Furman P A, Barry D W
Department of Virology, Burroughs Wellcome Company, Research Triangle Park, North Carolina 27709.
Am J Med. 1988 Aug 29;85(2A):176-81.
Zidovudine is a potent in vitro inhibitor of human immunodeficiency virus (HIV) with varying efficacy against other retroviruses. With the exception of Epstein-Barr virus, all non-retroviruses tested so far have been insensitive to inhibition by zidovudine. In vivo, efficacy of zidovudine was demonstrated against Rauscher murine leukemia virus and feline leukemia virus. In both experimental models, infections completely resolved in animals when the drug was administered soon after infection. These results suggest that prompt initiation of zidovudine therapy, following a known exposure to HIV, should be considered. Mechanism studies show that zidovudine is phosphorylated to the monophosphate and diphosphate derivatives by the host cell cytosolic thymidine kinase and thymidylate kinase, respectively. The identity of the enzyme that phosphorylates zidovudine diphosphate is not known, but is believed to be the cellular nucleoside diphosphate kinase. The triphosphate of zidovudine appears to be the active form of the drug. Zidovudine triphosphate competes well with thymidine 5'-triphosphate for binding to the HIV reverse transcriptase and also functions as an alternative substrate. Incorporation of zidovudine monophosphate results in chain termination. However, it is not clear which mechanism, chain termination or competition with thymidine 5'-triphosphate, or a combination of both, is responsible for the inhibition of HIV replication.
齐多夫定是一种强效的人免疫缺陷病毒（HIV）体外抑制剂，对其他逆转录病毒的疗效各异。除了EB病毒外，迄今测试的所有非逆转录病毒对齐多夫定的抑制均不敏感。在体内，齐多夫定对劳氏鼠白血病病毒和猫白血病病毒显示出疗效。在这两种实验模型中，感染后若尽早给药，动物体内的感染可完全消除。这些结果表明，在已知暴露于HIV后，应考虑尽早开始齐多夫定治疗。机制研究表明，齐多夫定分别被宿主细胞胞质胸苷激酶和胸苷酸激酶磷酸化为单磷酸盐和二磷酸盐衍生物。将齐多夫定二磷酸盐磷酸化的酶的身份尚不清楚，但据信是细胞核苷二磷酸激酶。齐多夫定三磷酸盐似乎是该药物的活性形式。齐多夫定三磷酸盐与胸苷5'-三磷酸盐竞争结合HIV逆转录酶的能力很强，并且还作为替代底物发挥作用。齐多夫定单磷酸盐的掺入导致链终止。然而，尚不清楚是哪种机制，即链终止还是与胸苷5'-三磷酸盐的竞争，或两者的结合，导致了HIV复制的抑制。
