Bozza, Patrícia Torres Aguillón, Anderson R. Siqueira Junior, Jarbas Macedo Junior, Sergio Andrade, Edineia L. Fadanni, Guilherme P. Tolouei, Sara E. L. Potrich, Francine B. Santos, Adara A. Marques, Naiani F. Calixto, João B. Rabi, Jaime A. |
dc.subject.mesh.en_US.fl_str_mv |
COVID-19 SARS-CoV-2 Antiviral Agents Kinetin |
topic |
COVID-19 SARS-CoV-2 Antiviral Agents Kinetin COVID-19 SARS-CoV-2 Antiviral MB-905 Virus-induced inflammation Kinetin COVID-19 SARS-CoV-2 Antiviral Agents Kinetin |
dc.subject.en.en_US.fl_str_mv |
COVID-19 SARS-CoV-2 Antiviral MB-905 Virus-induced inflammation Kinetin |
dc.subject.decs.en_US.fl_str_mv |
COVID-19 SARS-CoV-2 Antiviral Agents Kinetin |
description |
Open Access: This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
publishDate |
2023 |
dc.date.accessioned.fl_str_mv |
2023-01-24T13:50:56Z |
dc.date.available.fl_str_mv |
2023-01-24T13:50:56Z |
dc.date.issued.fl_str_mv |
2023 |
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 |
SOUZA, Thiago Moreno L. et al. Preclinical development of kinetin as a safe error-prone SARS-CoV-2 antiviral able to attenuate virus-induced inflammation. Nature Communications, v. 14, n. 199, p. 1-17, 2023. |
dc.identifier.uri.fl_str_mv |
https://www.arca.fiocruz.br/handle/icict/56575 |
dc.identifier.doi.none.fl_str_mv |
10.1038/s41467-023-35928-z |
identifier_str_mv |
SOUZA, Thiago Moreno L. et al. Preclinical development of kinetin as a safe error-prone SARS-CoV-2 antiviral able to attenuate virus-induced inflammation. Nature Communications, v. 14, n. 199, p. 1-17, 2023. 10.1038/s41467-023-35928-z |
url |
https://www.arca.fiocruz.br/handle/icict/56575 |
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 |
Nature |
publisher.none.fl_str_mv |
Nature |
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/56575/1/license.txt https://www.arca.fiocruz.br/bitstream/icict/56575/3/Preclinical_SARS_COV_2.pdf |
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repository.name.fl_str_mv |
Repositório Institucional da FIOCRUZ (ARCA) - Fundação Oswaldo Cruz (FIOCRUZ) |
repository.mail.fl_str_mv |
repositorio.arca@fiocruz.br |
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1813009179443462144 |