Grant: Travel Awards - Institute Community Support

Positive-strand RNA (+RNA) viruses including coronaviruses, flaviviruses, and picornaviruses remain a persistent global threat. Current antiviral strategies overwhelmingly target the viral RNA-dependent RNA polymerase (RdRp) complex, a replication machinery that rapidly acquires drug resistance. My research program proposes a paradigm shift: instead of inhibiting viral RNA polymerase, I aim to test the concept of a new generation of antivirals that block the pores on viral replication organelles through which viral mRNA must pass during genome replication. Recent studies have revealed that these molecular pores link RNA synthesis to exit from viral replication organelles, yet direct-acting-antivirals targeting these structures have not been found. This research focuses on testing, characterizing, and validating nucleoside analogs that are chemically modified to create steric hindrance within the RNA-transiting viral pores. We will integrate cell-based assays, biochemical reconstitutions and high-resolution imaging to determine: 1) if "bulky" nucleoside analogs are anti-coronaviral; 2) how the pore architecture interacts with viral nascent mRNA that incorporates "bulky" nucleoside analogs; and 3) if selected analogs are broadly effective against different +RNA viruses. By coupling antiviral assays with high-resolution structural insights, this research seeks to discover a new class of broad-spectrum antivirals that disrupt an essential step of viral life cycle, completely orthogonal to existing antiviral strategies. This approach directly advances Canada's priorities in pandemic preparedness and therapeutic innovation by laying the groundwork for next-generation antivirals with improved resilience against emerging +RNA viruses.