Over 12 million individuals globally are afflicted with chronic hepatitis D virus (HDV) infections, the most severe form of viral liver disease, which carries a significant risk of mortality due to liver cirrhosis and cancer. This disease is propagated by the HDV, which peculiarly hijacks the surface proteins of the hepatitis B virus (HBV) to gain entry into liver cells through a specific protein in the cell membrane—the bile salt transporter protein NTCP. The drug bulevirtide, marketed as Hepcludex, has been developed to block this entry mechanism and has recently been the subject of groundbreaking research. An international team has unveiled the molecular structure of bulevirtide in complex with the HBV/HDV receptor NTCP, providing critical insights as published in the prestigious Nature Communications. These findings could lead to more precise and potent therapies for the millions suffering from chronic HBV/HDV infections.
Bulevirtide is the pioneering and sole approved therapeutic agent for chronic HDV infections. It not only blocks viral replication effectively but also substantially enhances liver function. Before recent studies, the detailed interactions of bulevirtide with the virus entry receptor on liver cells—the bile salt transporter protein NTCP—remained a mystery.
To elucidate these interactions at a molecular level, researchers created an antibody fragment that specifically targets the NTCP-bulevirtide complex, allowing for its analysis when attached to nanoparticles. This complex was then scrutinised using cryo-electron microscopy, which depicted the structural nuances at an atomic scale. These results significantly advance understanding of the interaction between HBV/HDV and their cellular entry receptor NTCP and how bulevirtide effectively blocks this receptor.
The detailed analysis revealed that bulevirtide forms three functional domains in its interaction with the NTCP receptor: a myristoyl group that interfaces with the external cell membrane, a core sequence acting as a ‘plug’ that precisely fits into the bile salt transport tunnel of NTCP, akin to a key in a lock; and a chain of amino acids that extends over the receptor’s extracellular surface, encircling it like a brace.
Prof Stephan Urban, a key figure in developing bulevirtide at Heidelberg University, highlighted the uniqueness of the ‘plug’ formation in the transport tunnel and its role in inactivating the bile salt transporter. He noted this mechanism’s novelty among virus-receptor complexes and its crucial role in the therapeutic efficacy of bulevirtide.
Moreover, the structural insights provided by this study have spurred the development of smaller, more effective therapeutic agents known as peptidomimetics, which could be administered orally. Prof Joachim Geyer from Justus Liebig University Giessen also emphasised how these findings lay a groundwork for creating peptide-based drugs with enhanced pharmacological properties.
Additionally, the research shed light on an evolutionary adaptation of hepatitis B viruses to their hosts. It was discovered that a specific amino acid in the NTCP, crucial for virus-receptor interaction, could prevent the binding of HBV/HDV if altered, elucidating why certain primates, such as Old World monkeys, are resistant to these viruses.
These breakthroughs not only enhance our understanding of the evolutionary dynamics of hepatitis viruses but also set the stage for creating innovative, targeted therapies. Prof Dieter Glebe and Prof. Kaspar Locher, who also contributed to the study, stressed the importance of these findings in advancing the treatment and management of hepatitis D and B, paving the way for potentially more effective treatments for those affected by these chronic infections.
More information: Hongtao Liu et al, Structure of antiviral drug bulevirtide bound to hepatitis B and D virus receptor protein NTCP, Nature Communications. DOI: 10.1038/s41467-024-46706-w
Journal information: Nature Communications Provided by German Center for Infection Research
