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《Nature，4月9日，Structure of Mpro from COVID-19 virus and discovery of its inhibitors》

  • 来源专题：COVID-19科研动态监测
  • 编译者： zhangmin
  • 发布时间：2020-04-10

  • Structure of Mpro from COVID-19 virus and discovery of its inhibitors

    Zhenming Jin, Xiaoyu Du, […]Haitao Yang

    Nature (2020)

    Abstract

    A new coronavirus (CoV) identified as COVID-19 virus is the etiological agent responsible for the 2019-2020 viral pneumonia outbreak that commenced in Wuhan1–4. Currently there are no targeted therapeutics and effective treatment options remain very limited. In order to rapidly discover lead compounds for clinical use, we initiated a program of combined structure-assisted drug design, virtual drug screening and high-throughput screening to identify new drug leads that target the COVID-19 virus main protease (Mpro). Mpro is a key CoV enzyme, which plays a pivotal role in mediating viral replication and transcription, making it an attractive drug target for this virus5,6.

  • 原文来源：https://www.nature.com/articles/s41586-020-2223-y
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  • 《4月9日_COVID-19病毒蛋白酶Mpro结构解析及其抑制剂的筛选》
    • 来源专题：COVID-19科研动态监测
    • 编译者：xuwenwhlib
    • 发布时间：2020-04-10
    • 信息名称：COVID-19病毒蛋白酶Mpro结构解析及其抑制剂的筛选 1.时间：2020年4月9日 2.机构或团队：上海科技大学免疫化学研究所、清华大学、中国科学院上海药物研究所、军事医学科学院微生物流行病研究所、中国科学院武汉病毒研究所等 3.事件概要： 上海科技大学免疫化学研究所等于2020年4月9日在Nature期刊上发表题为“Structure of Mpro from COVID-19 virus and discovery of its inhibitors”的文章。文章指出，目前还没有针对COVID-19病毒的靶向治疗药物，有效的治疗方案仍然非常有限。为了快速发现可用于临床的靶向药物，研究人员启动了一个结构辅助药物设计、虚拟药物筛选和高通量筛选相结合的项目，以确定靶向COVID-19病毒主要蛋白酶（Mpro）的新药线索。Mpro是一种关键的COV酶，它在介导病毒复制和转录中起着关键作用，使其成为该病毒有吸引力的药物靶点。文章中，研究人员通过计算机辅助药物设计确定了一种抑制剂N3，并确定了COVID-19病毒Mpro与该化合物的复合物的晶体结构；研究人员通过基于结构的虚拟和高通量筛选相结合的方法，检测了超过10,000种化合物是否可作为Mpro的抑制剂，包括已批准的药物、临床试验中的候选药物和其他药理活性化合物。文中结果指出，其中有6种化合物对Mpro有抑制作用，IC50值在0.67～21.4μM之间；Ebselen在细胞实验中表现出了良好的抗病毒活性。作者指出，其研究结果证明了这一筛选策略的有效性，可以快速发现具有临床潜力的药物线索，以应对目前尚无特异性药物或疫苗的新发传染病。 4.附件： 原文链接 https://www.nature.com/articles/s41586-020-2223-y
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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.
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