Hepatitis C virus drugs that inhibit SARS-CoV-2 papain-like protease synergize with remdesivir to suppress viral replication in cell culture
Khushboo Bafna,
Kris White,
Balasubramanian Harish,
Romel Rosales,
Theresa A. Ramelot,
Thomas B. Acton,
Elena Moreno,
Thomas Kehrer,
Lisa Miorin,
Catherine A. Royer,
Adolfo García-Sastre,
Robert M. Krug,
Gaetano T. Montelione
Affiliations
Khushboo Bafna
Department of Chemistry and Chemical Biology, and Center for Biotechnology and Interdisciplinary Sciences, Rensselaer Polytechnic Institute, Troy, NY 12180, USA
Kris White
Department of Microbiology, and Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
Balasubramanian Harish
Department of Biology, and Center for Biotechnology and Interdisciplinary Sciences, Rensselaer Polytechnic Institute, Troy, NY 12180, USA
Romel Rosales
Department of Microbiology, and Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
Theresa A. Ramelot
Department of Chemistry and Chemical Biology, and Center for Biotechnology and Interdisciplinary Sciences, Rensselaer Polytechnic Institute, Troy, NY 12180, USA
Thomas B. Acton
Department of Chemistry and Chemical Biology, and Center for Biotechnology and Interdisciplinary Sciences, Rensselaer Polytechnic Institute, Troy, NY 12180, USA
Elena Moreno
Department of Microbiology, and Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
Thomas Kehrer
Department of Microbiology, and Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
Lisa Miorin
Department of Microbiology, and Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
Catherine A. Royer
Department of Biology, and Center for Biotechnology and Interdisciplinary Sciences, Rensselaer Polytechnic Institute, Troy, NY 12180, USA
Adolfo García-Sastre
Department of Microbiology, and Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Medicine, Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Corresponding author
Robert M. Krug
Department of Molecular Biosciences, John Ring LaMontagne Center for Infectious Disease, Institute for Cellular and Molecular Biology, University of Texas at Austin, Austin, TX 78712, USA; Corresponding author
Gaetano T. Montelione
Department of Chemistry and Chemical Biology, and Center for Biotechnology and Interdisciplinary Sciences, Rensselaer Polytechnic Institute, Troy, NY 12180, USA; Corresponding author
Summary: 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.
