Arabinogalactan (9kDa)-9-β-D-Arabinofuranosyladenine-5′-Monophosphate,A Novel Liver-Targeted Conjugate that Selectively Inhibits Hepatitis B virus Replication in Vitro

Abstract

Arabinogalactan (9kDa)-9-β-D-arabinofuranosyladenine-5′-monophosphate [AG (9kDa)-araAMP] was 25-fold more active than the parent compound 9-β-D-arabinofuranosyladenine (araA) in decreasing the amount of hepatitis B virus (HBV) DNA intracellular replicative intermediates in HBV-transfected 2.2.15 cells. The putative active 5′-triphosphate metabolite, araATP, exhibited a 50% inhibitory concentration (IC₅₀) of 5 μM toward woodchuck hepatitis virus DNA polymerase, consistent with the anti-HBV activity of these derivatives. AG (9kDa)-araAMP inhibited HepG2 cell proliferation by only 16% at a concentration as high as 822 μM (araA equivalents) and no effects were observed in the presence of 8.22 μM or 82.2 μM of the drug. Lactate production, mitochondrial DNA (mtDNA) content, and mitochondrial morphology were not affected by AG (9kDa)-araAMP at concentrations between 8.22 μM and 822 μM. In contrast, both araA and its in vivo metabolite, 9-β-D-arabinofuranosylhypoxanthine (araH), induced substantial dose-dependent effects on cell growth, lactate production and mtDNA steady-state levels at concentrations of 8.22 μM and 82.2 μM. Some loss of cristae within the mitochondria was also observed in cells incubated with araH. In summary, AG (9kDa)-araAMP exhibits a potent and selective anti-HBV activity and the lack of toxic effects on host cell mitochondrial functions supports its further development.