Crystallographic and electrophilic fragment screening of the SARS-CoV-2 main protease.
Crystallographic and electrophilic fragment screening of the SARS-CoV-2 main protease.
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DOI：
10.1038/s41467-020-18709-w
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发表时间：
2020-10-07
影响因子：
16.6
通讯作者：
Walsh MA
中科院分区：
文献类型：
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作者：
Douangamath A;Fearon D;Gehrtz P;Krojer T;Lukacik P;Owen CD;Resnick E;Strain-Damerell C;Aimon A;Ábrányi-Balogh P;Brandão-Neto J;Carbery A;Davison G;Dias A;Downes TD;Dunnett L;Fairhead M;Firth JD;Jones SP;Keeley A;Keserü GM;Klein HF;Martin MP;Noble MEM;O'Brien P;Powell A;Reddi RN;Skyner R;Snee M;Waring MJ;Wild C;London N;von Delft F;Walsh MA
由SARS-CoV-2引起的COVID-19缺乏有效的治疗方法。此外，尽管之前曾爆发过人畜共患疾病，但尚未开发出针对密切相关的冠状病毒SARS-CoV-1或MERS-CoV的抗病毒药物或疫苗。为了确定这种治疗方法的起点，我们通过质谱和X射线相结合的方法对SARS-CoV-2主要蛋白酶（病毒复制所必需的两种半胱氨酸病毒蛋白酶之一）进行了亲电体和非共价片段的大规模筛选。我们的晶体学筛选鉴定了71个跨越整个活性位点的命中，以及在二聚体界面处的3个命中。这些结构揭示了通过共价和非共价片段命中的合并快速开发更有效的抑制剂的途径;一系列低反应性、易处理的共价片段被开发以发现改进的结合剂。这些组合的命中提供了前所未有的结构和反应性信息，正在进行的基于结构的药物设计针对SARS-CoV-2主要蛋白酶。SARS-CoV-2主要蛋白酶是COVID-19治疗药物开发的重要靶点。在这里，作者结合联合收割机X射线晶体学和质谱，并进行了大规模的片段筛选活动，产生了96个配体结构的这种重要的病毒蛋白，是感兴趣的进一步药物开发工作。
COVID-19, caused by SARS-CoV-2, lacks effective therapeutics. Additionally, no antiviral drugs or vaccines were developed against the closely related coronavirus, SARS-CoV-1 or MERS-CoV, despite previous zoonotic outbreaks. To identify starting points for such therapeutics, we performed a large-scale screen of electrophile and non-covalent fragments through a combined mass spectrometry and X-ray approach against the SARS-CoV-2 main protease, one of two cysteine viral proteases essential for viral replication. Our crystallographic screen identified 71 hits that span the entire active site, as well as 3 hits at the dimer interface. These structures reveal routes to rapidly develop more potent inhibitors through merging of covalent and non-covalent fragment hits; one series of low-reactivity, tractable covalent fragments were progressed to discover improved binders. These combined hits offer unprecedented structural and reactivity information for on-going structure-based drug design against SARS-CoV-2 main protease. The SARS-CoV-2 main protease is an important target for the development of COVID-19 therapeutics. Here, the authors combine X-ray crystallography and mass spectrometry and performed a large scale fragment screening campaign, which yielded 96 liganded structures of this essential viral protein that are of interest for further drug development efforts.