@article{c74401081eb2478f902b4f53389327f2,
title = "Hepatitis C virus drugs that inhibit SARS-CoV-2 papain-like protease synergize with remdesivir to suppress viral replication in cell culture",
abstract = "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.",
keywords = "COVID-19, HCV protease inhibitors, SARS-CoV-2 3CL/M protease, SARS-CoV-2 PL protease, SARS-CoV-2 virus replication, antivirals, molecular docking, remdesivir, synergism",
author = "Khushboo Bafna and Kris White and Balasubramanian Harish and Romel Rosales and Ramelot, {Theresa A.} and Acton, {Thomas B.} and Elena Moreno and Thomas Kehrer and Lisa Miorin and Royer, {Catherine A.} and Adolfo Garc{\'i}a-Sastre and Krug, {Robert M.} and Montelione, {Gaetano T.}",
note = "Funding Information: A provisional patent application related to these studies has been filed. G.T.M. is a founder of Nexomics Biosciences, Inc. The A.G.-S. laboratory has received research support from Pfizer, Senhwa Biosciences, 7Hills Pharma, Avimex, Blade Therapeutics, Dynavax, ImmunityBio, Nanocomposix, Pharmamar, and Kenall Manufacturing, and A.G.-S. has consulting agreements for the following companies involving cash and/or stock: Vivaldi Biosciences, Pagoda, Contrafect, 7Hills Pharma, Avimex, Vaxalto, Accurius, Pfizer, and Esperovax. These relationships have no conflict of interest with respect to this study. Funding Information: We thank Drs. Y.P. Huang, G. Liu, L. Ma, S. Shukla, G.V.T. Swapna, and R. Xiao for helpful discussions and comments on the manuscript. We also thank J. Hunt and S. Krishna for a generous gift of SARS-CoV-2 PL pro enzyme and R. Albrecht for support with the BSL3 facility at the Icahn School of Medicine at Mount Sinai. This research was supported by grants from the National Institutes of Health ( R01-GM120574 to G.T.M.) and RPI Center for Computational Innovations (to K.B. and G.T.M.). This research was also partly funded by CRIP (Center for Research for Influenza Pathogenesis), a NIAID -supported Center of Excellence for Influenza Research and Surveillance ( HHSN272201400008C ), DARPA grant HR0011-19-2-0020 , NIAID grants U19AI142733 and U19AI135972 , DOD grant W81XWH-20-1-0270 , and by the generous support of the JPB Foundation , the Open Philanthropy Project ( 2020-215611 [5384) ), and anonymous donors to A.G.-S. Funding Information: We thank Drs. Y.P. Huang, G. Liu, L. Ma, S. Shukla, G.V.T. Swapna, and R. Xiao for helpful discussions and comments on the manuscript. We also thank J. Hunt and S. Krishna for a generous gift of SARS-CoV-2 PLpro enzyme and R. Albrecht for support with the BSL3 facility at the Icahn School of Medicine at Mount Sinai. This research was supported by grants from the National Institutes of Health (R01-GM120574 to G.T.M.) and RPI Center for Computational Innovations (to K.B. and G.T.M.). This research was also partly funded by CRIP (Center for Research for Influenza Pathogenesis), a NIAID-supported Center of Excellence for Influenza Research and Surveillance (HHSN272201400008C), DARPA grant HR0011-19-2-0020, NIAID grants U19AI142733 and U19AI135972, DOD grant W81XWH-20-1-0270, and by the generous support of the JPB Foundation, the Open Philanthropy Project (2020-215611 [5384)), and anonymous donors to A.G.-S. Conceptualization, K.B. K.W. B.H. C.A.R. A.G.-S. R.M.K. and G.T.M.; methodology, K.B. K.W. B.H. T.B.A. T.R. R.R. C.A.R. A.G.-S. R.M.K. and G.T.M.; validation, K.B. K.W. B.H. C.A.R. A.G.-S. R.M.K. and G.T.M.; formal analysis, K.B. K.W. B.H. T.R. C.A.R. A.G.-S. R.M.K. and G.T.M.; investigation, K.B. K.W. B.H. R.R. T.R. E.M. T.K. and L.M.; resources, C.A.R. A.G.-S. and G.T.M.; writing – original draft, K.B. K.W. A.G.-S. R.M.K. and G.T.M.; writing, review, and editing, K.B. K.W. B.H. C.A.R. A.G.-S. R.M.K. and G.T.M.; visualization, K.B. K.W. B.H. C.A.R. A.G.-S. R.M.K. and G.T.M.; supervision, K.W. C.A.R. A.G.-S. and G.T.M.; funding acquisition, C.A.R. A.G.-S. and G.T.M. A provisional patent application related to these studies has been filed. G.T.M. is a founder of Nexomics Biosciences, Inc. The A.G.-S. laboratory has received research support from Pfizer, Senhwa Biosciences, 7Hills Pharma, Avimex, Blade Therapeutics, Dynavax, ImmunityBio, Nanocomposix, Pharmamar, and Kenall Manufacturing, and A.G.-S. has consulting agreements for the following companies involving cash and/or stock: Vivaldi Biosciences, Pagoda, Contrafect, 7Hills Pharma, Avimex, Vaxalto, Accurius, Pfizer, and Esperovax. These relationships have no conflict of interest with respect to this study. Publisher Copyright: {\textcopyright} 2021 The Author(s)",
year = "2021",
month = may,
day = "18",
doi = "10.1016/j.celrep.2021.109133",
language = "English (US)",
volume = "35",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "7",
}