Anti-hepatitis B virus activity of ??-DDB-DU, a novel nucleoside analogue, in vitro and in vivo

摘要

??-DDB-DU, 2??-deoxy-3??-(4,4??-dimethoxy-2??- methoxycarbonyl-5,6,5??,6??-bis(methylenedioxy)-1,1??-biphenyl-2- carboxyl)uridine, is a novel nucleoside analogue accomplished by linking ??-DDB (??-dimenthoxy dicarboxylate biphenyl) and DU (2??-deoxyuridine) via an ester bond. In the current study, the anti-HBV activity and hepatoprotective effect of this compound were investigated both in vitro and in vivo. In the human HBV-transfected liver cell line HepG2.2.15, ??-DDB-DU effectively suppressed the secretion of the HBV antigens in a dose-dependent manner, with inhibition rate of 42.31% for HBsAg and 31.52% for HBeAg at 5 ??M on day 9. In addition, it could inhibit the viral DNA replication effectively at the concentration of 5 ??M, with 81.18% intracellular inhibition and 88.55% extracellular inhibition, respectively, on day 9. In the duck hepatitis B virus (DHBV) infected model, DHBV DNA levels were markedly reduced after treatment with the ??-DDB-DU at the dosages of 0.8 mg/kg day, 4 mg/kg day and 20 mg/kg day. The inhibition rate of ??-DDB-DU at the dose of 20 mg/kg day reached 93.75% and 89.43%, in duck serum and liver, respectively, on day 10. Furthermore, the levels of alanine transaminase (ALT) and aspartate aminotransferase (AST) in both serum and livers were notably reduced on day 10 and histopathological evaluation of the animals' livers indicated significant improvement. In conclusion, ??-DDB-DU possesses significant inhibitory activity against HBV replication and ameliorates hepatic pathology significantly. ? 2013 Elsevier B.V.