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

• Published in: Nature communications Vol. 11; no. 1; p. 4417
• Main Authors: Fu, Lifeng, Ye, Fei, Feng, Yong, Yu, Feng, Wang, Qisheng, Wu, Yan, Zhao, Cheng, Sun, Huan, Huang, Baoying, Niu, Peihua, Song, Hao, Shi, Yi, Li, Xuebing, Tan, Wenjie, Qi, Jianxun, Gao, George Fu
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 04.09.2020; Nature Publishing Group UK; Nature Portfolio
• Subjects: 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; Health risks; High-Throughput Screening Assays; Inhibitors; Maturation; Models, Molecular; 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; Severe acute respiratory syndrome; 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
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-18233-x

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 , 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 . 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 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.