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Antimicrobial Agents and Chemotherapy, July 2000, p. 1964-1969, Vol. 44, No. 7
Department of Medicine, University of
California, San Diego, La Jolla, California 92093-0676, and the
Veterans Affairs Medical Center, San Diego, California
921611; Department of Clinical Science,
College of Veterinary Medicine, Cornell University, Ithaca, New York
148532; and the Division of Molecular
Virology and Immunology, Georgetown University School of Medicine,
Rockville, Maryland 208523
Received 18 October 1999/Returned for modification 11 January
2000/Accepted 7 April 2000
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.
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
Antiviral Activities of Oral
1-O-Hexadecylpropanediol-3-Phosphoacyclovir and Acyclovir in
Woodchucks with Chronic Woodchuck Hepatitis Virus
Infection
*
Corresponding author. Mailing address: Department of
Medicine (0676), 9500 Gilman Dr., University of California, San Diego, La Jolla, CA 92093-0676. Phone: (858) 552-8585, ext. 2616. Fax: (858)
534-6133. E-mail: khostetler{at}ucsd.edu.
Antimicrobial Agents and Chemotherapy, July 2000, p. 1964-1969, Vol. 44, No. 7
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
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