Hepatitis C virus drugs that inhibit SARS-CoV-2 papain-like protease synergize with remdesivir to suppress viral replication in cell culture

Effective control of COVID-19 requires antivirals directed against SARS-CoV-2. We assessed 10 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) substrate-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 is 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.