Cryo-EM studies to design broad-spectrum antivirals against RNA polymerases of respiratory viruses

The lack of therapeutic strategies targeting respiratory RNA viruses poses a significant public health challenge. Reports indicate that approximately 40,000 hospitalizations due to respiratory viral infection occur seasonally in Canada. Considering the average cost per acute care hospital admission (~$6,000), this represents an economic burden exceeding $200 million in healthcare expenses. While vaccines are the gold standard for disease mitigation, the time needed for their development and distribution restricts their utility. Therefore, we require safe and effective antiviral drugs that can bridge the time required for vaccine development and can be used in treatment regimens. In the case of HIV, antiviral drugs have saved millions of lives even without vaccines. Here, I aim to use state-of-the-art imaging techniques to understand how respiratory viruses replicate at the molecular level. These insights will guide the design of antivirals that are more effective and safer, ultimately helping us prepare for future viral threats. My previous publications defined the mechanisms of action for several antivirals against the RNA-dependent RNA polymerase (RdRp) of key respiratory RNA viruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), respiratory syncytial virus (RSV), and influenza virus. The RdRp is the engine that drives viral replication and is a logical antiviral target. Our studies contributed to the approval and authorization of remdesivir and molnupiravir for the treatment of COVID-19. Yet, antiviral activity can vary substantially across different viral families. My current project will extend beyond biochemistry to structurally evaluate how antivirals engage diverse RdRps, ultimately aiding the development of next-generation antivirals with improved potency. My extensive experience characterizing viral RdRps biochemically has uniquely prepared me to lead this structural investigation.