Hepatitis C Virus Drugs Simeprevir and Grazoprevir Synergize with Remdesivir to Suppress SARS-CoV-2 Replication in Cell Culture

  1. Khushboo Bafna
  2. Kris White
  3. Balasubramanian Harish
  4. Romel Rosales
  5. Theresa A. Ramelot
  6. Thomas B. Acton
  7. Elena Moreno
  8. Thomas Kehrer
  9. Lisa Miorin
  10. Catherine A. Royer
  11. Adolfo García-Sastre
  12. Robert M. Krug
  13. Gaetano T. Montelione
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Abstract

Effective control of COVID-19 requires antivirals directed against SARS-CoV-2 virus. Here we assess ten available 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 M pro and HCV NS3/4A proteases, and virtual docking experiments show that all ten HCV drugs can potentially bind into the M pro binding cleft. Seven of these HCV drugs inhibit SARS-CoV-2 M pro protease activity, while four dock well into the PL pro substrate binding cleft and inhibit PL pro protease activity. These same seven HCV drugs inhibit SARS-CoV-2 virus replication in Vero and/or human cells, demonstrating that HCV drugs that inhibit M pro , or both M pro and PL pro , suppress virus replication. Two HCV drugs, simeprevir and grazoprevir synergize with the viral polymerase inhibitor remdesivir to inhibit virus replication, thereby increasing remdesivir inhibitory activity as much as 10-fold.

Highlights

  • Several HCV protease inhibitors are predicted to inhibit SARS-CoV-2 M pro and PL pro .

  • Seven HCV drugs inhibit M pro enzyme activity, four HCV drugs inhibit PL pro .

  • Seven HCV drugs inhibit SARS-CoV-2 replication in Vero and/or human cells.

  • HCV drugs simeprevir and grazoprevir synergize with remdesivir to inhibit SARS- CoV-2.

eTOC blurb

Bafna, White and colleagues report that several available hepatitis C virus drugs inhibit the SARS-CoV-2 M pro and/or PL pro proteases and SARS-CoV-2 replication in cell culture. Two drugs, simeprevir and grazoprevir, synergize with the viral polymerase inhibitor remdesivir to inhibit virus replication, increasing remdesivir antiviral activity as much as 10-fold.

Abstract Figure

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