Antiviral activities of oral 1-O-hexadecylpropanediol-3-phosphoacyclovir and acyclovir in woodchucks with chronic woodchuck hepatitis virus infection.

Abstract

Acyclovir triphosphate is a potent inhibitor of hepatitis B virus DNA polymerase, but acyclovir treatment provides no benefit in patients with hepatitis B virus infection. This is due in part to the fact that hepatitis B virus, unlike herpes simplex virus, does not code for a viral thymidine kinase which catalyzes the initial phosphorylation of acyclovir. We synthesized 1-O-octadecyl-sn-glycero-3-phospho (3-P)-acyclovir and found that it was highly active in reducing hepatitis B virus replication in 2.2. 15 cells, while acyclovir was inactive. The greater antiviral activity of 1-O-octadecyl-sn-glycero-3-P-acyclovir appeared to be due to liver cell metabolism of the compound to acyclovir monophosphate (K. Y. Hostetler et al., Biochem. Pharmacol. 53:1815-1822, 1997). However, a closely related compound without a hydroxyl group at the sn-2 position of glycerol, 1-O-hexadecylpropanediol-3-P-acyclovir, was more active and selective in 2.2.15 cells in vitro. In this study, we treated woodchucks chronically infected with woodchuck hepatitis virus with increasing oral doses of 1-O-hexadecylpropanediol-3-P-acyclovir and assessed the response to therapy versus acyclovir or a placebo. At a dosage of 10 mg/kg of body weight twice a day, the test compound significantly inhibited viral replication in vivo, as indicated by a 95% reduction in serum woodchuck hepatitis virus DNA levels and by a 54% reduction in levels of woodchuck hepatitis virus replicative intermediates in the liver. Higher doses were somewhat less effective. In contrast, 20 mg of acyclovir/kg twice daily, a 5. 3-fold-higher molar dosage, had no demonstrable activity against woodchuck hepatitis virus. Oral 1-O-hexadecylpropanediol-3-P-acyclovir appeared to be safe and effective in chronic woodchuck hepatitis virus infection.

• Authors: K Y Hostetler, J R Beadle, W E Hornbuckle, C A Bellezza, I A Tochkov, P J Cote, J L Gerin, B E Korba, B C Tennant
• Journal: Antimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 44 Issue 7 Pg. 1964-9 (Jul 2000) ISSN: 0066-4804 [Print] United States
• PMID: 10858362 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• 1-O-hexadecylpropanediol-3-phosphoacyclovir
• Antiviral Agents
• Acyclovir

Topics

• Acyclovir (analogs & derivatives, pharmacology, therapeutic use)
• Administration, Oral
• Animals
• Antiviral Agents (pharmacology, therapeutic use)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Female
• Hepatitis B (drug therapy)
• Hepatitis B Virus, Woodchuck (drug effects)
• Male
• Marmota (virology)
• Treatment Outcome