Hepatitis C virus drugs synergize with remdesivir to suppress SARS-CoV-2 replication

Effective control of COVID-19 requires antivirals directed against SARS-CoV-2 virus. We assessed 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^pro and HCV NS3/4A proteases, and virtual docking experiments show that all ten HCV drugs can potentially bind into the M^pro binding cleft. Seven of these HCV drugs also inhibit SARS-CoV-2 M^pro protease activity. These same seven HCV drugs inhibit SARS-CoV-2 virus replication in cell culture, Some of these drugs also synergize with the viral polymerase inhibitor remdesivir to inhibit virus replication, thereby increasing remdesivir inhibitory activity as much as 10-fold. Careful examination of these data suggests that these HCV drugs also function through a second target. Surprisingly, some of these HCV drugs were found to also bind to and inhibit the SARS-CoV-2 PL^pro protease. The synergistic activity of HCV drugs with remdesivir correlates with their ability to inhibit PL^pro, indicating this function is the primary basis for their synergy with remdesivir.