Over 12 million people worldwide suffer from chronic hepatitis D virus (HDV) infection, a severe liver disease associated with a high risk of liver cirrhosis and cancer. The virus enters liver cells through the bile salt transporter protein NTCP using hepatitis B virus (HBV) surface proteins. Bulevirtide, also known as Hepcludex, is the first approved drug to inhibit HDV replication and improve liver function. A recent study published in Nature Communications has uncovered the molecular structure of bulevirtide in complex with NTCP, paving the way for more targeted treatments for HBV/HDV infections.
The analysis revealed that bulevirtide interacts with NTCP through three functional domains: a myristoyl group interacting with the cell membrane, a core sequence fitting into the NTCP tunnel, and an amino acid chain encircling the receptor. This unique structure blocks the bile salt transporter function, explaining how bulevirtide inhibits virus entry. The research also identified the importance of an amino acid at position 158 of NTCP in the virus-receptor interaction, shedding light on the species specificity of HBV/HDV and their evolutionary adaptation to host species.
The study used cryo-electron microscopy to visualize structural details at the atomic level, providing insights into the interaction of HBV/HDV with NTCP and the mechanism of cell receptor blockade by bulevirtide. These findings have implications for the development of smaller active agents with improved pharmacological properties, potentially enabling oral administration. The research represents a significant milestone in understanding the molecular basis of the interaction between bulevirtide and NTCP in the context of HBV/HDV infection.
By understanding the structural details of bulevirtide and its binding to NTCP, researchers aim to develop more targeted and effective treatments for millions of people with chronic HBV/HDV infections. The study findings provide a foundation for the development of new drugs based on peptides and peptidomimetics, offering potential solutions for improving the current treatment options for hepatitis D and B. The insights gained from this research could lead to the development of innovative therapies that address the underlying mechanisms of HBV/HDV infection, ultimately benefiting patients worldwide.
