Structure-based design of antiviral drug candidates targeting the SARS-CoV-2 main protease

• Published in: Science (American Association for the Advancement of Science) Vol. 368; no. 6497; pp. 1331 - 1335
• Main Authors: Dai, Wenhao, Zhang, Bing, Jiang, Xia-Ming, Su, Haixia, Li, Jian, Zhao, Yao, Xie, Xiong, Jin, Zhenming, Peng, Jingjing, Liu, Fengjiang, Li, Chunpu, Li, You, Bai, Fang, Wang, Haofeng, Cheng, Xi, Cen, Xiaobo, Hu, Shulei, Yang, Xiuna, Wang, Jiang, Liu, Xiang, Xiao, Gengfu, Jiang, Hualiang, Rao, Zihe, Zhang, Lei-Ke, Xu, Yechun, Yang, Haitao, Liu, Hong
• Format: Journal Article
• Language: English
• Published: United States The American Association for the Advancement of Science 19.06.2020; American Association for the Advancement of Science
• Subjects: Aldehydes; Animals; Antiviral activity; Antiviral Agents - chemistry; Antiviral Agents - pharmacology; Antiviral drugs; Betacoronavirus - drug effects; Betacoronavirus - enzymology; Biochem; Biocompatibility; Catalytic Domain; Cell culture; Chlorocebus aethiops; Coronaviridae; Coronavirus 3C Proteases; Coronavirus Infections - drug therapy; Coronaviruses; COVID-19; Crystal structure; Cysteine Endopeptidases; Dogs; Drug Design; Drug development; Drug Evaluation, Preclinical; Etiology; Female; Humans; Lead compounds; Male; Mice; Molecular Structure; Pandemics; Pharmacokinetics; Pharmacology; Pneumonia, Viral - drug therapy; Protease; Protease inhibitors; Protein Structure, Tertiary; Proteinase inhibitors; Racing; Rats, Sprague-Dawley; Replication; Respiratory diseases; SARS-CoV-2; Severe acute respiratory syndrome coronavirus 2; Therapeutic targets; Toxicity; Toxicity testing; Toxicity Tests; Transcription; Vero Cells; Viral diseases; Viral Nonstructural Proteins - antagonists & inhibitors; Viruses
• ISSN: 0036-8075; 1095-9203; 1095-9203
• DOI: 10.1126/science.abb4489

With no vaccine or proven effective drug against the virus that causes coronavirus disease 2019 (COVID-19), scientists are racing to find clinical antiviral treatments. A promising drug target is the viral main protease M pro , which plays a key role in viral replication and transcription. Dai et al. designed two inhibitors, 11a and 11b, based on analyzing the structure of the M pro active site. Both strongly inhibited the activity of M pro and showed good antiviral activity in cell culture. Compound 11a had better pharmacokinetic properties and low toxicity when tested in mice and dogs, suggesting that this compound is a promising drug candidate. Science , this issue p. 1331 Two peptidomimetic aldehydes were designed, synthesized, and evaluated as antiviral drug candidates. SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) is the etiological agent responsible for the global COVID-19 (coronavirus disease 2019) outbreak. The main protease of SARS-CoV-2, M pro , is a key enzyme that plays a pivotal role in mediating viral replication and transcription. We designed and synthesized two lead compounds ( 11a and 11b ) targeting M pro . Both exhibited excellent inhibitory activity and potent anti–SARS-CoV-2 infection activity. The x-ray crystal structures of SARS-CoV-2 M pro in complex with 11a or 11b , both determined at a resolution of 1.5 angstroms, showed that the aldehyde groups of 11a and 11b are covalently bound to cysteine 145 of M pro . Both compounds showed good pharmacokinetic properties in vivo, and 11a also exhibited low toxicity, which suggests that these compounds are promising drug candidates.