Combination of Antiviral Drugs to Inhibit SARS-CoV-2 Polymerase and Exonuclease as Potential COVID-19 Therapeutics
| Autor(a) principal: | |
|---|---|
| Data de Publicação: | 2021 |
| 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/48718 |
Resumo: | 2021 |
| id |
CRUZ_c634a6263435b4fb404474ae08adbe44 |
|---|---|
| oai_identifier_str |
oai:www.arca.fiocruz.br:icict/48718 |
| network_acronym_str |
CRUZ |
| network_name_str |
Repositório Institucional da FIOCRUZ (ARCA) |
| repository_id_str |
2135 |
| spelling |
Wang, XuantingSacramento, Carolina Q.Jockusch, SteffenChaves, Otávio AugustoTao, ChuanjuanRodrigues, Natalia FintelmanChien, MinchenTemerozo, Jairo RamosXaioxu, LiKumar, ShivXie, WeiPatel, Dinshaw J.Meyer, CindyGarzia, AitorTuschi, ThomasBozza, Patrícia TorresRusso, James J.Souza, Thiago Moreno L.Ju, Jingyue2021-08-24T14:41:15Z2021-08-24T14:41:15Z2021WANG, Xuanting et al. Combination of Antiviral Drugs to Inhibit SARS-CoV-2 Polymerase and Exonuclease as Potential COVID-19 Therapeutics. bioRxiv, p. 1-37, Jul. 2021.https://www.arca.fiocruz.br/handle/icict/4871810.1101/2021.07.21.453274engbioRxiv preprintSARS-CoV-2Combinação de drogas antiviraisInibiçãoPolimerase e a exonucleaseTerapia potencialCOVID-19Antiviral DrugsInhibitSARS-CoV-2Polymerase and ExonucleasePotential COVID-19 TherapeuticsCombination of Antiviral Drugs to Inhibit SARS-CoV-2 Polymerase and Exonuclease as Potential COVID-19 Therapeuticsinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/article2021Center for Genome Technology and Biomolecular Engineering, Columbia University, New York, NY, USA / Department of Chemical Engineering, Columbia University, New York, NY, USA.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Imunofarmacologia. Rio de Janeiro, RJ, Brasil / Fundação Oswaldo Cruz. Centro de Desenvolvimento Tecnológico em Saúde. Instituto Nacional de Ciência e Tecnologia para Inovação em Doenças Negligenciadas. Rio de Janeiro, RJ, Brasil.Center for Genome Technology and Biomolecular Engineering, Columbia University, New York, NY, USA / Department of Chemistry, Columbia University, New York, NY, USA.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Imunofarmacologia. Rio de Janeiro, RJ, Brasil / Fundação Oswaldo Cruz. Centro de Desenvolvimento Tecnológico em Saúde. Instituto Nacional de Ciência e Tecnologia para Inovação em Doenças Negligenciadas. Rio de Janeiro, RJ, Brasil.Center for Genome Technology and Biomolecular Engineering, Columbia University, New York, NY, USA / Department of Chemical Engineering, Columbia University, New York, NY, USA.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Imunofarmacologia. Rio de Janeiro, RJ, Brasil / Fundação Oswaldo Cruz. Centro de Desenvolvimento Tecnológico em Saúde. Instituto Nacional de Ciência e Tecnologia para Inovação em Doenças Negligenciadas. Rio de Janeiro, RJ, Brasil.Center for Genome Technology and Biomolecular Engineering, Columbia University, New York, NY, USA / Department of Chemical Engineering, Columbia University, New York, NY, USA.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Pesquisa sobre o Timo. Rio de Janeiro, RJ, Brasil / Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Instituto Nacional de Ciência e Tecnologia em Neuroimunomodulação. Rio de Janeiro, RJ, Brasil / Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Instituto Nacional de Ciência e Tecnologia em Neuroimunomodulação. Rio de Janeiro, RJ, Brasil.Center for Genome Technology and Biomolecular Engineering, Columbia University, New York, NY, USA / Department of Chemical Engineering, Columbia University, New York, NY, USA.Laboratory of Structural Biology, Memorial Sloan-Kettering Cancer Center.New York, NY, USA.Laboratory of Structural Biology, Memorial Sloan-Kettering Cancer Center.New York, NY, USA.Laboratory of RNA Molecular Biology, Rockefeller University. New York, NY, USA.Laboratory of RNA Molecular Biology, Rockefeller University. New York, NY, USA.Laboratory of RNA Molecular Biology, Rockefeller University. New York, NY, USA.