SIRTUIN AGONISTS AS PAN INFLUENZA ANTIVIRALS

DESCRIPTIONprovided by applicantCurrent antivirals for influenza infection target specific viral proteinsDue to marked genetic diversitydifferent strains of influenza demonstrate differential sensitivity to marketed anti influenza drugsAdditionallycurrent drugs remain vulnerable to the rapid development of virus resistanceThe present project proposes to validate a paradigm shifting antiviral mechanism of actionthe activation of host encoded sirtuinsSirtuins are a family of seven NADdependent deacylases known for regulating numerous cellular and organismal functionsincluding metabolismcell cycle and longevitySirtuins may also be evolutionarily conserved broadspectrum viral restriction factors based on experiments demonstrating that activation of sirtuins in eukaryotic or prokaryotic host cells increases growth of diverse viruses including bacteriophagesKoyuncu et almBioeIn the case of influenza ASirtand Sirthave the largest effects on virus growthIndeed a small molecule screen for sirtuin agonists identified a Sirtand a Sirt andampactivatoreach with a distinct chemical scaffoldas potent broad spectrum antiviralscompleted medicinal chemistry improved the antiviral potency of the Sirt andampactivator compared to the screen identified molecule and a patent application was filed on this scaffoldIn additiontwo independently published mouse studies demonstrate in vivo anti influenza efficacy for two plant polyphenols resveratrol and isoquercetin that are now known to be SirtactivatorsImportantlyisoquercetin prevented the accumulation of viral resistance observed for direct acting antivirals amantadine and oseltamivir during serial passage in cultureProposed Phase I goals are to confirm sirtuin activation provides efficacy against multiple seasonalpandemicand resistant influenza A and B strainsand a high barrier against future acquired resistance in cell cultureand to reproduce the apparent antiviral efficacy observed in mouse influenza challenge for proposed proprietary activators as was demonstrated for tool compoundsSirtactivators isoquercetin and resveratrolOnce a lead series is prioritized based on the Phase I resultsthe Phase II component of the grant will further progress a medicinal chemistry campaign to improve the potency and pharmacokinetic properties of the lead series to deliver advanced compounds with oral bioavailability and comparable efficacy as stand alone or in combination with oseltamivir in the mouse modelSuch a product will address unmet medical need compared to oseltamivirbecause compared to oseltamivirthese drugs shouldbroadly inhibit all subtypes of influenza A and Bblock the replication of viruses resistant to current therapiesanddramatically reduce the development of viral resistance during standalone or combination treatment PUBLIC HEALTH RELEVANCESeasonal flu annually causes considerable morbidity and mortalityits overall burden to the U Seconomy is estimated to be $B per yearFORGE Life Science is developing antiviral drugs that boost a patientandapos s own innate cellular defense against the flu causing virusinfluenza Aby activating viral restriction factors of the human host cell when infected by virusCompared to current anti influenza drugsFORGE antivirals will provide an advanced therapeutic option in treatment of flu byproviding protection against a wide range of flu causing virus typesinfluenza A and Bstrains both sensitive and resistant to existing flu antiviralsand bygreatly reducing acquired viral resistance