LIVER-TARGETED ANTIVIRAL NUCLEOSIDES - ENHANCED ANTIVIRAL ACTIVITY OFPHOSPHATIDYL-DIDEOXYGUANOSINE VERSUS DIDEOXYGUANOSINE IN WOODCHUCK HEPATITIS-VIRUS INFECTION IN-VIVO

it would be desirable to develop antiviral agents that can be targeted to liver to enhance their antiviral effects and reduce nonhepatic tox city. 2',3'-Dideoxyguanosine (ddG) has been found to be a potent and s elective antihepatitis B agent both in vitro and in vivo, To evaluate ddG and its liver-targeted analog, we synthesized a series of phosphat idyl-ddGs and incubated them with 2.2,15 cells, which chronically prod uce hepatitis B virus, 1,2-Dipalmitoylphosphatidyl-dideoxyguano (DPP-d dG) inhibited the production of hepatitis B virus (HBV) DNA in the cul ture medium by 90% at 4.5 mu mol/L versus 9.1 mu mol/L for ddG, while the liposome vehicle itself had no effect, To compare the efficacy of free ddG with its lipid prodrug in vivo, we treated woodchucks that we re experimentally infected with woodchuck hepatitis virus (WHV) for 4 weeks by intraperitoneal injection of 2.6 mu mol/kg/d of free ddG or L iposomes containing 2.8 mu mol/kg/d of DPP-ddG, Liposomal DPP-ddG redu ced serum WHV DNA by 23- to 46-fold at the end of the fourth week whil e free ddG reduced serum WW DNA by 2.2- to 10.4-fold Treatment with sm all unilamellar liposomes containing DPP-ddG is substantially more eff ective than free ddG in reducing WHV-DNA levels in serum in WHV-infect ed woodchucks, The data suggest that the use of lipid prodrugs to targ et the liver may be useful in enhancing antiviral therapy of hepatitis .