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.