Commercially Available Flavonols Are Better SARS-CoV-2 Inhibitors than Isoflavone and Flavones
| Autor(a) principal: | |
|---|---|
| Data de Publicação: | 2022 |
| 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/54654 |
Resumo: | 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 em Inovação em Doenças Negligenciadas. Rio de Janeiro, RJ, Brasil. |
| id |
CRUZ_0a3d979e8249304cdf95d2d90ccc0c98 |
|---|---|
| oai_identifier_str |
oai:www.arca.fiocruz.br:icict/54654 |
| network_acronym_str |
CRUZ |
| network_name_str |
Repositório Institucional da FIOCRUZ (ARCA) |
| repository_id_str |
2135 |
| spelling |
Chaves, Otávio AugustoRodrigues, Natalia FintelmanWang, XuantingSacramento, Carolina Q.Temerozo, Jairo R.Ferreira, André C. .Mattos, MayaraDutra, Filipe PereiraBozza, PatríciaFaria Neto, Hugo Caire CastroRusso, James J.Ju, JingyueSouza, Thiago Moreno L.2022-08-16T12:50:02Z2022-08-16T12:50:02Z2022CHAVES, Otávio Augusto. Commercially Available Flavonols Are Better SARS-CoV-2 Inhibitors than Isoflavone and Flavones. Viruses, v. 14, 1458, p. 1 - 17, June 2022.1999-4915https://www.arca.fiocruz.br/handle/icict/5465410.3390/v14071458engMDPISARS-CoV-2COVID-19Produtos naturaisFlavonóidesAncoragem molecularCélulas Calu-3ExonucleaseProteaseSARS-CoV-2COVID-19Natural productsFlavonoidsMolecular dockingCalu-3 cellsExonucleaseProteaseCommercially Available Flavonols Are Better SARS-CoV-2 Inhibitors than Isoflavone and Flavonesinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleFundação 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 em Inovação em Doenças Negligenciadas. 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 em Inovação em Doenças Negligenciadas. Rio de Janeiro, RJ, Brasil.Center for Genome Technology and Biomolecular Engineering. Columbia University. New York, NY 10027, USA / Department of Chemical Engineering, Columbia University, New York, NY 10027, USA.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 em Inovação em Doenças Negligenciadas. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Pesquisa sobre o Timo. Rio de Janeiro, RJ, Brasil / Fundação Oswaldo Cruz. 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 / Fundação Oswaldo Cruz. Centro de Desenvolvimento Tecnológico em Saúde. Rio de Janeiro, RJ, Brasil / Instituto Nacional de Ciência e Tecnologia em Inovação em Doenças Negligenciadas. Rio de Janeiro, RJ, Brasil / Universidade Iguaçu. Laboratório de Pesquisa Pré-clínica. 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 / Instituto Nacional de Ciência e Tecnologia em Inovação em Doenças Negligenciadas. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Imunofarmacologia. Rio de Janeiro, RJ, BrasilFundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Imunofarmacologia. Rio de Janeiro, RJ, BrasilFundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Imunofarmacologia. Rio de Janeiro, RJ, BrasilCenter for Genome Technology and Biomolecular Engineering. Columbia University. New York, NY 10027, USA / Department of Chemical Engineering, Columbia University, New York, NY 10027, USA.Center for Genome Technology and Biomolecular Engineering. Columbia University. New York, NY 10027, USA / Department of Chemical Engineering, Columbia University, New York, NY 10027, USA / Department of Molecular Pharmacology and Therapeutics, Columbia University, New York, NY 10032, USA.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 em Inovação em Doenças Negligenciadas. Rio de Janeiro, RJ, Brasil.Despite the fast development of vaccines, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is still circulating and generating variants of concern (VoC) that escape the humoral immune response. In this context, the search for anti-SARS-CoV-2 compounds is still essential. A class of natural polyphenols known as flavonoids, frequently available in fruits and vegetables, is widely explored in the treatment of different diseases and used as a scaffold for the design of novel drugs. Therefore, herein we evaluate seven flavonoids divided into three subclasses, isoflavone (genistein), flavone (apigenin and luteolin) and flavonol (fisetin, kaempferol, myricetin, and quercetin), for COVID-19 treatment using cell-based assays and in silico calculations validated with experimental enzymatic data. The flavonols were better SARS-CoV-2 inhibitors than isoflavone and flavones. The increasing number of hydroxyl groups in ring B of the flavonols kaempferol, quercetin, and myricetin decreased the 50% effective concentration (EC50) value due to their impact on the orientation of the compounds inside the target. Myricetin and fisetin appear to be preferred candidates; they are both anti-inflammatory (decreasing TNF- levels) and inhibit SARS-CoV-2 mainly by targeting the processability of the main protease (Mpro) in a non-competitive manner, with a potency comparable to the repurposed drug atazanavir. However, fisetin and myricetin might also be considered hits that are