Hepatitis B virus PreS1 domain and Hepatitis delta virus large antigen (HBV PreS1 / HDV L-HDAg)

The Hepatitis B virus (HBV) PreS1 domain and the Hepatitis delta virus (HDV) large antigen (L-HDAg) are essential viral proteins that serve as primary targets for therapeutic intervention and immune-mediated recognition. The PreS1 domain, located at the N-terminus of the Large Hepatitis B surface protein (L-HBsAg), is the key ligand for the sodium taurocholate cotransporting polypeptide (NTCP) receptor, facilitating viral entry into hepatocytes (Yan et al., 2012, eLife). The HDV large antigen is a structural protein required for the assembly of HDV particles, as it mediates the interaction between the HDV ribonucleoprotein and the HBV envelope proteins (Casey, 2006, Chem Rev). Immune-mediated recognition of these antigens, through the use of multi-antigen vaccines or monoclonal antibodies, aims to overcome the immune exhaustion typical of chronic infections and promote viral clearance. Drugs such as Bulevirtide exploit the PreS1 sequence to block viral entry, while others like Lonafarnib target the post-translational modification of L-HDAg to disrupt the viral life cycle (Bogomolov et al., 2016, J Hepatol; Koh et al., 2015, Lancet Infect Dis). These targets are central to the development of functional cures for chronic Hepatitis B and D, which are major causes of global liver disease and cancer.

Other names

Pre-S1 antigenLarge Hepatitis B surface proteinL-HBsAgLarge delta antigenL-HDAgp27 antigenHBV/HDV envelope components

Bulevirtide acts as an entry inhibitor by mimicking the PreS1 domain to competitively bind the NTCP receptor, preventing HBV and HDV infection of new hepatocytes (Bogomolov et al., 2016, J Hepatol). Lonafarnib inhibits farnesyltransferase, an enzyme that adds a farnesyl group to the HDV large antigen, which is a prerequisite for viral assembly and release (Koh et al., 2015, Lancet Infect Dis). Therapeutic vaccines like BRII-179 and prophylactic vaccines like PreHevbrio induce neutralizing antibodies and T-cell responses against the PreS1 and PreS2 domains to enhance viral clearance and provide broader protection than standard S-antigen vaccines (PreHevbrio FDA Label).