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      Hepatitis C Virus Drugs That Inhibit the SARS-CoV-2 Papain-Like Protease Synergize with Remdesivir to Suppress Viral Replication in Cell Culture

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          Abstract

          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 (M pro) and HCV NS3/4A protease. Virtual docking experiments show that these HCV drugs can potentially bind into the M pro binding cleft. We show that seven HCV drugs inhibit both SARS-CoV-2 M pro protease activity and SARS-CoV-2 virus replication in Vero and/or human cells. However, their M pro 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 (PL pro). HCV drugs that inhibit PL pro 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 M pro do not synergize with remdesivir.

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          Abstract

          Bafna et al. 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. The four HCV drugs that inhibit PL pro enzyme activity also synergize with remdesivir to inhibit virus replication, increasing remdesivir and HCV drugs antiviral activity.

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          Author and article information

          Journal
          Cell Rep
          Cell Rep
          Cell Reports
          The Author(s).
          2211-1247
          27 April 2021
          27 April 2021
          : 109133
          Affiliations
          [1 ]Department of Chemistry and Chemical Biology, and Center for Biotechnology and Interdisciplinary Sciences, Rensselaer Polytechnic Institute, Troy, NY, 12180, USA
          [2 ]Department of Microbiology, and Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
          [3 ]Department of Biology, and Center for Biotechnology and Interdisciplinary Sciences, Rensselaer Polytechnic Institute, Troy, NY, 12180 USA
          [4 ]Department of Medicine, Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
          [5 ]The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
          [6 ]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
          Author notes
          []Corresponding authors:
          [#]

          These two investigators made equal contributions to this project.

          [‡]

          Lead Contact: Gaetano T. Montelione, monteg3@rpi.edu

          Article
          S2211-1247(21)00472-1 109133
          10.1016/j.celrep.2021.109133
          8075848
          33984267
          a3b546e0-52f1-4ef0-b6a9-aa41c439e1df
          © 2021 The Author(s)

          Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

          History
          : 16 November 2020
          : 18 March 2021
          : 23 April 2021
          Categories
          Article

          Cell biology
          covid-19,sars-cov-2 3cl/mpro protease,sars-cov-2 pl protease,hcv protease inhibitors,molecular docking,sars-cov-2 virus replication,synergism,remdesivir,antivirals

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