PLoS One. 2017 Jun 21;12(6):e0179697. doi: 10.1371/journal.pone.0179697. eCollection 2017.
Inhibition of hepatitis B viral entry by nucleic acid polymers in HepaRG cells and primary human hepatocytes.Guillot C1, Martel N1, Berby F1, Bordes I1, Hantz O1, Blanchet M2, Sureau C3, Vaillant A2, Chemin I1. Author information 1Centre de Recherche en Cancérologie de Lyon INSERM U1052, CNRS UMR5286, Université de Lyon, Lyon, France.2Replicor Inc. Montréal, Canada.3Molecular Virology Laboratory, Institut National de la Transfusion Sanguine (INTS), CNRS INSERM U1134, Paris, France.
AbstractHepatitis B virus (HBV) infection remains a major public health concern worldwide with 240 million individuals chronically infected and at risk of developing cirrhosis and hepatocellular carcinoma. Current treatments rarely cure chronic hepatitis B infection, highlighting the need for new anti-HBV drugs. Nucleic acid polymers (NAPs) are phosphorothioated oligonucleotides that have demonstrated a great potential to inhibit infection with several viruses. In chronically infected human patients, NAPs administration lead to a decline of blood HBsAg and HBV DNA and to HBsAg seroconversion, the expected signs of functional cure. NAPs have also been shown to prevent infection of duck hepatocytes with the Avihepadnavirus duck hepatitis B virus (DHBV) and to exert an antiviral activity against established DHBV infection in vitro and in vivo. In this study, we investigated the specific anti-HBV antiviral activity of NAPs in the HepaRG human hepatoma cell line and primary cultures of human hepatocytes. NAPs with different chemical features (phosphorothioation, 2'O-methyl ribose, 5-methylcytidine) were assessed for antiviral activity when provided at the time of HBV inoculation or post-inoculation. NAPs dose-dependently inhibited HBV entry in a phosphorothioation-dependent, sequence-independent and size-dependent manner. This inhibition of HBV entry by NAPs was impaired by 2'O-methyl ribose modification. NAP treatment after viral inoculation did not elicit any antiviral activity.
"Altogether, our study demonstrates the ability of NAPs to block HBV entry into hepatocytes. A NAP structure/activity relationship similar to that documented with other enveloped viruses is observed, with the exception of the 2’O-Me modification having a detrimental effect on antiviral activity against HBV. Results from the present study, along with previous in vivo and clinical studies, highlight the potential of NAPs as therapeutic antiviral agents in general, and as anti-HBV drug in particular. Combination of NAPs with currently available therapies may represent a new relevant step toward an HBV cure."