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

Bafna, Khushboo; White, Kris; Harish, Balasubramanian; Rosales, Romel; Ramelot, Theresa A.; Acton, Thomas B.; Moreno, Elena; Kehrer, Thomas; Miorin, Lisa; Royer, Catherine A.; García-Sastre, Adolfo; Krug, Robert M.; Montelione, Gaetano T.

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. Highlights Several 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.