TY - JOUR T1 - Hepatitis C Virus Drugs Simeprevir and Grazoprevir Synergize with Remdesivir to Suppress SARS-CoV-2 Replication in Cell Culture JF - bioRxiv DO - 10.1101/2020.12.13.422511 SP - 2020.12.13.422511 AU - Khushboo Bafna AU - Kris White AU - Balasubramanian Harish AU - Romel Rosales AU - Theresa A. Ramelot AU - Thomas B. Acton AU - Elena Moreno AU - Thomas Kehrer AU - Lisa Miorin AU - Catherine A. Royer AU - Adolfo GarcĂ­a-Sastre AU - Robert M. Krug AU - Gaetano T. Montelione Y1 - 2020/01/01 UR - http://biorxiv.org/content/early/2020/12/14/2020.12.13.422511.abstract N2 - 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 Mpro and HCV NS3/4A proteases, and virtual docking experiments show that all ten HCV drugs can potentially bind into the Mpro binding cleft. Seven of these HCV drugs inhibit SARS-CoV-2 Mpro protease activity, while four dock well into the PLpro substrate binding cleft and inhibit PLpro 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 Mpro, or both Mpro and PLpro, 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.HighlightsSeveral HCV protease inhibitors are predicted to inhibit SARS-CoV-2 Mpro and PLpro.Seven HCV drugs inhibit Mpro enzyme activity, four HCV drugs inhibit PLpro.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 Mpro and/or PLpro 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.Competing Interest StatementA provisional patent application related to these studies has been filed. GTM is a founder of Nexomics Biosciences, Inc. This relationship has no conflict of interest with respect to this study. GTM and RMK are inventors in patents owned jointly by Rutgers University and the University of Texas at Austin concerning the use of specific compounds as antivirals against influenza virus. These patents have no conflict of interest for this study. AG-S is inventor in patents and patent application owned by the Icahn School of Medicine concerning the use of specific antiviral compounds. This inventorship has no conflict of interest with respect to this study. ER -