Seasonal influenza A virus (IAV)
infections are among the most important global health problems. FDA-approved
antiviral therapies against IAV include
neuraminidase inhibitors, M2 inhibitors, and polymerase inhibitor
baloxavir. Resistance against adamantanes (
amantadine and
rimantadine) is widespread as virtually all IAV strains currently circulating in the human population are resistant to adamantanes through the acquisition of the S31N mutation. The
neuraminidase inhibitor-resistant strains also contain the M2-S31N mutant, suggesting M2-S31N is a high-profile
antiviral drug target. Here we report the development of a novel
deuterium-containing M2-S31N inhibitor UAWJ280. UAWJ280 had broad-spectrum
antiviral activity against both
oseltamivir sensitive and -resistant
influenza A strains and had a synergistic
antiviral effect in combination with
oseltamivir in cell culture. In vivo pharmacokinetic (PK) studies demonstrated that UAWJ280 had favourable PK properties. The in vivo mouse model study showed that UAWJ280 was effective alone or in combination with
oseltamivir in improving clinical signs and survival after lethal challenge with an
oseltamivir sensitive IAV H1N1 strain. Furthermore, UAWJ280 was also able to ameliorate clinical signs and increase survival when mice were challenged with an
oseltamivir-resistant IAV H1N1 strain. In conclusion, we show for the first time that the M2-S31N channel blocker UAWJ280 has in vivo
antiviral efficacy in mice that are infected with either
oseltamivir sensitive or -resistant IAVs, and it has a synergistic
antiviral effect with
oseltamivir.