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

Hongtao Liu, Dariusz Zakrzewicz, Kamil Nosol, Rossitza N. Irobalieva, Somnath Mukherjee, Rose Bang-Sørensen, Nora Goldmann, Sebastian Kunz, Lorenzo Rossi, Anthony A. Kossiakoff (), Stephan Urban (), Dieter Glebe (), Joachim Geyer () and Kaspar P. Locher ()
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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
Sebastian Kunz: Justus Liebig University Giessen
Lorenzo Rossi: ETH Zürich
Anthony A. Kossiakoff: The University of Chicago
Stephan Urban: Heidelberg University
Dieter Glebe: Justus Liebig University Giessen
Joachim Geyer: Justus Liebig University Giessen
Kaspar P. Locher: ETH Zürich

Nature Communications, 2024, vol. 15, issue 1, 1-13

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-46706-w

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