Influenza virus hemagglutinin (HA) trimer stem hydrophobic cavity (HA stem hydrophobic cavity)

The Influenza virus hemagglutinin (HA) trimer stem hydrophobic cavity at the protomer–protomer interface is a critical regulatory site within the HA protein, the primary surface glycoprotein of the influenza virus. This cavity is located in the upper stem region of the HA trimer, specifically at the interface where two of the three protomers meet. It is structurally distinct from the receptor-binding site in the head domain and the lower stem epitopes targeted by many broadly neutralizing antibodies. The cavity serves as a binding pocket for small-molecule fusion inhibitors, most notably the antiviral drug Umifenovir (Arbidol). When a drug binds in this pocket, it acts as a molecular glue that stabilizes the HA trimer in its prefusion state. This stabilization prevents the large-scale conformational changes that are normally triggered by the acidic environment of the host cell endosome. By blocking these structural rearrangements, the drug prevents the fusion of the viral envelope with the endosomal membrane, thereby halting the release of the viral genome into the host cell and stopping the infection. This site is highly conserved across multiple influenza subtypes, making it an important target for the development of broad-spectrum antivirals.

Other names

Arbidol binding siteHA stem protomer-protomer interface cavityHemagglutinin stem hydrophobic pocketHA fusion inhibitor binding site

Stabilization of the prefusion conformation of hemagglutinin to prevent pH-induced membrane fusion.