Hepatitis B virus surface antigen pre-S2 domain (pre-S2 (HBV))

The pre-S2 domain is a ~55–amino–acid N-terminal extension to the S domain present in the middle (MHBs) and large (LHBs) hepatitis B surface proteins that together with the small (SHBs) form HBsAg; pre-S2 is absent from SHBs and present in both MHBs and LHBs[5][3]. Pre-S2 in MHBs carries an N-linked glycosylation site at Asn-4 (N4) that supports proper folding, assembly, secretion, and immunogenicity; LHBs contains pre-S2 but its N4 site is not glycosylated due to conformation with pre-S1[8]. Sequence analyses indicate the pre-S region (pre-S1/pre-S2) influences HBV invasion, assembly, replication, and immune interactions; mutations or deletions in pre-S2 can affect HBsAg expression/secretion and clinical phenotypes[2]. Experimental work shows that while deletions larger than ~20 amino acids in pre-S2 of L impair virion assembly, the specific pre-S2 sequence is largely dispensable for entry and infectivity in vitro when M is absent, consistent with a spacer role facilitating L protein conformation during nucleocapsid envelopment; viruses with randomized pre-S2 in L remained infectious and susceptible to pre-S1–mediated entry inhibition[6][1]. As part of HBsAg, pre-S2 contributes to subviral particle formation and antigenicity relevant to vaccination; pre-S–containing HBsAg preparations have been produced recombinantly, and their glycosylation state influences particle formation and immunogenicity[4][5]. Pre-S mutations, including in pre-S2, are frequently detected in chronic HBV and have been associated with hepatocellular carcinoma in observational and experimental studies[8].

Other names

HBV pre-S2 domainPreS2 regionPre-S2 region of HBsAgN-terminal pre-S2 of MHBs/LHBs

Not applicable for direct drug targeting of pre-S2. Entry inhibitors act via pre-S1–NTCP blockade; pre-S2 is not essential for this entry pathway and does not provide an alternative route. Vaccines including pre-S1/pre-S2 aim to broaden neutralizing antibody responses to HBsAg, including pre-S epitopes.