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Journal of Virology, February 2005, p. 1613-1622, Vol. 79, No. 3
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.3.1613-1622.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Efficient Inhibition of Hepatitis B Virus Infection by Acylated Peptides Derived from the Large Viral Surface Protein{dagger}

Philippe Gripon,1 Isabelle Cannie,1 and Stephan Urban2*

Institut National de la Santé et de la Recherche Médicale (INSERM) U522, Hôpital de Pontchaillou, Rennes, France,1 Molekulare Virologie, Otto-Meyerhof-Zentrum (OMZ), Universität Heidelberg, Heidelberg, Germany2

Received 7 July 2004/ Accepted 8 October 2004

The lack of an appropriate in vitro infection system for the major human pathogen hepatitis B virus (HBV) has prevented a molecular understanding of the early infection events of HBV. We used the novel HBV-infectible cell line HepaRG and primary human hepatocytes to investigate the interference of infection by HBV envelope protein-derived peptides. We found that a peptide consisting of the authentically myristoylated N-terminal 47 amino acids of the pre-S1 domain of the large viral envelope protein (L protein) specifically prevented HBV infection, with a 50% inhibitory concentration (IC50) of 8 nM. The replacement of myristic acid with other hydrophobic moieties resulted in changes in the inhibitory activity, most notably by a decrease in the IC50 to picomolar concentrations for longer unbranched fatty acids. The obstruction of HepaRG cell susceptibility to HBV infection after short preincubation times with the peptides suggested that the peptides efficiently target and inactivate a receptor at the hepatocyte surface. Our data both shed light on the molecular mechanism of HBV entry into hepatocytes and provide a basis for the development of potent hepadnaviral entry inhibitors as a novel therapeutic concept for the treatment of hepatitis B.

* Corresponding author. Mailing address: Molekulare Virologie, Otto-Meyerhof-Zentrum (OMZ), Universität Heidelberg, Im Neuenheimer Feld 350, 69120 Heidelberg, Germany. Phone: 49-6221-562910. Fax: 49-6221-561946. E-mail: Stephan_Urban{at}med.uni-heidelberg.de.

{dagger} In memory of Peter Hans Hofschneider.

Journal of Virology, February 2005, p. 1613-1622, Vol. 79, No. 3
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.3.1613-1622.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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