Structure of hepatitis B/D antiviral drug Bulevirtide bound to its receptor protein NTCP

Liu, H.; Zakrzewicz, D.; Nosol, K.; Irobalieva, R. N.; Mukherjee, S.; Bang-Soerensen, R.; Goldmann, N.; Kunz, S.; Rossi, L.; Kossiakoff, A. A.; Urban, S.; Glebe, D.; Geyer, J.; Locher, K. P.

doi:10.1101/2024.01.22.576510

bioRxiv · 10.1101/2024.01.22.576510

Structure of hepatitis B/D antiviral drug Bulevirtide bound to its receptor protein NTCP

Liu, H.·Zakrzewicz, D.·Nosol, K.·Irobalieva, R. N.·Mukherjee, S.·Bang-Soerensen, R.·Goldmann, N.·Kunz, S.·Rossi, L.·Kossiakoff, A. A.·Urban, S.·Glebe, D.·Geyer, J.·Locher, K. P.

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Abstract

Cellular entry of the hepatitis B and D viruses (HBV/HDV) require binding of the viral surface polypeptide preS1 to the hepatobiliary transporter NTCP. This interaction can be blocked by bulevirtide (BLV, formerly Myrcludex B), a preS1 derivative and approved drug for treating HDV infection. 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 receptors 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.

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Liu, H., Zakrzewicz, D., Nosol, K., Irobalieva, R. N., Mukherjee, S., Bang-Soerensen, R., Goldmann, N., Kunz, S., Rossi, L., Kossiakoff, A. A., Urban, S., Glebe, D., Geyer, J., Locher, K. P.. 2024-01-22. Structure of hepatitis B/D antiviral drug Bulevirtide bound to its receptor protein NTCP. https://doi.org/10.1101/2024.01.22.576510

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