Differential patterns of intracellular metabolism of 2',3'-didehydro-2',3'-dideoxythymidine and 3'-azido-2',3'-dideoxythymidine, two potent anti-human immunodeficiency virus compounds.
Differential patterns of intracellular metabolism of 2',3'-didehydro-2',3'-dideoxythymidine and 3'-azido-2',3'-dideoxythymidine, two potent anti-human immunodeficiency virus compounds.
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DOI：
10.1016/s0021-9258(18)83322-1
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发表时间：
1989-04
期刊：
影响因子：
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通讯作者：
J. Balzarini;P. Herdewijn;E. Clercq
中科院分区：
文献类型：
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作者：
J. Balzarini;P. Herdewijn;E. Clercq
3 ' -叠氮-2 ',3 ' -二脱氧胸腺嘧啶（AZT）和2 ',3 ' -二氢-2 ',3 ' -二脱氧胸腺嘧啶（D4T）是人类免疫缺陷病毒在MT-4和ATH8细胞中复制的有效选择性抑制剂。它们也抑制小鼠逆转录病毒的复制，即。Moloney小鼠肉瘤病毒诱导的C3H细胞转化。在MT-4细胞中，AZT很容易被磷酸化为5 ' -单磷酸，而5 ' -二磷酸和5 ' -三磷酸的产生程度比5 ' -单磷酸低200 - 600倍。D4T在MT-4细胞中磷酸化为其5 ' -单磷酸，磷酸化程度比AZT低300 - 600倍。在胸苷激酶缺陷细胞系（Raji/TK−）中AZT的磷酸化水平严重降低，而在Raji/TK−中D4T的磷酸化水平与Raji/0细胞相比仅略有降低。D4T对粗MT-4细胞提取物的磷酸化亲和力比AZT低10倍（分别为Km， 142和14µM）， D4T的磷酸化vmax仅为AZT的5%。MT-4细胞提取物磷酸化D4T的效率比AZT低约180倍（Vmax/Km， D4T为0.06，AZT为11），这与完整的MT-4细胞中形成的D4T和AZT磷酸化产物数量的差异一致。AZT和D4T的5′-三磷酸对人免疫缺陷病毒和鼠白血病病毒的逆转录酶具有相同的抑制作用。
3′-Azido-2′,3′-dideoxythymidine (AZT) and 2′,3′-didehydro-2′,3′-dideoxythymidine (D4T) are potent and selective inhibitors of human immunodeficiency virus replication in MT-4 and ATH8 cells. They are also inhibitory to the replication of murine retroviruses,i.e.Moloney murine sarcoma virus-induced transformation of C3H cells. In MT-4 cells AZT is readily phosphorylated to its 5′-monophosphate, while the 5′-di- and 5′-triphosphates are generated to a 200–600-fold lower extent than the 5′-monophosphate. D4T is phosphorylated in MT-4 cells to its 5′-monophosphate at a 300–600-fold lower extent than AZT. The phosphorylation of AZT in the thymidine kinasedeficient cell line (Raji/TK−) is severely depressed, while D4T phosphorylation is only slightly diminished in Raji/TK−as compared to Raji/0 cells. D4T has a 10-fold lower affinity for phosphorylation by crude MT-4 cell extracts than AZT (Km, 142 and 14 µM, respectively), and theVmaxfor phosphorylation of D4T is only 5% that of AZT. D4T is phosphorylated by MT-4 cell extracts about 180-fold less efficiently than AZT (Vmax/Km, 0.06 for D4T, as compared to 11 for AZT), and this is consistent with the differences found in the amounts of phosphorylated products of D4T and AZT formed in intact MT-4 cells. The 5′-triphosphates of AZT and D4T are equipotent in their inhibitory effects on the reverse transcriptases from human immunodeficiency virus and Moloney murine leukemia virus.