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SARS-CoV-2 Mpro inhibitors and activity-based probes for patient-sample imaging.

SARS-CoV-2用于患者样本成像的Mpro抑制剂和基于活性的探针。

  • 影响因子:9.33
  • DOI:10.1038/s41589-020-00689-z
  • 作者列表:"Rut W","Groborz K","Zhang L","Sun X","Zmudzinski M","Pawlik B","Wang X","Jochmans D","Neyts J","Młynarski W","Hilgenfeld R","Drag M
  • 发表时间:2021-02-01
Abstract

:In December 2019, the first cases of infection with a novel coronavirus, SARS-CoV-2, were diagnosed. Currently, there is no effective antiviral treatment for COVID-19. To address this emerging problem, we focused on the SARS-CoV-2 main protease that constitutes one of the most attractive antiviral drug targets. We have synthesized a combinatorial library of fluorogenic substrates with glutamine in the P1 position. We used it to determine the substrate preferences of the SARS-CoV and SARS-CoV-2 main proteases. On the basis of these findings, we designed and synthesized a potent SARS-CoV-2 inhibitor (Ac-Abu-DTyr-Leu-Gln-VS, half-maximal effective concentration of 3.7 µM) and two activity-based probes, for one of which we determined the crystal structure of its complex with the SARS-CoV-2 Mpro. We visualized active SARS-CoV-2 Mpro in nasopharyngeal epithelial cells of patients suffering from COVID-19 infection. The results of our work provide a structural framework for the design of inhibitors as antiviral agents and/or diagnostic tests.

摘要

: 2019年12月,第一批感染新型冠状病毒的病例被诊断为SARS-CoV-2。目前,新型冠状病毒肺炎尚无有效的抗病毒治疗方法。为了解决这个新出现的问题,我们关注了构成最有吸引力的抗病毒药物靶标之一的SARS-CoV-2主要蛋白酶。我们已经在P1位置合成了具有谷氨酰胺的荧光底物的组合文库。我们用它来确定SARS-CoV和SARS-CoV-2主要蛋白酶的底物偏好。基于这些发现,我们设计并合成了一种有效的SARS-CoV-2抑制剂 (Ac-Abu-DTyr-Leu-Gln-VS,半数最大有效浓度为3.7 μ m) 和两种基于活性的探针,其中一个我们用SARS-CoV-2 Mpro测定了其配合物的晶体结构。我们在患有SARS-CoV-2感染的患者的鼻咽上皮细胞中观察到活性新型冠状病毒肺炎Mpro。我们的工作结果为作为抗病毒剂和/或诊断测试的抑制剂的设计提供了结构框架。

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发表时间:2021-02-01
DOI:10.1007/s11033-021-06155-w
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发表时间:2021-02-01
DOI:10.1080/14656566.2020.1814255
作者列表:["Sawada H","Oeda T","Kohsaka M","Tomita S","Umemura A","Park K","Yamamoto K","Kiyohara K"]

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发表时间:2021-03-24
DOI:10.1007/s11033-021-06299-9
作者列表:["Louvrier A","Terranova L","Meyer C","Meyer F","Euvrard E","Kroemer M","Rolin G"]

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