Prevention of hepatitis B virus infection in vivo by entry inhibitors derived from the large envelope protein.
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.
Petersen
Joerg
J
Department of Medicine, University of Hamburg, Eppendorf, D-20246 Hamburg, Germany.
Dandri
Maura
M
Mier
Walter
W
Lütgehetmann
Marc
M
Volz
Tassilo
T
von Weizsäcker
Fritz
F
Haberkorn
Uwe
U
Fischer
Lutz
L
Pollok
Joerg-Matthias
JM
Erbes
Berit
B
Seitz
Stefan
S
Urban
Stephan
S
D000215:Acylation; D000595:Amino Acid Sequence; D000818:Animals; D053819:Atelinae / Q000821:virology; D004268:DNA-Binding Proteins / Q000235:genetics; D006509:Hepatitis B / Q000517:prevention & control* / Q000821:virology; D006514:Hepatitis B Surface Antigens / Q000737:chemistry; D006515:Hepatitis B virus / Q000187:drug effects* / Q000502:physiology*; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000378:metabolism / Q000821:virology; D008297:Male; D051379:Mice; D014018:Tissue Distribution; D014183:Transplantation, Heterologous; D014417:Tupaia; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics; D014759:Viral Envelope Proteins / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*
D004268:DNA-Binding Proteins; D006514:Hepatitis B Surface Antigens; C096362:L protein, hepatitis B virus; C499308:Rag2 protein, mouse; D014759:Viral Envelope Proteins; D014568:Urokinase-Type Plasminogen Activator