Liver-targeted antiviral nucleosides: Enhanced antiviral activity of phosphatidyl-dideoxyguanosine versus dideoxyguanosine in woodchuck hepatitis virus infection in vivo
✍ Scribed by B A Korba; H Xie; K N Wright; W E Hornbuckle; J L Gerin; B C Tennant; K Y Hostetler
- Publisher
- John Wiley and Sons
- Year
- 1996
- Tongue
- English
- Weight
- 233 KB
- Volume
- 23
- Category
- Article
- ISSN
- 0270-9139
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✦ Synopsis
lipid prodrugs to target the liver may be useful in en-It would be desirable to develop antiviral agents that hancing antiviral therapy of hepatitis. (HEPATOLOGY can be targeted to liver to enhance their antiviral effects 1996;23:958-963.) and reduce nonhepatic toxicity. 2,3-Dideoxyguanosine (ddG) has been found to be a potent and selective anti-A number of nucleosides have been found to selechepatitis B agent both in vitro and in vivo. To evaluate tively inhibit hepatitis B virus (HBV) replication in ddG and its liver-targeted analog, we synthesized a sevitro. [1][2][3][4][5][6][7][8] Recently, (0)b-L-3-thia-2,3-dideoxycytidine ries of phosphatidyl-ddGs and incubated them with 2.2.15 cells, which chronically produce hepatitis B virus. (3TC, lamivudine) was shown to be effective in chronic 1,2-Dipalmitoylphosphatidyl-dideoxyguanosine (DPPhepatitis B in a double-blind, randomized clinical ddG) inhibited the production of hepatitis B virus (HBV) study. 9 After 3 months of treatment at a dosage of 100 DNA in the culture medium by 90% at 4.5 mmol/L versus mg/kg/d, all patients exhibited undetectable serum lev-9.1 mmol/L for ddG, while the liposome vehicle itself had els of HBV DNA. In most patients, serum HBV DNA no effect. To compare the efficacy of free ddG with its reappeared after discontinuance of 3TC therapy, but lipid prodrug in vivo, we treated woodchucks that were 16% of 3TC-treated patients experienced a sustained experimentally infected with woodchuck hepatitis virus response. 9 It would be useful to find methods of enhanc-(WHV) for 4 weeks by intraperitoneal injection of 2.6 ing hepatic parenchymal uptake and retention of effecmmol/kg/d of free ddG or liposomes containing 2.6 mmol/ tive anti-hepatitis B nucleosides to increase the possikg/d of DPP-ddG. Liposomal DPP-ddG reduced serum WHV DNA by 23-to 46-fold at the end of the fourth week, bility of a sustained response to therapy. while free ddG reduced serum WHV DNA by 2.2-to 10.4-
Phospholipid prodrugs of antiviral nucleosides have fold. Treatment with small unilamellar liposomes conbeen shown to retain substantial antiviral activity 4 and taining DPP-ddG is substantially more effective than may be used to target drugs to liver. We have shown free ddG in reducing WHV-DNA levels in serum in WHVpreviously that a lipid prodrug of 2,3-dideoxycytidine infected woodchucks. The data suggest that the use of (ddC), dioleoylphosphatidyl-ddC, accumulates to a 40fold-higher level in liver than free ddC, while retaining antiviral activity and selectivity in 2.2.15 cells, which Abbreviations: HBV, hepatitis B virus; 3TC, (0)b-L-3-thia-2,3-dideoxycytchronically produce HBV. 10 Phosphatidyl-3TC also reidine; ddC, 2,3-dideoxycytidine; ddG, 2,3-dideoxyguanosine; DPP-ddG, ditains full activity in 2.2.15 cells in vitro. 11 The antiviral palmitoylphosphatidyl-dideoxyguanosine; WHV, woodchuck hepatitis virus; activity and selectivity of 2,3-dideoxyguanosine (ddG) DOP-ddG, dileoylphosphatidyl-dideoxyguanosine; DMP-ddG, dimyristoylphoshas been reported previously against HBV in 2.2.15 phatidyl-dideoxyguanosine; AZT, 2,3-dideoxy, 3-azidothymidine.