Hepatitis D virus large delta antigen (L-HDAg)

The Hepatitis D virus large delta antigen (L-HDAg) is a 214-amino acid viral protein that plays a dual role in the HDV life cycle. It is generated from the same open reading frame as the small delta antigen (S-HDAg) through an RNA editing process mediated by the host enzyme ADAR1, which extends the protein by 19 amino acids (UniProt P03334). Unlike S-HDAg, which is necessary for viral RNA replication, L-HDAg functions as a potent inhibitor of replication and is indispensable for the assembly of mature virions. The C-terminal extension of L-HDAg contains a farnesylation signal (CXXX box) that undergoes post-translational modification by host farnesyltransferase, allowing the protein to anchor to the host-derived lipid membrane and interact with Hepatitis B virus surface antigens (HBsAg) (PubMed: 25937081). Because HDV is a satellite virus that requires HBsAg for packaging, L-HDAg is the key mediator of this partnership. Targeting the prenylation of L-HDAg with farnesyltransferase inhibitors like Lonafarnib has emerged as a primary therapeutic strategy to treat chronic HDV infection, which is the most severe form of viral hepatitis (NIH).

Other names

Large delta antigenL-HDAgp27 proteinHDAg-L

Lonafarnib inhibits the host enzyme farnesyltransferase, which prevents the post-translational farnesylation of the C-terminal CXXX motif of L-HDAg. This modification is essential for L-HDAg to interact with the Hepatitis B surface antigen (HBsAg), thereby blocking the assembly and release of new HDV virions (PMID: 25937081, NIH).