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. 2014, mBio 5:e02249). In the case of influenza A, Sirt1 and Sirt6 have the largest effects on virus growth. Indeed a small molecule screen for sirtuin agonists identified a Sirt1 and a Sirt1&6 activator, each with a distinct chemical scaffold, as potent broad-spectrum antivirals; completed medicinal chemistry improved the antiviral potency of the Sirt1&6 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 Sirt1 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, Sirt1 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 1) broadly inhibit all subtypes of influenza A and B; 2) block the replication of viruses resistant to current therapies; and 3) dramatically reduce the development of viral resistance during stand- alone or combination treatment.
Public Health Relevance Statement: Public Health Relevance: Seasonal flu annually causes considerable morbidity and mortality; its overall burden to the U.S. economy is estimated to be $83B per year. FORGE Life Science is developing antiviral drugs that boost a patient'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 (1) 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 (2) greatly reducing acquired viral-resistance.
Project Terms: Address; Agonist; Amantadine; anti-influenza; anti-influenza drug; Antiviral Agents; Attenuated; Bacteriophages; base; Biological Availability; Biological Sciences; Cell Culture Techniques; Cell Cycle; Cells; Chemicals; Clinical; commercialization; Cytomegalovirus; Development; DNA Viruses; Dose; Drug Exposure; Drug Kinetics; Drug resistance; Enzyme Activation; Exhibits; Family; Ferrets; flu; Future; Genetic; Genome; Goals; Grant; Growth; Human; improved; In Vitro; in vitro activity; in vivo; Influenza; Influenza A virus; Influenza B Virus; Influenza Therapeutic; influenzavirus; Lead; lead series; Legal patent; Literature; Longevity; Lung; man; Marketing; Medical; meetings; Metabolic; Metabolism; Modeling; Monitor; Morbidity - disease rate; mortality; mouse model; Mus; Mutation; novel therapeutics; Oral; Oseltamivir; pandemic disease; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase; Plants; Plasma; polyphenol; Population; prevent; Property; public health relevance; Publishing; Regimen; Reporting; Research; research study; Resistance; Resistance development; Resistance profile; resistant strain; respiratory; Resveratrol; scaffold; seasonal influenza; Seasons; Serial Passage; Series; Sirtuins; small molecule; standard of care; Structure-Activity Relationship; Symptoms; Testing; Therapeutic; Therapeutic Index; Time; tool; Triage; Vaccines; Variant; Variation (Genetics); Viral; Viral Proteins; viral resistance; Virulent; Virus; Virus Replication
