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《Science，4月24日，Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved α-ketoamide inhibitors》

  • 来源专题：COVID-19科研动态监测
  • 编译者： zhangmin
  • 发布时间：2020-04-25

  • Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved α-ketoamide inhibitors

    Linlin Zhang1,2, Daizong Lin1,3, Xinyuanyuan Sun1,2, Ute Curth4, Christian Drosten5, Lucie Sauerhering6,7, Stephan Becker6,7, Katharina Rox8,9, Rolf Hilgenfeld1,2,*

    See all authors and affiliations

    Science 24 Apr 2020:

    Vol. 368, Issue 6489, pp. 409-412

    DOI: 10.1126/science.abb3405

    Abstract

    The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome–coronavirus 2 (SARS-CoV-2) is a global health emergency. An attractive drug target among coronaviruses is the main protease (Mpro, also called 3CLpro) because of its essential role in processing the polyproteins that are translated from the viral RNA. We report the x-ray structures of the unliganded SARS-CoV-2 Mpro and its complex with an α-ketoamide inhibitor. This was derived from a previously designed inhibitor but with the P3-P2 amide bond incorporated into a pyridone ring to enhance the half-life of the compound in plasma. On the basis of the unliganded structure, we developed the lead compound into a potent inhibitor of the SARS-CoV-2 Mpro. The pharmacokinetic characterization of the optimized inhibitor reveals a pronounced lung tropism and suitability for administration by the inhalative route.

  • 原文来源：https://science.sciencemag.org/content/368/6489/409
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    • 编译者：xuwenwhlib
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    • 来源专题：COVID-19科研动态监测
    • 编译者：zhangmin
    • 发布时间：2020-12-23
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