Anti-Epstein-Barr virus (EBV) activity of beta-L-5-iododioxolane uracil is dependent on EBV thymidine kinase.
Anti-Epstein-Barr virus (EBV) activity of beta-L-5-iododioxolane uracil is dependent on EBV thymidine kinase.
复制标题
β-L-5-碘二氧戊环尿嘧啶的抗 Epstein-Barr 病毒 (EBV) 活性依赖于 EBV 胸苷激酶。
DOI：
10.1128/aac.44.12.3278-3284.2000
复制
发表时间：
2000
影响因子：
4.9
通讯作者：
Cheng,YC
中科院分区：
文献类型：
--
作者：
Kira,T;Grill,SP;Dutschman,GE;Lin,JS;Qu,F;Choi,Y;Chu,CK;Cheng,YC
β-1-5-碘二氧戊环尿嘧啶显示出具有强效抗Epstein-巴尔病毒（EBV）活性（50%有效浓度= 0.03 μM）和低细胞毒性（50%细胞毒性浓度= 1，000 μM）。它通过抑制复制的EBV DNA和病毒蛋白质合成来发挥其抗病毒活性。该化合物在EBV复制的细胞中磷酸化，但在EBV潜伏的细胞中不磷酸化。EBV特异性胸苷激酶可将β-l-5-碘二氧戊环尿嘧啶磷酸化为单磷酸代谢产物。β-1-5-碘二氧戊环尿嘧啶与EBV胸苷激酶的Km值为5.5 μM，与胸苷相似，但比2′-氟-5-甲基-β-1-阿拉伯呋喃糖基尿嘧啶高5倍。2′-氟-5-甲基-β-1-阿拉伯呋喃糖基尿嘧啶是发现的第一个具有抗EBV活性的核苷类似物。相对Vmax是胸苷的7倍。5′-乙炔胸苷能抑制β-1-5-碘二氧戊环尿嘧啶的抗EBV活性及其胞内磷酸化。目前的研究表明，β-l-5-碘二氧戊环尿嘧啶在磷酸化后发挥其作用;因此，EBV胸苷激酶对该药物的抗病毒作用至关重要。
β-l-5-Iododioxolane uracil was shown to have potent anti-Epstein-Barr virus (EBV) activity (50% effective concentration = 0.03 μM) with low cytotoxicity (50% cytotoxic concentration = 1,000 μM). It exerts its antiviral activity by suppressing replicative EBV DNA and viral protein synthesis. This compound is phosphorylated in cells where the EBV is replicating but not in cells where the EBV is latent. EBV-specific thymidine kinase could phosphorylate β-l-5-iododioxolane uracil to the monophosphate metabolite. TheKmof β-l-5-iododioxolane uracil with EBV thymidine kinase was estimated to be 5.5 μM, which is similar to that obtained with thymidine but about fivefold higher than that obtained with 2′ fluoro-5-methyl-β-l-arabinofuranosyl uracil, the firstl-nucleoside analogue discovered to have anti-EBV activity. The relativeVmaxis seven times higher than that of thymidine. The anti-EBV activity of β-l-5-iododioxolane uracil and its intracellular phosphorylation could be inhibited by 5′-ethynylthymidine, a potent EBV thymidine kinase inhibitor. The present study suggests that β-l-5-iododioxolane uracil exerts its action after phosphorylation; therefore, EBV thymidine kinase is critical for the antiviral action of this drug.