Design and evaluation of novel inhibitors targeting SARS-CoV-2 polymerase to create lead compounds to develop more effective treatments of COVID-19 [Added supplement: COVID-19 Variant Supplement]

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which causes COVID-19 produces a key enzyme, nsp12, essential for replicating the viral genome. In combination with the sequence of nsp12 from SARS-CoV-2, previous studies on closely related enzymes from other viruses provide insights into how nsp12 functions. Our analysis indicates how the specific structural features of nsp12 provide new opportunities for creating inhibitors with higher activity and specificity, and thus likely to act as more effective medications for treating COVID-19. Our models of the 3D structures of nsp12 bound to RNA and drugs like remdesivir indicate how existing inhibitor compounds developed to treat other viral diseases could be modified to work more effectively for treating COVID-19. We propose to synthesize a series of modified inhibitors tailored to fit the structure of nsp12 and then test the activity of these inhibitors on purified nsp12 using a previously published assay procedure. The ability of different inhibitors to disrupt the activity of nsp12 will be measured using this assay. The most effective inhibitors will be cocrystallized into a hybrid form of the norovirus polymerase to provide timely structural information about how inhibitors are likely to bind to nsp12. This structural information will help to further refine the design and improvement of the next generation of inhibitors. Promising inhibitors will be passed on to collaborators and the general community to evaluate their effectiveness in cell culture infection models and ultimately in human clinical trials. We expect to synthesize the first series of novel inhibitors within 4-6 months and to be able to evaluate their activity by the end of 2020. Additional structural characterization will take another 4-6 months. Based on this information, a second generation of inhibitors will be prepared and characterized by the end of the 2-year project.