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Prevention of hepatitis B virus infection in vivo by entry inhibitors derived from the large envelope protein

Nature Biotechnology volume 26, pages 335–341 (2008)Cite this article

Abstract

360 million people are chronically infected with the human hepatitis B virus (HBV) and are consequently prone to develop liver cirrhosis and hepatocellular carcinoma1. As approved therapeutic regimens—which modulate patients' antiviral defenses or inhibit the viral reverse transcriptase—are generally noncurative, strategies interfering with other HBV replication steps are required. Expanding on our demonstration that acylated peptides derived from the large HBV envelope protein block virus entry in vitro2,3,4,5, we show their applicability to prevent HBV or woolly monkey hepatitis B virus infection in vivo, using immunodeficient urokinase-type plasminogen activator (uPA) mice repopulated with primary human or Tupaia belangeri hepatocytes6,7. Accumulation of the peptides in the liver, their extraordinary inhibitory potency and specific mode of action permit subcutaneous delivery at very low doses. Inhibition of hepadnavirus entry thus constitutes a therapeutic approach to prevent primary HBV infection, such as after liver transplantation, and might also restrain virus spread in chronically infected patients.

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Figure 1: Schematic representation of the HBV particle, the HBV L-protein and HBVpreS-derived peptides used in this study.
Figure 2: Repopulation rates, experimental design and analysis of in vivo inhibition experiments with TH-repopulated mice.
Figure 3: Biodistribution and liver stability of HBVpreS-derived lipopeptides after s.c. delivery.
Figure 4: Experimental design and serological analysis of hepadnaviral markers in TH- and HH-transplanted mice after s.c. delivery of HBVpreS/2-48-lipopeptides.

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Acknowledgements

We thank P. Gripon and J. Taylor for many helpful discussions, R. Bartenschlager for continuous support and critical reading of the manuscript, R. Reusch, N. Jaeger and H. Eskerski for excellent animal care and C. Kuhn for help with the cryosections. This work was supported by the German Competence Network for Viral Hepatitis (Hep-Net), funded by the German Ministry of Education and Research (BMBF), grant no. 01 KI 0418. S.U. and J.P. were supported by the Deutsche Forschungsgemeinschaft (DFG), grant no. UR72/1-3, UR72/1-4 and Pe608/2-5. J.P. was also supported by the European Union Vigilance Network for the management of antiviral drug resistance (Virgil).

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Author notes

  1. Fritz von Weizsäcker

    Present address: Present address: Department of Medicine I, Schlosspark Klinik, Heubnerweg 2, D-14059 Berlin, Germany.,

  2. Joerg Petersen and Maura Dandri: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Medicine, University of Hamburg, Eppendorf, D-20246, Hamburg, Germany

    Joerg Petersen, Maura Dandri, Marc Lütgehetmann & Tassilo Volz

  2. Department of Nuclear Medicine, University of Heidelberg, D-29120, Heidelberg, Germany

    Walter Mier & Uwe Haberkorn

  3. Department of Medicine II, University of Freiburg, D-79106, Freiburg, Germany

    Fritz von Weizsäcker

  4. Department of Hepatobiliary Surgery, University Hospital Hamburg-Eppendorf, D-20246, Hamburg, Germany

    Lutz Fischer & Joerg-Matthias Pollok

  5. Department of Molecular Virology, University of Heidelberg, Otto-Meyerhof-Zentrum (OMZ), Im Neuenheimer Feld 350, D-69120, Heidelberg, Germany

    Berit Erbes, Stefan Seitz & Stephan Urban

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  1. Joerg Petersen
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Contributions

J.P. and M.D. designed research, analyzed data and wrote the manuscript; W.M. and U.H. synthesized and labeled peptides and performed biodistribution experiments; M.L. performed transplantation experiments and immunohistochemistry; T.V. performed transplantation experiments and molecular assays; F.v.W. provided Tupaia belangeri hepatocytes; L.F. and J.-M.P. provided human hepatocytes; B.E. performed in situ biodistribution experiments; S.S. purified HBV virus stocks and analyzed data; S.U. initiated and designed research, analyzed data and wrote the manuscript.

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Correspondence to Stephan Urban.

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Petersen, J., Dandri, M., Mier, W. et al. Prevention of hepatitis B virus infection in vivo by entry inhibitors derived from the large envelope protein. Nat Biotechnol 26, 335–341 (2008). https://doi.org/10.1038/nbt1389

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