Diamond Light Source Ltd., Harwell Science and Innovation Campus, Didcot, OX11 0QX, UK.
Research Complex at Harwell, Harwell Science and Innovation Campus, Didcot, OX11 0FA, UK.
Nat Commun. 2020 Oct 7;11(1):5047. doi: 10.1038/s41467-020-18709-w.
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.
新型冠状病毒病（COVID-19）由严重急性呼吸综合征冠状病毒 2（SARS-CoV-2）引起，目前尚无有效的治疗方法。此外，尽管此前发生过动物源性冠状病毒 SARS-CoV-1 和中东呼吸综合征冠状病毒（MERS-CoV）的人间暴发，但仍未针对这两种密切相关的冠状病毒开发出抗病毒药物或疫苗。为了寻找针对这种疾病的治疗方法的切入点，我们针对 SARS-CoV-2 的主要蛋白酶（两种半胱氨酸病毒蛋白酶之一，对病毒复制至关重要）进行了大规模的亲电和亲脂小分子及非共价小分子筛选，该筛选方法结合了质谱和 X 射线技术。我们的晶体筛选鉴定出 71 个跨越整个活性位点的结合物，以及 3 个在二聚体界面的结合物。这些结构揭示了通过融合共价和非共价片段结合物来快速开发更有效的抑制剂的途径；一系列低反应性、易于处理的共价片段已被推进，以发现更好的结合物。这些组合的结合物为针对 SARS-CoV-2 主要蛋白酶的正在进行的基于结构的药物设计提供了前所未有的结构和反应性信息。
