Current Development of Small Molecules Against Influenza A Virus by Targeting Hemagglutinin

Influenza A virus (IAV) continues to be one of the most serious health burdens causing widespread illness and mortality. Limited efficacy and reduced susceptibility of available drugs and vaccines to the emergence of resistant strains have spurred the pursuit of alternative treatment strategies. Hemagglutinin (HA), essential for viral attachment and membrane fusion in the first step of the virus infection cycle, has emerged as an attractive target. Over the past few decades, HA has garnered considerable attention, and significant progress has been achieved in the discovery of HA modulators, even though no anti-IAV drugs targeting HA have been approved by the FDA. This article provides a comprehensive overview of the current landscape of HA inhibitors and degraders, mainly focusing on the systematic structure-activity relationship (SAR) exploration of both synthetic and natural product (NP)-derived small molecules endowed with abundant structural frameworks, together with a brief introduction of different binding modes based on cocrystal structures of IAV HAs and HA inhibitors. We anticipate that this review will serve as practical guidance for the development of urgently needed, more effective, and structurally innovative HA-targeting drugs capable of addressing the escalating challenge of drug resistance.