Combination of antiviral drugs to inhibit SARS-CoV-2 polymerase and exonuclease as potential COVID-19 therapeutics

Columbia University. Center for Genome Technology and Biomolecular Engineering. New York, NY, USA / Columbia University. Department of Chemical Engineering. 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 da População Negligenciada. Rio de Janeiro, RJ, Brasil.
Columbia University. Center for Genome Technology and Biomolecular Engineering. New York, NY, USA / Columbia University. Department of Chemistry. 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 da População Negligenciada. Rio de Janeiro, RJ, Brasil.
Columbia University. Center for Genome Technology and Biomolecular Engineering. New York, NY, USA / Columbia University. Department of Chemical Engineering. 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 da População Negligenciada. Rio de Janeiro, RJ, Brasil.
Columbia University. Center for Genome Technology and Biomolecular Engineering. New York, NY, USA / Columbia University. Department of Chemical Engineering. 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.
Columbia University. Center for Genome Technology and Biomolecular Engineering. New York, NY, USA / Columbia University. Department of Chemical Engineering. New York, NY, USA.
Columbia University. Center for Genome Technology and Biomolecular Engineering. New York, NY, USA / Columbia University. Department of Chemical Engineering. New York, NY, USA.
Memorial Sloan-Kettering Cancer Center. Laboratory of Structural Biology. New York, NY, USA.
Memorial Sloan-Kettering Cancer Center. Laboratory of Structural Biology. New York, NY, USA.
Rockefeller University. Laboratory of RNA Molecular Biology. New York, NY, USA.
Rockefeller University. Laboratory of RNA Molecular Biology. New York, NY, USA.
Rockefeller University. Laboratory of RNA Molecular Biology. New York, NY, USA.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Imunofarmacologia. Rio de Janeiro, RJ, Brasil.
Columbia University. Center for Genome Technology and Biomolecular Engineering. New York, NY, USA / Columbia University. Department of Chemical Engineering. 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 da População Negligenciada. Rio de Janeiro, RJ, Brasil.
Columbia University. Center for Genome Technology and Biomolecular Engineering. New York, NY, USA / Columbia University. Department of Chemical Engineering. New York, NY, USA / Columbia University. Department of Molecular Pharmacology and Therapeutics. New York, NY, USA.

Abstract

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.

Keywords in Portuguese

SARS-CoV-2
Combinação de drogas antivirais
Inibição
Polimerase e a exonuclease
Terapia potencial
COVID-19

Keywords

Antiviral Drugs
Inhibit
SARS-CoV-2
Polymerase and Exonuclease
Potential COVID-19 Therapeutics

Publisher

bioRxiv preprint

Later version

https://www.arca.fiocruz.br/handle/icict/53619

Citation

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.

DOI

10.1101/2021.07.21.453274

Notes

Produção científica do Laboratório de Imunofarmacologia.
Produção científica do Laboratório de Pesquisa sobre o Timo.

Please use this identifier to cite or link to this item: https://www.arca.fiocruz.br/handle/icict/48718

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Open access

Embargo date

2021

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