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Structure of antiviral drug bulevirtide bound to hepatitis B and D virus receptor protein NTCP

Author

Listed:
  • Hongtao Liu

    (ETH Zürich)

  • Dariusz Zakrzewicz

    (Justus Liebig University Giessen)

  • Kamil Nosol

    (ETH Zürich)

  • Rossitza N. Irobalieva

    (ETH Zürich)

  • Somnath Mukherjee

    (The University of Chicago)

  • Rose Bang-Sørensen

    (ETH Zürich)

  • Nora Goldmann

    (Justus Liebig University Giessen
    German Center for Infection Research (DZIF) - Giessen-Marburg-Langen Partner Site)

  • Sebastian Kunz

    (Justus Liebig University Giessen)

  • Lorenzo Rossi

    (ETH Zürich)

  • Anthony A. Kossiakoff

    (The University of Chicago)

  • Stephan Urban

    (Heidelberg University
    German Center for Infection Research (DZIF) - partner site Heidelberg)

  • Dieter Glebe

    (Justus Liebig University Giessen
    German Center for Infection Research (DZIF) - Giessen-Marburg-Langen Partner Site)

  • Joachim Geyer

    (Justus Liebig University Giessen)

  • Kaspar P. Locher

    (ETH Zürich)

Abstract

Cellular entry of the hepatitis B and D viruses (HBV/HDV) requires binding of the viral surface polypeptide preS1 to the hepatobiliary transporter Na+-taurocholate co-transporting polypeptide (NTCP). This interaction can be blocked by bulevirtide (BLV, formerly Myrcludex B), a preS1 derivative and approved drug for treating HDV infection. Here, to elucidate the basis of this inhibitory function, we determined a cryo-EM structure of BLV-bound human NTCP. BLV forms two domains, a plug lodged in the bile salt transport tunnel of NTCP and a string that covers the receptor’s extracellular surface. The N-terminally attached myristoyl group of BLV interacts with the lipid-exposed surface of NTCP. Our structure reveals how BLV inhibits bile salt transport, rationalizes NTCP mutations that decrease the risk of HBV/HDV infection, and provides a basis for understanding the host specificity of HBV/HDV. Our results provide opportunities for structure-guided development of inhibitors that target HBV/HDV docking to NTCP.

Suggested Citation

  • Hongtao Liu & Dariusz Zakrzewicz & Kamil Nosol & Rossitza N. Irobalieva & Somnath Mukherjee & Rose Bang-Sørensen & Nora Goldmann & Sebastian Kunz & Lorenzo Rossi & Anthony A. Kossiakoff & Stephan Urba, 2024. "Structure of antiviral drug bulevirtide bound to hepatitis B and D virus receptor protein NTCP," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-46706-w
    DOI: 10.1038/s41467-024-46706-w
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