Endothelial lipase-binding peptides similar to netrin-1 inhibit hepatitis B virus infection

Hepatitis B virus (HBV) infects cells by attaching to heparan sulfate proteoglycans (HSPG) and Na⁺/taurocholate cotransporting polypeptide (NTCP). The endothelial lipase LIPG bridges HSPG and HBV, facilitating HBV attachment. From a randomized peptide expression library, we identified a short sequence binding to LIPG. This identified sequence closely resembled a sequence in the V domain of netrin-1, a protein known to bind heparin through its V domain. We designed two synthetic peptides based on this sequence and found that both synthetic peptides and netrin-1 suppressed HBV infection in chimeric mice with humanized livers and in primary hepatocytes isolated from them. The data reveal an antiviral function of the peptides and netrin-1 in HBV infection that is independent of LIPG lipase activity.