Characterization and structures of the SARS-CoV-2 polymerase and its complex with RNA or potential inhibitors

While severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2, short name CoV-2) is currently spreading globally and imposing a tremendous public health threat, no vaccines and therapeutic agents against CoV-2 are currently available. Discovery and development of any antiviral therapeutic agents require a great deal of basic mechanistic knowledge that can guide both target discovery and assay development. In particular, viral polymerases have been major therapeutic targets, as seen in multiple drug discovery successes in various viral pathogens, including HIV-1, HCV, and HBV. Drug design and target search heavily rely on an accurate understanding of the structure and functions of the target molecules, and, for this reason, various viral polymerases have been extensively investigated for their structures and functions. Due to this current CoV-2 outbreak, demands for the fundamental scientific knowledge on the CoV-2 target molecules have been growing significantly in both academics and industry worldwide. Recently, we launched a research and discovery project for anti-CoV-2 RNA polymerase agents with structure and function analysis. In this application, we propose to gain high-resolution structures of the CoV-2 RNA polymerase (a complex of nsp12:nsp7:nsp8) and its complex with RNA or potential inhibitors by cryo-electron microscopy (cryo-EM). Overall, these in-depth biophysical and biochemical investigations aim to provide high-resolution accurate structural and mechanistic knowledge of the CoV-2 RNA polymerase that can be used for therapeutic target discovery and development.