Small Molecule Influenza Virus Fusion Inhibitors Targeting Viral Hemagglutinin: Chemical Insights and Antiviral Evaluation

Abstract: Influenza viruses are major human pathogens that cause widespread respiratory infections, affecting millions of people globally and contributing to significant morbidity and mortality. Several currently available anti-influenza drugs are facing increasing levels of viral resistance. Therefore, the discovery of therapeutics targeting novel mechanisms of action is becoming increasingly important. A key viral protein involved in the infection process is the envelope glycoprotein Hemagglutinin (HA), which facilitates both host cell receptor binding and membrane fusion, two essential steps required for viral entry and replication. Due to its central role in the early stages of infection, HA has emerged as a highly promising target for antiviral drug development. Many smallmolecule HA inhibitors have been identified with potential anti-influenza activity by stabilizing the HA structure and preventing its conformational change during the membrane fusion process. This review presents a detailed chemical evaluation of these HA-targeting compounds based on studies reported in the literature, highlighting their core chemical scaffolds and structural features. The antiviral efficacy of these compounds is discussed based on in vitro and in vivo data, along with insights into their mechanisms of action. A comprehensive literature search was conducted, and studies meeting the predefined inclusion criteria were thoroughly reviewed. By focusing on the chemical structure of these inhibitors, this review provides information for the rational design of new therapeutic agents aimed at preventing or limiting influenza virus infections.