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-Ohexadecylpropanediol-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-Ohexadecylpropanediol-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.Acyclovir [ACV; 9-(2-hydroxyethoxymethyl)guanine] is remarkably effective against herpes simplex virus (HSV) infection (7, 27). ACV is phosphorylated by an HSV-coded thymidine kinase (9) and is subsequently converted to ACV triphosphate by cellular enzymes (22). ACV triphosphate inhibits the DNA polymerase of HSV (6) and is incorporated into viral DNA, causing chain termination because ACV lacks the equivalent of a 3Ј-hydroxyl group.ACV triphosphate also inhibits the DNA polymerase of hepatitis B virus (HBV) and the DNA polymerase of woodchuck hepatitis virus (WHV) by 50% at 0.9 and 0.7 M, respectively (13). Nevertheless, ACV treatment of patients with HBV infection had no additional effect on serum HBeAg levels in patients also treated with alpha interferon (3). ACV given intravenously for 28 days had only a weak effect on viral replication and did not significantly increase the rate of seroconversion to anti-HBe in chronically infected patients (1). Zidovudine (AZT) triphosphate inhibits HBV DNA polymerase by 50% at 0.3 M (4), but AZT treatment had no effect on serum HBV DNA levels in AIDS patients with concomitant HBV infection (12,17). Poor phosphorylation of ACV has been noted previously in HepG2 cells (15) and in 2.2.15 cells (29). Thus, ...

Comparative Activities of Lipid Esters of Cidofovir and Cyclic Cidofovir against Replication of Herpesviruses In Vitro

“…Although CDV is highly active against most drug-resistant mutants, its lack of activity when given orally and the potential for producing nephrotoxicity have limited its usefulness. Hostetler and colleagues (16,17) reported that ether lipid ester analogs of PCV, GCV, and PFA had significantly increased activity against HSV and CMV as well as HBV and woodchuck hepatitis virus (15,16). These findings were subsequently extended to the synthesis of lipid conjugates for other antivirals, including CDV.…”

“…In addition, studies with hepatitis B virus (HBV) suggest that an alkoxyalkyl-phosphate-ACV analog had significant activity in vitro and in vivo against woodchuck hepatitis virus (15,16). The hexadecyloxypropyl-phospho-ACV (HDP-P-ACV) compound also exhibited little or no toxicity (17).…”

“…To obtain drug activity when the drug was given orally, lipid conjugates for ACV, GCV, and PCV were prepared; these conjugates had been reported to be effective against drugresistant herpes simplex viruses and experimental infections caused by human CMV (HCMV) (15,16,17,24,25). In addition, studies with hepatitis B virus (HBV) suggest that an alkoxyalkyl-phosphate-ACV analog had significant activity in vitro and in vivo against woodchuck hepatitis virus (15,16).…”

Enhanced Inhibition of Orthopoxvirus Replication In Vitro by Alkoxyalkyl Esters of Cidofovir and Cyclic Cidofovir

“…Furthermore, these compounds are active orally in animal models of herpesvirus disease (16) and hepatitis (15). To obtain better oral activity with CDV, we synthesized a new series of analogs by esterification using two long-chain alkoxyalkanols, 3-hexadecyloxy-1-propanol (HDP-CDV; HDP-cCDV) and 3-octadecyloxy-1-ethanol (ODE-CDV; ODE-cCDV) (Fig.…”

Lipid-Based Drug Carriers for Prodrugs to Enhance Drug Delivery

“…The monophosphate form is then converted into the active NTP (Fig. 2b) (45). Another example of a nucleoside lipid prodrug is YNK-01, an AraC analog (46).…”