SIRTUIN AGONISTS AS PAN INFLUENZA ANTIVIRALS

DESCRIPTION provided by applicant Current antivirals for influenza infection target specific viral proteins Due to marked genetic diversity different strains of influenza demonstrate differential sensitivity to marketed anti influenza drugs Additionally current drugs remain vulnerable to the rapid development of virus resistance The present project proposes to validate a paradigm shifting antiviral mechanism of action the activation of host encoded sirtuins Sirtuins are a family of seven NAD dependent deacylases known for regulating numerous cellular and organismal functions including metabolism cell cycle and longevity Sirtuins may also be evolutionarily conserved broad spectrum viral restriction factors based on experiments demonstrating that activation of sirtuins in eukaryotic or prokaryotic host cells increases growth of diverse viruses including bacteriophages Koyuncu et al mBio e In the case of influenza A Sirt and Sirt have the largest effects on virus growth Indeed a small molecule screen for sirtuin agonists identified a Sirt and a Sirt andamp activator each with a distinct chemical scaffold as potent broad spectrum antivirals completed medicinal chemistry improved the antiviral potency of the Sirt andamp activator compared to the screen identified molecule and a patent application was filed on this scaffold In addition two independently published mouse studies demonstrate in vivo anti influenza efficacy for two plant polyphenols resveratrol and isoquercetin that are now known to be Sirt activators Importantly isoquercetin prevented the accumulation of viral resistance observed for direct acting antivirals amantadine and oseltamivir during serial passage in culture Proposed Phase I goals are to confirm sirtuin activation provides efficacy against multiple seasonal pandemic and resistant influenza A and B strains and a high barrier against future acquired resistance in cell culture and to reproduce the apparent antiviral efficacy observed in mouse influenza challenge for proposed proprietary activators as was demonstrated for tool compounds Sirt activators isoquercetin and resveratrol Once a lead series is prioritized based on the Phase I results the 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 model Such a product will address unmet medical need compared to oseltamivir because compared to oseltamivir these drugs should broadly inhibit all subtypes of influenza A and B block the replication of viruses resistant to current therapies and dramatically reduce the development of viral resistance during stand alone or combination treatment PUBLIC HEALTH RELEVANCE Seasonal flu annually causes considerable morbidity and mortality its overall burden to the U S economy is estimated to be $ B per year FORGE Life Science is developing antiviral drugs that boost a patientandapos s own innate cellular defense against the flu causing virus influenza A by activating viral restriction factors of the human host cell when infected by virus Compared to current anti influenza drugs FORGE antivirals will provide an advanced therapeutic option in treatment of flu by providing protection against a wide range of flu causing virus types influenza A and B strains both sensitive and resistant to existing flu antivirals and by greatly reducing acquired viral resistance