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Imunofarmacologia. Rio de Janeiro, RJ, Brasil.Center for Genome Technology and Biomolecular Engineering, Columbia University, New York, NY, USA / Department of Chemical Engineering, Columbia University, New York, NY, USA.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Imunofarmacologia. Rio de Janeiro, RJ, Brasil / Fundação Oswaldo Cruz. Centro de Desenvolvimento Tecnológico em Saúde. Instituto Nacional de Ciência e Tecnologia para Inovação em Doenças Negligenciadas. Rio de Janeiro, RJ, Brasil.Center for Genome Technology and Biomolecular Engineering, Columbia University, New York, NY, USA / Department of Chemical Engineering, Columbia University, New York, NY 10027. USA. / Department of Molecular Pharmacology and Therapeutics, Columbia University, New York, NY, USA.SARS-CoV-2 has an exonuclease-based proofreader, which removes nucleotide inhibitors such as Remdesivir that are incorporated into the viral RNA during replication, reducing the efficacy of these drugs for treating COVID-19. Combinations of inhibitors of both the viral RNA-dependent RNA polymerase and the exonuclease could overcome this deficiency. Here we report the identification of hepatitis C virus NS5A inhibitors Pibrentasvir and Ombitasvir as SARS-CoV-2 exonuclease inhibitors. In the presence of Pibrentasvir, RNAs terminated with the active forms of the prodrugs Sofosbuvir, Remdesivir, Favipiravir, Molnupiravir and AT-527 were largely protected from excision by the exonuclease, while in the absence of Pibrentasvir, there was rapid excision. Due to its unique structure, Tenofovir-terminated RNA was highly resistant to exonuclease excision even in the absence of Pibrentasvir. Viral cell culture studies also demonstrate significant synergy using this combination strategy. This study supports the use of combination drugs that inhibit both the SARS-CoV-2 polymerase and exonuclease for effective COVID-19 treatment.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/48718/1/license.txt5a560609d32a3863062d77ff32785d58MD51ORIGINALCarolinaSacramento_OtavioChaves_etal_IOC_2021.pdfCarolinaSacramento_OtavioChaves_etal_IOC_2021.pdfapplication/pdf7394957https://www.arca.fiocruz.br/bitstream/icict/48718/2/CarolinaSacramento_OtavioChaves_etal_IOC_2021.pdf77794c4a9913435a67c1a0021ce06476MD52TEXTCarolinaSacramento_OtavioChaves_etal_IOC_2021.pdf.txtCarolinaSacramento_OtavioChaves_etal_IOC_2021.pdf.txtExtracted texttext/plain88170https://www.arca.fiocruz.br/bitstream/icict/48718/3/CarolinaSacramento_OtavioChaves_etal_IOC_2021.pdf.txteb6cf91ebb9761142f9c7ff3f37592f1MD53icict/487182023-02-13 14:15:43.947oai:www.arca.fiocruz.br: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ório InstitucionalPUBhttps://www.arca.fiocruz.br/oai/requestrepositorio.arca@fiocruz.bropendoar:21352023-02-13T17:15:43Repositório Institucional da FIOCRUZ (ARCA) - Fundação Oswaldo Cruz (FIOCRUZ)false |
| dc.title.pt_BR.fl_str_mv |
Combination of Antiviral Drugs to Inhibit SARS-CoV-2 Polymerase and Exonuclease as Potential COVID-19 Therapeutics |
| title |
Combination of Antiviral Drugs to Inhibit SARS-CoV-2 Polymerase and Exonuclease as Potential COVID-19 Therapeutics |
| spellingShingle |
Combination of Antiviral Drugs to Inhibit SARS-CoV-2 Polymerase and Exonuclease as Potential COVID-19 Therapeutics Wang, Xuanting SARS-CoV-2 Combinação de drogas antivirais Inibição Polimerase e a exonuclease Terapia potencial COVID-19 Antiviral Drugs Inhibit SARS-CoV-2 Polymerase and Exonuclease Potential COVID-19 Therapeutics |
| title_short |
