Receptor recognition of hepatitis B and D viruses: Structural insight and its application to drug discovery.

Hepatitis B and D viruses (HBV, HDV) infect host hepatocytes through interaction of its N-terminal preS1 domain of the viral surface protein to the host entry receptor, sodium taurocholate cotransporting polypeptide (NTCP). The successful development of bulevirtide as the first clinically-approved anti-HDV drug has highlighted the NTCP-mediated entry process as an attractive antiviral target. Recent structural studies of NTCP, including its complex with preS1 peptide, have revealed a unique mechanism by which HBV and HDV recognize their receptor. These structural information have also provided the molecular basis how NTCP exerts the two functions, bile acid transporter and viral receptor, and are applicable to design viral entry inhibitors. In this article, we summarize recent advances in the understanding of viral recognition of NTCP and the drug development targeting this process. We also discuss how emerging structural insights into NTCP and its interaction with preS1 can guide the rational design of next-generation antiviral drugs.