Abstract:Flaviviruses are primarily insect-borne associated with global morbidity and mortality and found on everyinhabited continent. Unfortunately current therapeutic options for treating diseases associated with these virusesare limited. All flaviviruses encode methyltransferases (MTases)flaviviral NS5 for both N-7 and 2'-Omethylations of viral genomic RNA. The N-7 MTase function is essential for replication of the viral RNA genomewhereas 2'-O MTase function is required for the virus to evade the host innate immune response. These activitiesare conserved among the flaviviruses. For this project our collaborative team will optimize the current leadcompounds perform high throughput screening (HTS) to identify additional lead candidates chemically optimizethe lead candidates and define structure activity relationships. Optimizing current lead compounds using cutting-edge medicinal chemistry the team will perform a large scale HTS campaign using innovative fluorescencechemical probes to identify additional small molecule inhibitors of flavivirus RNA capping MTases. We willperform an in-depth investigation of the model of action and antiviral efficacy using in vitro biochemistry structuralbiology virology in vivo pharmacokinetics and in vivo animal models which will allow the development of noveleffective broad-spectrum and druglike therapeutic agents against both flaviviruses. Preliminary progress hasbeen made in the identification of initial lead inhibitors of these MTases demonstrating low nanomolar antiviralactivity. We will advance these compounds to further develop potent antiviral compounds while conducting large-scale screening in parallel for additional structural scaffold discoveries. Complementary expertise among ourinvestigators will synergize and expedite the progress of this research. Our collaborative objective is to providefirst-in-class drug candidates for the treatment or prevention of these viral infections.