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

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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.