Hepatitis C virus drugs that inhibit SARS-CoV-2 papain-like protease synergize with remdesivir to suppress viral replication in cell culture

Cell Rep. 2021 May 18;35(7):109133. doi: 10.1016/j.celrep.2021.109133. Epub 2021 Apr 27.


Effective control of COVID-19 requires antivirals directed against SARS-CoV-2. We assessed 10 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 substrate-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 is 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.

Keywords: COVID-19; HCV protease inhibitors; SARS-CoV-2 3CL/M(pro) protease; SARS-CoV-2 PL protease; SARS-CoV-2 virus replication; antivirals; molecular docking; remdesivir; synergism.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Monophosphate / analogs & derivatives
  • Adenosine Monophosphate / pharmacology
  • Alanine / analogs & derivatives
  • Alanine / pharmacology
  • Antiviral Agents / pharmacology*
  • COVID-19 / drug therapy*
  • COVID-19 / virology
  • Cell Culture Techniques
  • Cell Line
  • Coronavirus Papain-Like Proteases / antagonists & inhibitors*
  • Coronavirus Papain-Like Proteases / metabolism
  • Drug Repositioning / methods
  • Drug Synergism
  • Hepacivirus / drug effects
  • Hepatitis C / drug therapy
  • Humans
  • Molecular Docking Simulation
  • Molecular Dynamics Simulation
  • Protease Inhibitors / pharmacology
  • SARS-CoV-2 / drug effects*
  • SARS-CoV-2 / enzymology*
  • Virus Replication / drug effects


  • Antiviral Agents
  • Protease Inhibitors
  • remdesivir
  • Adenosine Monophosphate
  • Coronavirus Papain-Like Proteases
  • papain-like protease, SARS-CoV-2
  • Alanine

Supplementary concepts

  • COVID-19 drug treatment