Journal Article

Combination of antiviral drugs inhibits SARS-CoV-2 polymerase and exonuclease and demonstrates COVID-19 therapeutic potential in viral cell culture

Temerozo, Jairo R., Chien, Minchen, Bozza, Patrícia T., Kumar, Shiv, Souza, Thiago Moreno L., Sacramento, Carolina Q., Tao, Chuanjuan, Chaves, Otávio Augusto, Meyer, Cindy, Fintelman-Rodrigues, Natalia, Jockusch, Steffen, Garzia, Aitor, Tuschl, Thomas, Li, Xiaoxu, Xie, Wei, Wang, Xuanting, Russo, James J., Patel, Dinshaw J., Ju, Jingyue

2022

Overview

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. In this paper, the hepatitis C virus inhibitors Pibrentasvir and Ombitasvir are found to inhibit the SARS-CoV-2 exonuclease and are shown to have therapeutic potential when combined with SARS-CoV-2 polymerase inhibitors in viral cell cultures.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 631/154/436 / 692/4017 / Amino Acid Sequence / Anilides - pharmacology / Animals / Antiviral agents / Antiviral Agents - pharmacology / Base Sequence / Benzimidazoles - pharmacology / Biology / Biomedical and Life Sciences / Cell culture / Cell Line, Tumor / Chlorocebus aethiops / Coronaviruses / COVID-19 / COVID-19 - virology / COVID-19 Drug Treatment / DNA-directed RNA polymerase / Drug Synergism / Exonuclease / Exonucleases - antagonists & inhibitors / Exonucleases - genetics / Exonucleases - metabolism / Hepatitis / Hepatitis C / Humans / Life Sciences / Proline - pharmacology / Pyrrolidines - pharmacology / RNA polymerase / RNA, Viral - genetics / RNA, Viral - metabolism / RNA-Dependent RNA Polymerase - antagonists & inhibitors / RNA-Dependent RNA Polymerase - genetics / RNA-Dependent RNA Polymerase - metabolism / RNA-directed RNA polymerase / SARS-CoV-2 - drug effects / SARS-CoV-2 - genetics / SARS-CoV-2 - physiology / Severe acute respiratory syndrome coronavirus 2 / Tenofovir / Valine - pharmacology / Vero Cells / Viral Nonstructural Proteins - antagonists & inhibitors / Viral Nonstructural Proteins - genetics / Viral Nonstructural Proteins - metabolism / Virus Replication - drug effects / Virus Replication - genetics