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.

• Authors: Xuanting Wang, Carolina Q Sacramento, Steffen Jockusch, Otávio Augusto Chaves, Chuanjuan Tao, Natalia Fintelman-Rodrigues, Minchen Chien, Jairo R Temerozo, Xiaoxu Li, Shiv Kumar, Wei Xie, Dinshaw J Patel, Cindy Meyer, Aitor Garzia, Thomas Tuschl, Patrícia T Bozza, James J Russo, Thiago Moreno L Souza, Jingyue Ju
• Journal: Communications biology (Commun Biol) Vol. 5 Issue 1 Pg. 154 (02 22 2022) ISSN: 2399-3642 [Electronic] England
• PMID: 35194144 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022. The Author(s).

Chemical References

• Anilides
• Antiviral Agents
• Benzimidazoles
• Pyrrolidines
• RNA, Viral
• Viral Nonstructural Proteins
• ombitasvir
• pibrentasvir
• Proline
• RNA-Dependent RNA Polymerase
• Exonucleases
• Valine

Topics

• Amino Acid Sequence
• Anilides (pharmacology)
• Animals
• Antiviral Agents (pharmacology)
• Base Sequence
• Benzimidazoles (pharmacology)
• COVID-19 (virology)
• Cell Line, Tumor
• Chlorocebus aethiops
• Drug Synergism
• Exonucleases (antagonists & inhibitors, genetics, metabolism)
• Humans
• Proline (pharmacology)
• Pyrrolidines (pharmacology)
• RNA, Viral (genetics, metabolism)
• RNA-Dependent RNA Polymerase (antagonists & inhibitors, genetics, metabolism)
• SARS-CoV-2 (drug effects, genetics, physiology)
• Valine (pharmacology)
• Vero Cells
• Viral Nonstructural Proteins (antagonists & inhibitors, genetics, metabolism)
• Virus Replication (drug effects, genetics)
• COVID-19 Drug Treatment