Biphenyl dimethyl dicarboxylate (
DDB) is a hepatoprotectant, which is used as an adjuvant agent in a treatment for
chronic hepatitis.
Amantadine is an
antiviral agent, which is utilized primarily in the treatment of
influenza, but also, occasionally in the treatment of
hepatitis C. In a previous study, we reported that
DDB, coupled with
amantadine, would exert an anti-HBV effect, via the induction of
interferon-inducible gene expression in the HepG2 2.2.15 cell line. The primary objective of the present study was to determine whether or not
DDB and/or
amantadine exhibit anti-HBV properties, and what mechanisms of action might be involved in such properties. In our study, we were able to determine that
DDB stimulates Jak/Stat signaling, and induces the expression of
interferon alpha (IFN-alpha) stimulated genes, most notably 6-16 and ISG12. In addition, the
antiviral effectors induced by IFN-alpha, PKR, OAS, and MxA, were regulated in the presence of
DDB at its optimal concentration (250 microg/mL), to a degree commensurate with the degree of induction associated with the IFN-alpha treated group. Finally, we determined that the replication of pregenomic
RNA and
HBeAg was inhibited by
DDB treatment, and this inhibition was maximized when coupled with the administration of
amantadine (25 microg/mL). In conclusion, the results of this study demonstrated clearly that
DDB, as well as the combination of
DDB/
amantadine, directly inhibited IFN-alpha signaling-mediated replication of HBV in infected hepatocytes, and thus may represent a novel treatment for
chronic hepatitis B, which would be characterized principally by its improved safety over other treatment strategies.