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《Nature，9月4日，Both Boceprevir and GC376 efficaciously inhibit SARS-CoV-2 by targeting its main protease》

  • 来源专题：COVID-19科研动态监测
  • 编译者： zhangmin
  • 发布时间：2020-09-15

  • Both Boceprevir and GC376 efficaciously inhibit SARS-CoV-2 by targeting its main protease
    Lifeng Fu, Fei Ye, Yong Feng, Feng Yu, Qisheng Wang, Yan Wu, Cheng Zhao, Huan Sun, Baoying Huang, Peihua Niu, Hao Song, Yi Shi, Xuebing Li, Wenjie Tan, Jianxun Qi & George Fu Gao
    Nature Communications volume 11, Article number: 4417 (2020)

    Abstract
    COVID-19 was declared a pandemic on March 11 by WHO, due to its great threat to global public health. The coronavirus main protease (Mpro, 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 Mpro. 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 Mpro 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.

  • 原文来源：https://www.nature.com/articles/s41467-020-18233-x
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  • 《9月4日_Boceprevir和GC376可有效抑制SARS-CoV-2》
    • 来源专题：COVID-19科研动态监测
    • 编译者：zhangmin
    • 发布时间：2020-09-15
    • Nature Communications 于9月4日出版了中国科学院微生物研究所、中国科学院新发突发传染病研究与交流卓越中心、中国疾病预防控制中心病毒病预防控制所等机构的研究论文“Both Boceprevir and GC376 efficaciously inhibit SARS-CoV-2 by targeting its main protease”。文章指出，冠状病毒主要蛋白酶（Mpro，也称为3CLpro）对于病毒多聚蛋白的加工和成熟至关重要，因此被公认为是一个有吸引力的药物靶标。该文章中，研究表明，一种临床批准的抗HCV（丙型肝炎病毒）药物Boceprevir（波普瑞韦）和一种针对猫传染性腹膜炎病毒（FIPV）的临床前抑制剂GC376，均通过靶向Mpro有效抑制了Vero细胞中的SARS-CoV-2。此外，将GC376与Remdesivir（瑞德西韦）组合使用，可产生累加的消毒作用。进一步的结构分析表明，两种抑制剂与SARS-CoV-2蛋白酶Mpro的催化活性侧结合是抑制的主要机理。文章表示，该发现可能为优化和设计针对SARS-CoV-2病毒的更有效的抑制剂提供关键信息。 原文链接：https://www.nature.com/articles/s41467-020-18233-x
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  • 《Nature，6月15日，Boceprevir, GC-376, and calpain inhibitors II, XII inhibit SARS-CoV-2 viral replication by targeting the viral main protease》
    • 来源专题：COVID-19科研动态监测
    • 编译者：zhangmin
    • 发布时间：2020-06-16
    • Boceprevir, GC-376, and calpain inhibitors II, XII inhibit SARS-CoV-2 viral replication by targeting the viral main protease Chunlong Ma, Michael Dominic Sacco, Brett Hurst, Julia Alma Townsend, Yanmei Hu, Tommy Szeto, Xiujun Zhang, Bart Tarbet, Michael Thomas Marty, Yu Chen & Jun Wang Cell Research (2020) Abstract A new coronavirus SARS-CoV-2, also called novel coronavirus 2019 (2019-nCoV), started to circulate among humans around December 2019, and it is now widespread as a global pandemic. The disease caused by SARS-CoV-2 virus is called COVID-19, which is highly contagious and has an overall mortality rate of 6.35% as of May 26, 2020. There is no vaccine or antiviral available for SARS-CoV-2. In this study, we report our discovery of inhibitors targeting the SARS-CoV-2 main protease (Mpro). Using the FRET-based enzymatic assay, several inhibitors including boceprevir, GC-376, and calpain inhibitors II, and XII were identified to have potent activity with single-digit to submicromolar IC50 values in the enzymatic assay. The mechanism of action of the hits was further characterized using enzyme kinetic studies, thermal shift binding assays, and native mass spectrometry. Significantly, four compounds (boceprevir, GC-376, calpain inhibitors II and XII) inhibit SARS-CoV-2 viral replication in cell culture with EC50 values ranging from 0.49 to 3.37 µM. Notably, boceprevir, calpain inhibitors II and XII represent novel chemotypes that are distinct from known substrate-based peptidomimetic Mpro inhibitors. A complex crystal structure of SARS-CoV-2 Mpro with GC-376, determined at 2.15 Å resolution with three protomers per asymmetric unit, revealed two unique binding configurations, shedding light on the molecular interactions and protein conformational flexibility underlying substrate and inhibitor binding by Mpro. Overall, the compounds identified herein provide promising starting points for the further development of SARS-CoV-2 therapeutics.
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