Potential Role of Endonuclease Inhibition and Other Targets in the Treatment of Influenza

Background: Influenza is a single-stranded RNA virus that is highly contagious and infects millions of people in the U.S. annually. Due to complications, approximately 959,000 people were hospitalized and another 79,400 people died during the 2017-2018 flu season. While the best methods of prevention continue to be vaccination and hygiene, antiviral treatments may help reduce symptoms for those who are infected. Until recently, the only antiviral drugs in use have been the neuraminidase inhibitors: oseltamivir, zanamivir, and peramivir. Objective: We reviewed novel drug targets that can be used in the treatment of influenza, particularly in the case of neuraminidase inhibitor-resistant strains that may emerge. Results: More recently, a drug with a new mechanism of action has been approved. Baloxavir marboxil inhibits the influenza cap-dependent endonuclease that is needed for the virus to initiate replication within the host cell. This endonuclease target is within the polymerase acid (PA) subunit of RNA polymerase. Since the RNA-dependent RNA polymerase consists of two other subunits, polymerase basic 1 and 2, RNA polymerase has several targets that prevent viral replication. Other targets still under investigation include viral kinases, endocytosis, and viral fusion. Conclusion: Due to the possibility of viral mutations and resistance, it is important to have antivirals with different mechanisms available, especially in the case of a new pandemic strain. Several novel antivirals are within various stages of development and may represent new classes of treatments that can reduce symptoms and complications in those patients who may be at higher risk.