High-resolution structure, function, and anti-viral inhibition of the SARS-CoV2 E protein ion channel

SARS-CoV2 E蛋白离子通道的高分辨率结构、功能和抗病毒抑制作用

• 批准号: BB/V01997X/1
• 负责人: Ulrich Zachariae
• 金额: $ 64.11万
• 依托单位: University of Dundee
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FV01997X%2F1
• 关键词: resolution; structure; function; anti; viral

The Covid19-causing SARS-coronavirus-2 (SARS-CoV2) contains a small number of proteins, three of which reside in its membrane. They include the spike protein (S), responsible for attachment to the host, the membrane protein (M), and a cation-channel (membrane pore) formed by the envelope protein (E), CoV2E. Cation flow through the E-protein of SARS-coronaviruses (SARS-CoV) plays a role in virus replication in host cells. Inhibitors of the E-protein channel have been shown to substantially diminish virulence of SARS-CoV, the coronavirus responsible for the SARS outbreak in 2003. Inhibitors of CoV2E cation flux are expected to attenuate SARS-CoV2 pathogenicity and their discovery is the goal of this application. Repurposing drugs originally developed for other diseases offer a fast-track to new treatments. These will be included in the current study to expedite delivery of effective drugs. Structure-based drug design is another means to accelerate the discovery of drugs by enabling focused, rational approaches to design and repurposing. However, the structure of CoV2E is only partially known. We thus propose to (i) solve high-resolution crystal-structures of CoV2E, (ii) apply computational electrophysiology and in silico screens including cheminformatics/machine learning approaches to identify CoV2E inhibitors from libraries of commercially available and repurposing drugs, and (iii) perform lead validation and further development of inhibitors by electrophysiology and crystallography.

引起Covid 19的SARS冠状病毒2（SARS-CoV 2）含有少量蛋白质，其中三种蛋白质位于其膜上。它们包括负责附着于宿主的刺突蛋白（S）、膜蛋白（M）和由包膜蛋白（E）CoV 2 E形成的阳离子通道（膜孔）。通过SARS冠状病毒（SARS-CoV）E蛋白的阳离子流在宿主细胞中的病毒复制中起作用。E蛋白通道的抑制剂已被证明可以大大降低SARS-CoV的毒力，SARS-CoV是导致2003年SARS爆发的冠状病毒。CoV 2 E阳离子通量的抑制剂有望减弱SARS-CoV 2的致病性，它们的发现是本申请的目标。重新使用最初为其他疾病开发的药物为新的治疗方法提供了快速通道。这些将被纳入目前的研究，以加快有效药物的交付。基于结构的药物设计是另一种加速药物发现的手段，它通过实现集中、合理的设计和再利用方法来实现。然而，CoV 2 E的结构仅部分已知。因此，我们建议（i）解决CoV 2 E的高分辨率晶体结构，（ii）应用计算电生理学和计算机屏幕，包括化学信息学/机器学习方法，从市售和再利用药物库中识别CoV 2 E抑制剂，以及（iii）通过电生理学和晶体学进行先导验证和进一步开发抑制剂。