Target intelligence / Profile preview

Influenza hemagglutinin long alpha helix (HA-LAH) (HA-LAH)

Target
HA-LAH
Molecular classification
Viral surface glycoprotein, Class I viral fusion protein, Type I transmembrane protein
01

Overview

The Influenza hemagglutinin long alpha helix (LAH) is a highly conserved structural domain located within the HA2 subunit of the influenza virus hemagglutinin protein (Sui et al., 2009). It forms the central core of the HA stalk and is critical for the pH-induced conformational change that drives the fusion of the viral envelope with the host cell endosomal membrane (Wang et al., 2010). Unlike the globular head of the hemagglutinin, which undergoes rapid antigenic drift, the LAH is remarkably stable across various influenza A subtypes, making it a premier target for the development of universal influenza vaccines (Impagliazzo et al., 2015). Therapeutic strategies targeting the LAH involve the use of broadly neutralizing antibodies (bnAbs) that bind to this region and sterically inhibit the structural rearrangements necessary for viral entry (Krammer & Palese, 2013). While the LAH is naturally subdominant in the immune response, novel immunogen designs aim to redirect the immune system to produce high titers of LAH-specific antibodies to provide broad protection against seasonal and pandemic influenza strains (Corti et al., 2011).

Other names
HA2 long alpha helixHemagglutinin stalk domainHA2 helix AHemagglutinin stem helixHA2-LAH
02

Mechanism of action

Inhibition of the pH-dependent conformational change of the HA2 subunit, which prevents the fusion of the viral envelope with the host cell endosomal membrane (Krammer & Palese, 2013).

03

Biological functions

Viral entryMembrane fusionStructural stability of the HA trimer
04

Disease associations

Influenza A infectionInfluenza B infectionPandemic influenza
05

Safety considerations

Low natural immunogenicity due to HA head immunodominance (Impagliazzo et al., 2015)Potential for antibody-dependent enhancement (ADE)Structural stability challenges in vaccine formulationPotential for rare viral escape mutations in the stalk region
06

Interacting drugs

CR6261

5 more in the full profile.

07

Biomarkers

Anti-HA stalk antibody titers (ELISA)HA2-specific memory B cell frequencyStalk-reactive IgG levels

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