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.
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.