Combination of antiviral drugs inhibits SARS-CoV-2 polymerase and exonuclease and demonstrates COVID-19 therapeutic potential in viral cell culture Journal Article
| Authors: | Wang, X.; Sacramento, C. Q.; Jockusch, S.; Chaves, O. A.; Tao, C.; Fintelman-Rodrigues, N.; Chien, M.; Temerozo, J. R.; Li, X.; Kumar, S.; Xie, W.; Patel, D. J.; Meyer, C.; Garzia, A.; Tuschl, T.; Bozza, P. T.; Russo, J. J.; Souza, T. M. L.; Ju, J. |
| Article Title: | Combination of antiviral drugs inhibits SARS-CoV-2 polymerase and exonuclease and demonstrates COVID-19 therapeutic potential in viral cell culture |
| 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. © 2022, The Author(s). |
| Keywords: | genetics; drug potentiation; animal; metabolism; animals; drug effect; cell line, tumor; physiology; virology; drug synergism; amino acid sequence; virus rna; nucleotide sequence; tumor cell line; base sequence; antivirus agent; virus replication; drug therapy; exonuclease; anilides; benzimidazole derivative; benzimidazoles; rna, viral; valine; vero cells; exonucleases; anilide; proline; antiviral agents; pyrrolidines; viral nonstructural proteins; humans; human; pyrrolidine derivative; chlorocebus aethiops; vero cell line; covid-19; sars-cov-2; viral protein; ombitasvir; pibrentasvir; rna-dependent rna polymerase |
| Journal Title: | Communications Biology |
| Volume: | 5 |
| ISSN: | 2399-3642 |
| Publisher: | Springer Nature |
| Date Published: | 2022-02-22 |
| Start Page: | 154 |
| Language: | English |
| DOI: | 10.1038/s42003-022-03101-9 |
| PUBMED: | 35194144 |
| PROVIDER: | scopus |
| PMCID: | PMC8863796 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 April 2022 -- Source: Scopus |
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