Preventing the Entry of Hepatitis B and D Viruses

The entry of hepatitis B and D viruses (HBV/HDV) into cells is essential for initiating infection, involving the attachment of the preS1 viral surface protein to the hepatobiliary transporter known as Na+-taurocholate co-transporting polypeptide (NTCP). Bulevirtide (BLV) works by inhibiting the crucial binding between the virus and NTCP. However, the precise mechanism by which BLV impedes this interaction is yet to be completely understood. HDV combined with coinfections such as HBV, disease management can be difficult.

The cryo-EM structure revealed that BLV interacts with NTCP through 2 distinct domains, a plug domain that lodges in the bile salt transport tunnel of NTCP and a string domain that covers the receptor’s extracellular surface. The N-terminally attached myristoyl group of BLV was found to interact with the lipid-exposed surface of NTCP. This structural configuration inhibits the transport function of NTCP, preventing the entry of HBV/HDV into the host cell. The structure provided insights into specific NTCP mutations that decrease the risk of HBV/HDV infection and illuminated aspects of host specificity for these viruses.

“Our study reveals the molecular basis of viral preS1 interactions with its receptor NTCP and the inhibition of this interaction by the commercial drug BLV/Hepcludex,” according to the investigators. “The results also rationalize why the binding of BLV affects bile salt transport by NTCP. Furthermore, our data corroborates previous biochemical results regarding which residues in the BLV sequence are critical for inhibiting viral infection.”¹

The study investigates how BLV impedes the interaction of HBV/HDV with NTCP, investigators employed cryo-electron microscopy (cryo-EM) to ascertain the structure of human NTCP in complex with BLV. This method facilitated an atomic-level view of the complex, offering an understanding of the structural foundation of BLV's inhibitory effect.

“Our findings allow us to rationalize HBV/HDV specificity for human NTCP and explain why the S267F mutation in humans presents a compromised bile salt transport with simultaneous resistance to HBV/HDV,” explains investigators. “We identified BLV residues that face the solvent and do not appear to interact with NTCP. These might be amenable for the design of smaller drugs (peptidomimetics) that improve the pharmacology of BLV to prevent HBV and HDV binding and infection.”¹

According to previous reporting by Contagion, with the potential severity of chronic HDV and the coinfections and limited treatment options, there is an unmet need for therapies. BLV (Hepcludex, Gilead) is a first-in-class entry inhibitor that was approved in the European Union for chronic HDV infection in HDV RNA-positive adult patients with compensated liver disease.
“What BLV does is it essentially binds to and then inactivates the NTCP receptor, which then has the goal of preventing new infections in the hepatocytes, and then inhibits the propagation of HDV itself,” Anu Osinusi, MD, vice president, Clinical Research for Hepatitis, Respiratory, and Emerging Viruses, Gilead, said. ²

In conclusion, this study offers an understanding of how BLV interacts with the NTCP receptor to prevent HBV/HDV infection. The findings from cryo-EM analysis offer insights into the structural basis of this interaction, highlighting the potential for developing new therapeutic strategies against HBV and HDV.

References

• Liu H, Zakrzewicz D, Nosol K, Irobalieva R, et. Al. Structure of Antiviral Drug Bulevirtide Bound to Hepatitis B and D Virus Receptor Protein NTCP. Nature Communication. Published March 20, 2024. Accessed March 26, 2024. Doi: https://doi.org/10.1038/s41467-024-46706-w
• Parkinson J. Bulevirtide Demonstrates Efficacy, Safety for Hepatitis D Treatment. Contagion. Published March 11, 2024. Accessed March 26, 2024. https://www.contagionlive.com/view/bulevirtide-demonstrates-efficacy-safety-for-hepatitis-d-treatment