Antiviral activity of a conjugate of adenine-9-beta-D-arabinofuranoside 5'-monophosphate and a 9 kDa fragment of arabinogalactan.

An arabinogalactan conjugate containing a 9 kDa fragment of arabinogalactan and adenine-9-beta-D-arabinofuranoside 5'-monophosphate (araAMP), denoted AG(9 kDa)-araAMP, has been synthesized and characterized. In 2.2.15 (human hepatoblastoma) cells, the attachment of araAMP to AG(9 kDa), a ligand of the asialoglycoprotein receptor, decreased the effective concentration for inhibiting extracellular hepatitis B virus (HBV) production by 90% (EC90) from 17 to 0.9 microM adenine arabinoside (araA) equivalents, and increased the cytotoxic concentration (CC50) from 188 to > 17 300 microM araA equivalents. Hence, the selectivity index (CC50/EC90) of araA was improved from 11 (188/17) to > 19200 (17 300/0.9) by conjugation with the 9 kDa fragment of arabinogalactan. AG(9 kDa)-araAMP did not affect the production of viral RNA or viral proteins. In the woodchuck hepatitis model, AG(9 kDa)-araAMP inhibited woodchuck hepatitis virus (WHV) DNA replication at a dose of 0.3 mg of araA equivalents per kg; in this case, AG(9 kDa)-araAMP was 20-30 times more potent than was unconjugated araA. AG(9 kDa)-araAMP was effective by intramuscular or subcutaneous administration. The reduction in HBV DNA levels obtained in 2.2.15 cells and of WHV DNA levels in woodchucks was sustained after treatment with AG(9 kDa)-araAMP ceased. In both cases, viral DNA gradually returned to pre-treatment levels.