A Novel Antiviral Drug Candidate Acts by Binding to the Hemagglutinin Stem.

Abstract

Due to the high pandemic risk of influenza and increasing drug resistance, novel antivirals are urgently needed. Influenza hemagglutinin (HA) fusion inhibitors, which block the initial steps of viral infection and promote neutralization, have gradually gained recognition as valuable targets in modern drug development. However, with only one approved HA-targeting drug, umifenovir, which possesses poor pharmacokinetic properties, the development of new HA fusion inhibitors remains a key objective. In this study, we identified a novel benzothiophene-based class of small-molecule inhibitors of influenza A virus. The most promising leads, 12126081 and 12126084, were thoroughly evaluated for in vitro potency, ADME properties, pharmacokinetic profiles, and in vivo efficacy in a lethal mouse infection model. For lead 12126081, mechanism-of-action studies strongly suggested HA as its molecular target. Given its acceptable pharmacokinetic properties, confirmed mechanism, and robust therapeutic effect observed in vivo, compound 12126081 can be considered a highly promising antiviral drug candidate.