Journal Article

Both Boceprevir and GC376 efficaciously inhibit SARS-CoV-2 by targeting its main protease

Feng, Yong, Wang, Qisheng, Shi, Yi, Li, Xuebing, Tan, Wenjie, Fu, Lifeng, Qi, Jianxun, Zhao, Cheng, Yu, Feng, Song, Hao, Gao, George Fu, Ye, Fei, Wu, Yan, Huang, Baoying, Sun, Huan, Niu, Peihua

2020

Overview

COVID-19 was declared a pandemic on March 11 by WHO, due to its great threat to global public health. The coronavirus main protease (M pro , also called 3CLpro) is essential for processing and maturation of the viral polyprotein, therefore recognized as an attractive drug target. Here we show that a clinically approved anti-HCV drug, Boceprevir, and a pre-clinical inhibitor against feline infectious peritonitis (corona) virus (FIPV), GC376, both efficaciously inhibit SARS-CoV-2 in Vero cells by targeting M pro . Moreover, combined application of GC376 with Remdesivir, a nucleotide analogue that inhibits viral RNA dependent RNA polymerase (RdRp), results in sterilizing additive effect. Further structural analysis reveals binding of both inhibitors to the catalytically active side of SARS-CoV-2 protease M pro as main mechanism of inhibition. Our findings may provide critical information for the optimization and design of more potent inhibitors against the emerging SARS-CoV-2 virus. Coronavirus main protease is essential for viral polyprotein processing and maturation. Here Fu et al. report efficient inhibition of SARS-CoV-2 replication using two inhibitors - Boceprevir and GC376 - targeting the active site of the main viral protease.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 631/154/1435/2163 / 631/326/596/4130 / 631/45/607/468 / 631/535/1266/1265 / 82/47 / 82/80 / 82/83 / Animals / Antiviral Agents - pharmacology / Antiviral drugs / Betacoronavirus - drug effects / Betacoronavirus - enzymology / Binding Sites - drug effects / Catalytic Domain / Chlorocebus aethiops / Coronavirus 3C Proteases / Coronavirus Infections - drug therapy / Coronavirus Infections - virology / Coronaviruses / COVID-19 / COVID-19 Drug Treatment / Crystallography, X-Ray / Cysteine Endopeptidases - chemistry / Cysteine Endopeptidases - metabolism / Design optimization / Disease Models, Animal / DNA-directed RNA polymerase / Feline infectious peritonitis / High-Throughput Screening Assays / Humanities and Social Sciences / Inhibitors / Maturation / Models, Molecular / multidisciplinary / Nucleotide analogs / Nucleotides / Pandemics / Peritonitis / Pneumonia, Viral - drug therapy / Pneumonia, Viral - virology / Proline - analogs & derivatives / Proline - pharmacology / Protease / Protease Inhibitors - pharmacology / Proteinase / Public health / Pyrrolidines - pharmacology / RNA polymerase / RNA-Dependent RNA Polymerase - antagonists & inhibitors / RNA-Dependent RNA Polymerase - chemistry / RNA-Dependent RNA Polymerase - metabolism / SARS-CoV-2 / Science / Science (multidisciplinary) / Severe acute respiratory syndrome coronavirus 2 / Structural analysis / Sulfonic Acids / Therapeutic targets / Vero Cells / Viral diseases / Viral Nonstructural Proteins - antagonists & inhibitors / Viral Nonstructural Proteins - chemistry / Viral Nonstructural Proteins - metabolism / Virus Replication - drug effects / Viruses