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

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^proand HCV NS3/4A proteases, and virtual docking experiments show that all ten HCV drugs can potentially bind into the M^probinding cleft. Seven of these HCV drugs inhibit SARS-CoV-2 M^proprotease activity, while four dock well into the PL^prosubstrate binding cleft and inhibit PL^proprotease 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^proand 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.