新型核苷衍生物十八烷氧乙基替诺福韦酯的体内外抗乙型肝炎病毒作用研究

The in vivo and in vitro anti-hepatitis B virus activities of a novel nucleosides derivative octadecyloxyethyl-tenofovir

目的评价新型核苷衍生物十八烷氧乙基替诺福韦酯(ODE-TFV)在体外及体内的抗乙型肝炎病毒的活性并研究其改善肝脏病理的作用。方法分别以乙型肝炎病毒基因转染的人肝癌2.2.15细胞和DHBV感染的1日龄北京鸭为体外和体内模型,评价ODE-TFV抑制乙型肝炎病毒复制的活性。结果 2.2.15细胞培养法实验结果显示,ODE-TFV抑制HBV DNA复制的IC50值为(0.38±0.18)μmol/L,抑制活性较阳性药TFV-DF和3TC分别强约18倍和13倍;ODE-TFV 100mg/kg和200mg/kg组,在给药7d和停药3d显示有显著性的DHBV-DNA抑制活性(P<0.01、P<0.05);在鸭体内模型中,ODE-TFV 100mg/kg和200mg/kg能够明显改善DHBV引起的肝细胞坏死和炎细胞浸润,有一定量效关系。结论 ODE-TFV不仅在2.2.15细胞内对HBV-DNA有抑制活性,而且能有效地抑制鸭体内DHBV-DNA的复制,并具有改善肝脏病理的作用。

Objective To evaluate the in vitro and in vivo anti-hepatitis B virus activities of octadecyloxyethyl-tenofovir （ODE-TFV） and observe the changes of hepatic pathology. Methods The anti-hepatitis B virus activities of ODE-TFV were estimated in both cultured HBV-transfected human hepatoma 2.2.15 cells and one-day old DHBV infected Beijing ducklings model. Results On the basis of 2.2.15 cells-method, the ICs0 of ODE-TFV was （0.38 ~： 0.18）~mol/L, and the inhibitory activity of ODE-TFV was about 18 times and 13 times stronger than that of TFV-DV and 3TC, respectively; On the 7th day of medication and the 3rd day after medication both of the high- and middle-dosage ODE-TFV groups showed obvious inhibitory effect compared with the DHBV control group （P 〈 0.05 or P 〈 0.01）; the high- and middle-dosage ODE-TFV were able to improve hepatocellular necrosis and inflammatory cell infiltration clearly caused by DHBV. Conclusion The results show that ODE-TFV can not only inhibit the HBV-DNA or DHBV-DNA in cell line 2.2.15 or DHBV-infected ducklings, but also be capable of ameliorating hepatic pathology change.