Project 458197

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease of 2019 (COVID-19), revealed the debilitating potential of RNA viruses in the absence of effective medical countermeasures. Neither vaccines nor antiviral drugs were available when the World Health Organization (WHO) declared the pandemic. While the rapid development of COVID-19 vaccines is currently viewed as a "game changer", the toll of the disease has been enormous with > 3.8M deaths worldwide and >25,000 in Canada. To be prepared for future outbreaks or another pandemic, we need effective tools for immediate use that help to bridge the time required for the development of vaccines. These tools are potent antiviral drugs. In the case of HIV, antiviral drugs have saved millions of lives even in the absence of vaccines. Here I propose to lay the foundation for the development of broad-spectrum antivirals that can serve as the first line of defense in outbreak situations with RNA viruses. My previous publications defined the mechanism of action (MOA) for two different antivirals, remdesivir (RDV) and molnupiravir (MLP), against the RNA-dependant RNA polymerase (RdRp) of SARS-CoV-2. The RdRp is the engine that drives viral propagation, and a logical antiviral target. RDV is currently the only approved antiviral for COVID-19 treatment, while MLP is in phase 3 clinical trials. RDV and MLP are broad-spectrum antivirals inhibiting multiple RNA viruses, however the MOA remains unknown. Our lab has worked diligently to express and characterize an expansive platform of RdRp enzymes from RNA viruses the WHO has classified as priority pathogens. This project will elucidate a unified MOA for RDV and MLP across multiple viral RdRps, ultimately assisting in the development of next generation antivirals. My strong history of work with the SARS-CoV-2 RdRp has positioned me to lead this project.