Unique metabolism of a novel antiviral L-nucleoside analog, 2′-fluoro-5-methyl-β-L-arabinofuranosyluracil:: a substrate for both thymidine kinase and deoxycytidine kinase
Unique metabolism of a novel antiviral L-nucleoside analog, 2′-fluoro-5-methyl-β-L-arabinofuranosyluracil:: a substrate for both thymidine kinase and deoxycytidine kinase
复制标题
DOI：
10.1128/aac.42.4.833
复制
发表时间：
1998-04-01
影响因子：
4.9
通讯作者：
Cheng, YC
中科院分区：
文献类型：
--
作者：
Liu, SH;Grove, KL;Cheng, YC
2 '-氟-5-甲基-β-L-阿拉伯呋喃糖基尿嘧啶（L-FMAU）是第一个发现的具有低细胞毒性的L-核苷类似物，其对B型肝炎病毒和EB病毒都具有有效的抗病毒活性，但对人类免疫缺陷病毒没有活性。该活性谱不同于所检查的其他L-核苷类似物。L-FMAU通过平衡敏感和不敏感的核苷转运以及通过非易化被动扩散进入细胞。L-FMAU在细胞中被逐步磷酸化成其单磷酸、二磷酸和三磷酸形式。在本研究中，确定了负责L-FMAU磷酸化第一步的酶。这是第一个胸苷类似物不仅是细胞溶质胸苷激酶和线粒体脱氧嘧啶激酶的底物，而且也是脱氧胞苷激酶的底物。这一发现表明，L-FMAU的抗病毒活性不会受到这些脱氧核苷激酶的丢失或改变的限制。
2'-Fluoro-5-methyl-beta-L-arabinofuranosyluracil (L-FMAU) is the first L-nucleoside analog with low cytotoxicity discovered to have potent antiviral activities against both hepatitis B virus and Epstein-Barr virus but not human immunodeficiency virus. This spectrum of activity is different from those of the other L-nucleoside analogs examined. L-FMAU enters cells through equilibrative-sensitive and -insensitive nucleoside transport as well as through nonfacilitated passive diffusion. L-FMAU is phosphorylated stepwise in cells to its mono-, di-, and triphosphate forms. In the present study the enzymes responsible for the first step of L-FMAU phosphorylation were identified. This is the first thymidine analog shown to be a substrate not only for cytosolic thymidine kinase and mitochondrial deoxypyrimidine kinase but also for deoxycytidine kinase. This finding suggests that the antiviral activity of L-FMAU will not be limited by the loss or alteration of any of these deoxynucleoside kinases.