Hepatitis C virus drugs that inhibit SARS-CoV-2 papain-like protease synergize with remdesivir to suppress viral replication in cell culture
| Autor: | Catherine A. Royer, Gaetano T. Montelione, Khushboo Bafna, Kris M. White, Lisa Miorin, Thomas Kehrer, Elena Moreno, Thomas B. Acton, Robert M. Krug, Romel Rosales, Adolfo García-Sastre, T.A. Ramelot, Balasubramanian Harish |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Simeprevir Antagonists & inhibitors HCV protease inhibitors QH301-705.5 viruses medicine.medical_treatment Vaniprevir Hepatitis C virus remdesivir medicine.disease_cause Article General Biochemistry Genetics and Molecular Biology SARS-CoV-2 virus replication 03 medical and health sciences chemistry.chemical_compound antivirals 0302 clinical medicine synergism medicine Biology (General) SARS-CoV-2 PL protease Protease Chemistry fungi COVID-19 virus diseases molecular docking Virology 030104 developmental biology Viral replication Grazoprevir Paritaprevir SARS-CoV-2 3CL/Mpro protease 030217 neurology & neurosurgery |
| Zdroj: | Cell Reports, Vol 35, Iss 7, Pp 109133-(2021) Cell Reports |
| ISSN: | 2211-1247 |
| DOI: | 10.1016/j.celrep.2021.109133 |
| Popis: | Effective control of COVID-19 requires antivirals directed against SARS-CoV-2. We assessed ten hepatitis C virus (HCV) protease-inhibitor drugs as potential SARS-CoV-2 antivirals. There is a striking structural similarity of the substrate binding clefts of SARS-CoV-2 main protease (Mpro) and HCV NS3/4A protease. Virtual docking experiments show that these HCV drugs can potentially bind into the Mpro binding cleft. We show that seven HCV drugs inhibit both SARS-CoV-2 Mpro protease activity and SARS-CoV-2 virus replication in Vero and/or human cells. However, their Mpro inhibiting activities did not correlate with their antiviral activities. This conundrum was resolved by demonstrating that four HCV protease inhibitor drugs, simeprevir, vaniprevir, paritaprevir, and grazoprevir inhibit the SARS CoV-2 papain-like protease (PLpro). HCV drugs that inhibit PLpro synergize with the viral polymerase inhibitor remdesivir to inhibit virus replication, increasing remdesivir’s antiviral activity as much as 10-fold, while those that only inhibit Mpro do not synergize with remdesivir. Graphical Abstract Bafna et al. report that several available hepatitis C virus drugs inhibit the SARS-CoV-2 Mpro and/or PLpro proteases, and SARS-CoV-2 replication in cell culture. The four HCV drugs that inhibit PLpro enzyme activity also synergize with remdesivir to inhibit virus replication, increasing remdesivir and HCV drugs antiviral activity. |
| Databáze: | OpenAIRE |
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