Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved α-ketoamide inhibitors
Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved α-ketoamide inhibitors
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DOI：
10.1126/science.abb3405
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发表时间：
2020-04-24
期刊：
影响因子：
56.9
通讯作者：
Hilgenfeld, Rolf
中科院分区：
文献类型：
--
作者：
Zhang, Linlin;Lin, Daizong;Hilgenfeld, Rolf
由严重急性呼吸系统综合征-冠状病毒2 （SARS-CoV-2）引起的2019冠状病毒病（COVID-19）大流行是全球突发卫生事件。在冠状病毒中，一个有吸引力的药物靶标是主要蛋白酶（M-pro，也称为3CL(pro)），因为它在处理从病毒RNA翻译的多蛋白方面起着重要作用。我们报道了非配体SARS-CoV-2 M-pro及其与α -酮酰胺抑制剂复合物的x射线结构。这是从先前设计的抑制剂衍生出来的，但将P3-P2酰胺键结合到吡酮环中，以提高化合物在血浆中的半衰期。在非配体结构的基础上，我们将先导化合物开发成一种有效的SARS-CoV-2 Mpro抑制剂。优化后的抑制剂的药代动力学特征显示了明显的肺向性和通过吸入途径给药的适用性。
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 (M-pro, also called 3CL(pro)) 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 M-pro and its complex with an alpha-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.