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

• Published in: Nature biotechnology 2008-03, Vol.26 (3), p.335-341
• Main Authors: Urban, Stephan, Petersen, Joerg, Dandri, Maura, Mier, Walter, Lütgehetmann, Marc, Volz, Tassilo, von Weizsäcker, Fritz, Haberkorn, Uwe, Fischer, Lutz, Pollok, Joerg-Matthias, Erbes, Berit, Seitz, Stefan
• Format: Article
• Language: English
• Subjects: Acylation; Agriculture; Amino Acid Sequence; Animals; Atelinae - virology; Bioinformatics; Biological and medical sciences; Biomedical and Life Sciences; Biomedical Engineering/Biotechnology; Biomedicine; Biotechnology; Disease prevention; DNA-Binding Proteins - genetics; Fundamental and applied biological sciences. Psychology; Genetic aspects; Health aspects; Health. Pharmaceutical industry; Hepadnavirus; Hepatitis; Hepatitis B; Hepatitis B - prevention & control; Hepatitis B - virology; Hepatitis B Surface Antigens - chemistry; Hepatitis B virus; Hepatitis B virus - drug effects; Hepatitis B virus - physiology; Hepatocytes - cytology; Hepatocytes - metabolism; Humans; Industrial applications and implications. Economical aspects; Infections; Inhibitor drugs; letter; Life Sciences; Liver; Liver - metabolism; Liver - virology; Liver transplantation; Male; Membrane proteins; Mice; Miscellaneous; Mode of action; Peptides; Prevention; Proteins; Risk factors; Rodents; Tissue Distribution; Tissue plasminogen activator; Transplantation, Heterologous; Tupaia; Tupaia belangeri; Urokinase-Type Plasminogen Activator - genetics; Viral Envelope Proteins - administration & dosage; Viral Envelope Proteins - chemistry; Viral Envelope Proteins - pharmacokinetics; Viral Envelope Proteins - pharmacology; Viruses
• ISSN: 1087-0156; 1546-1696
• DOI: 10.1038/nbt1389

360 million people are chronically infected with the human hepatitis B virus (HBV) and are consequently prone to develop liver cirrhosis and hepatocellular carcinoma. 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 vitro, 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 hepatocytes. 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.