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

引起SARS的SARS冠状病毒-2(SARS-CoV2)含有少量蛋白质，其中三种存在于其膜上。它们包括负责与宿主结合的刺突蛋白(S)、膜蛋白(M)和由包膜蛋白(E)形成的阳离子通道(膜孔)CoV2E。SARS冠状病毒(SARS-CoV)E蛋白阳离子流在宿主细胞内的病毒复制中起作用。E蛋白通道的抑制剂已被证明可显著降低SARS-CoV的毒力，SARS-CoV是导致2003年SARS爆发的冠状病毒。CoV2E阳离子通量的抑制剂有望减弱SARS-CoV2的致病性，他们的发现是本应用的目标。改变最初为其他疾病开发的药物的用途，为新的治疗提供了一条快速通道。这些将包括在目前的研究中，以加快有效药物的交付。基于结构的药物设计是加速药物发现的另一种手段，它使有针对性的、合理的设计和再利用方法成为可能。然而，CoV2E的结构还只是部分已知。因此，我们建议(I)解决CoV2E的高分辨率晶体结构，(Ii)应用计算电生理学和电子筛选，包括化学信息学/机器学习方法，从商业可获得和再利用的药物库中识别CoV2E抑制剂，以及(Iii)通过电生理学和结晶学进行铅验证和进一步开发抑制剂。

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.