amenable to synthetic modification to improve their anti-SARS-CoV-2 profile by inhibiting not only Mpro, but also the 30–50 exonuclease (ExoN).info: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/54654/1/license.txt5a560609d32a3863062d77ff32785d58MD51ORIGINALOtavioChaves_HugoCastro_etal_IOC_2022.pdfOtavioChaves_HugoCastro_etal_IOC_2022.pdfapplication/pdf4216761https://www.arca.fiocruz.br/bitstream/icict/54654/2/OtavioChaves_HugoCastro_etal_IOC_2022.pdf3dceef0102ff5f50a8569acd18a13781MD52icict/546542022-08-16 09:50:02.205oai:www.arca.fiocruz.br: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ório InstitucionalPUBhttps://www.arca.fiocruz.br/oai/requestrepositorio.arca@fiocruz.bropendoar:21352022-08-16T12:50:02Repositório Institucional da FIOCRUZ (ARCA) - Fundação Oswaldo Cruz (FIOCRUZ)false |
| dc.title.pt_BR.fl_str_mv |
Commercially Available Flavonols Are Better SARS-CoV-2 Inhibitors than Isoflavone and Flavones |
| title |
Commercially Available Flavonols Are Better SARS-CoV-2 Inhibitors than Isoflavone and Flavones |
| spellingShingle |
Commercially Available Flavonols Are Better SARS-CoV-2 Inhibitors than Isoflavone and Flavones Chaves, Otávio Augusto SARS-CoV-2 COVID-19 Produtos naturais Flavonóides Ancoragem molecular Células Calu-3 Exonuclease Protease SARS-CoV-2 COVID-19 Natural products Flavonoids Molecular docking Calu-3 cells Exonuclease Protease |
| title_short |
Commercially Available Flavonols Are Better SARS-CoV-2 Inhibitors than Isoflavone and Flavones |
| title_full |
Commercially Available Flavonols Are Better SARS-CoV-2 Inhibitors than Isoflavone and Flavones |
| title_fullStr |
Commercially Available Flavonols Are Better SARS-CoV-2 Inhibitors than Isoflavone and Flavones |
| title_full_unstemmed |
Commercially Available Flavonols Are Better SARS-CoV-2 Inhibitors than Isoflavone and Flavones |
| title_sort |
Commercially Available Flavonols Are Better SARS-CoV-2 Inhibitors than Isoflavone and Flavones |
| author |
Chaves, Otávio Augusto |
| author_facet |
Chaves, Otávio Augusto Rodrigues, Natalia Fintelman Wang, Xuanting Sacramento, Carolina Q. Temerozo, Jairo R. Ferreira, André C. . Mattos, Mayara Dutra, Filipe Pereira Bozza, Patrícia Faria Neto, Hugo Caire Castro Russo, James J. Ju, Jingyue Souza, Thiago Moreno L. |
| author_role |
author |
| author2 |
Rodrigues, Natalia Fintelman Wang, Xuanting Sacramento, Carolina Q. Temerozo, Jairo R. Ferreira, André C. . Mattos, Mayara Dutra, Filipe Pereira Bozza, Patrícia Faria Neto, Hugo Caire Castro Russo, James J. Ju, Jingyue Souza, Thiago Moreno L. |
| author2_role |
author author author author author author author author author author author author |
| dc.contributor.author.fl_str_mv |
Chaves, Otávio Augusto Rodrigues, Natalia Fintelman Wang, Xuanting Sacramento, Carolina Q. Temerozo, Jairo R. Ferreira, André C. . Mattos, Mayara Dutra, Filipe Pereira Bozza, Patrícia Faria Neto, Hugo Caire Castro Russo, James J. Ju, Jingyue Souza, Thiago Moreno L. |
| dc.subject.other.pt_BR.fl_str_mv |
SARS-CoV-2 COVID-19 Produtos naturais Flavonóides Ancoragem molecular Células Calu-3 Exonuclease Protease |
| topic |
SARS-CoV-2 COVID-19 Produtos naturais Flavonóides Ancoragem molecular Células Calu-3 Exonuclease Protease SARS-CoV-2 COVID-19 Natural products Flavonoids Molecular docking Calu-3 cells Exonuclease Protease |
| dc.subject.en.pt_BR.fl_str_mv |
SARS-CoV-2 COVID-19 Natural products Flavonoids Molecular docking Calu-3 cells Exonuclease Protease |
| description |
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 em Inovação em Doenças Negligenciadas. Rio de Janeiro, RJ, Brasil. |
| publishDate |
2022 |
| dc.date.accessioned.fl_str_mv |
2022-08-16T12:50:02Z |
| dc.date.available.fl_str_mv |
2022-08-16T12:50:02Z |
| dc.date.issued.fl_str_mv |
2022 |
| 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 |
CHAVES, Otávio Augusto. Commercially Available Flavonols Are Better SARS-CoV-2 Inhibitors than Isoflavone and Flavones. Viruses, v. 14, 1458, p. 1 - 17, June 2022. |
| dc.identifier.uri.fl_str_mv |
https://www.arca.fiocruz.br/handle/icict/54654 |
| dc.identifier.issn.pt_BR.fl_str_mv |
1999-4915 |
| dc.identifier.doi.none.fl_str_mv |
10.3390/v14071458 |
| identifier_str_mv |
CHAVES, Otávio Augusto. Commercially Available Flavonols Are Better SARS-CoV-2 Inhibitors than Isoflavone and Flavones. Viruses, v. 14, 1458, p. 1 - 17, June 2022. 1999-4915 10.3390/v14071458 |
| url |
https://www.arca.fiocruz.br/handle/icict/54654 |
| 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 |
MDPI |
| publisher.none.fl_str_mv |
MDPI |
| 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/54654/1/license.txt https://www.arca.fiocruz.br/bitstream/icict/54654/2/OtavioChaves_HugoCastro_etal_IOC_2022.pdf |
| bitstream.checksum.fl_str_mv |
5a560609d32a3863062d77ff32785d58 3dceef0102ff5f50a8569acd18a13781 |
| bitstream.checksumAlgorithm.fl_str_mv |
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_ |
1813009246601609216 |