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

• DOI: 10.1016/j.celrep.2021.109133
• Publication Date: 2021-04-27T05:28:29Z
• Authors: Khushboo Bafna; Kris White; Balasubramanian H...; Romel Rosales; Theresa A. Ramelot; Thomas B. Acton; Elena Moreno; Thomas Kehrer; Lisa Miorin; Catherine A. Royer; Adolfo García-Sastre; Robert M. Krug; Gaetano T. Montel...
• Keywords: HCV protease inhibitors; QH301-705.5; Cell Culture Techniques; Coronavirus Papain-Like Proteases; Hepacivirus; Molecular Dynamics Simulation; Virus Replication; Antiviral Agents; Article; Cell Line; SARS-CoV-2 virus replication; 03 medical and health sciences; Humans; Protease Inhibitors; Biology (General); SARS-CoV-2 PL protease; 0303 health sciences; Alanine; SARS-CoV-2; Drug Repositioning; COVID-19; Drug Synergism; molecular docking; Hepatitis C; Adenosine Monophosphate; COVID-19 Drug Treatment; 3. Good health; Molecular Docking Simulation; SARS-CoV-2 3CL/Mpro protease

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 (Mpro) and HCV NS3/4A protease. Virtual docking experiments show that these HCV drugs can potentially bind into the Mpro substrate-binding cleft. We show that seven HCV drugs inhibit both SARS-CoV-2 Mpro protease activity and SARS-CoV-2 virus replication in Vero and/or human cells. However, their Mpro 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 (PLpro). HCV drugs that inhibit PLpro 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 Mpro do not synergize with remdesivir.