Combination of Antiviral Drugs to Inhibit SARS-CoV-2 Polymerase and Exonuclease as Potential COVID-19 Therapeutics |
| title_full |
Combination of Antiviral Drugs to Inhibit SARS-CoV-2 Polymerase and Exonuclease as Potential COVID-19 Therapeutics |
| title_fullStr |
Combination of Antiviral Drugs to Inhibit SARS-CoV-2 Polymerase and Exonuclease as Potential COVID-19 Therapeutics |
| title_full_unstemmed |
Combination of Antiviral Drugs to Inhibit SARS-CoV-2 Polymerase and Exonuclease as Potential COVID-19 Therapeutics |
| title_sort |
Combination of Antiviral Drugs to Inhibit SARS-CoV-2 Polymerase and Exonuclease as Potential COVID-19 Therapeutics |
| author |
Wang, Xuanting |
| author_facet |
Wang, Xuanting Sacramento, Carolina Q. Jockusch, Steffen Chaves, Otávio Augusto Tao, Chuanjuan Rodrigues, Natalia Fintelman Chien, Minchen Temerozo, Jairo Ramos Xaioxu, Li Kumar, Shiv Xie, Wei Patel, Dinshaw J. Meyer, Cindy Garzia, Aitor Tuschi, Thomas Bozza, Patrícia Torres Russo, James J. Souza, Thiago Moreno L. Ju, Jingyue |
| author_role |
author |
| author2 |
Sacramento, Carolina Q. Jockusch, Steffen Chaves, Otávio Augusto Tao, Chuanjuan Rodrigues, Natalia Fintelman Chien, Minchen Temerozo, Jairo Ramos Xaioxu, Li Kumar, Shiv Xie, Wei Patel, Dinshaw J. Meyer, Cindy Garzia, Aitor Tuschi, Thomas Bozza, Patrícia Torres Russo, James J. Souza, Thiago Moreno L. Ju, Jingyue |
| author2_role |
author author author author author author author author author author author author author author author author author author |
| dc.contributor.author.fl_str_mv |
Wang, Xuanting Sacramento, Carolina Q. Jockusch, Steffen Chaves, Otávio Augusto Tao, Chuanjuan Rodrigues, Natalia Fintelman Chien, Minchen Temerozo, Jairo Ramos Xaioxu, Li Kumar, Shiv Xie, Wei Patel, Dinshaw J. Meyer, Cindy Garzia, Aitor Tuschi, Thomas Bozza, Patrícia Torres Russo, James J. Souza, Thiago Moreno L. Ju, Jingyue |
| dc.subject.other.pt_BR.fl_str_mv |
SARS-CoV-2 Combinação de drogas antivirais Inibição Polimerase e a exonuclease Terapia potencial COVID-19 |
| topic |
SARS-CoV-2 Combinação de drogas antivirais Inibição Polimerase e a exonuclease Terapia potencial COVID-19 Antiviral Drugs Inhibit SARS-CoV-2 Polymerase and Exonuclease Potential COVID-19 Therapeutics |
| dc.subject.en.pt_BR.fl_str_mv |
Antiviral Drugs Inhibit SARS-CoV-2 Polymerase and Exonuclease Potential COVID-19 Therapeutics |
| description |
2021 |
| publishDate |
2021 |
| dc.date.accessioned.fl_str_mv |
2021-08-24T14:41:15Z |
| dc.date.available.fl_str_mv |
2021-08-24T14:41:15Z |
| dc.date.issued.fl_str_mv |
2021 |
| 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 |
WANG, Xuanting et al. Combination of Antiviral Drugs to Inhibit SARS-CoV-2 Polymerase and Exonuclease as Potential COVID-19 Therapeutics. bioRxiv, p. 1-37, Jul. 2021. |
| dc.identifier.uri.fl_str_mv |
https://www.arca.fiocruz.br/handle/icict/48718 |
| dc.identifier.doi.pt_BR.fl_str_mv |
10.1101/2021.07.21.453274 |
| identifier_str_mv |
WANG, Xuanting et al. Combination of Antiviral Drugs to Inhibit SARS-CoV-2 Polymerase and Exonuclease as Potential COVID-19 Therapeutics. bioRxiv, p. 1-37, Jul. 2021. 10.1101/2021.07.21.453274 |
| url |
https://www.arca.fiocruz.br/handle/icict/48718 |
| 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 |
bioRxiv preprint |
| publisher.none.fl_str_mv |
bioRxiv preprint |
| 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/48718/1/license.txt https://www.arca.fiocruz.br/bitstream/icict/48718/2/CarolinaSacramento_OtavioChaves_etal_IOC_2021.pdf https://www.arca.fiocruz.br/bitstream/icict/48718/3/CarolinaSacramento_OtavioChaves_etal_IOC_2021.pdf.txt |
| bitstream.checksum.fl_str_mv |
5a560609d32a3863062d77ff32785d58 77794c4a9913435a67c1a0021ce06476 eb6cf91ebb9761142f9c7ff3f37592f1 |
| 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_ |
1798324769455603712 |