9-([2-HYDROXY-1-(HYDROXYMETHYL)ETHOXY]METHYL)GUANINE - A SELECTIVE INHIBITOR OF HERPES GROUP VIRUS-REPLICATION
9-([2-HYDROXY-1-(HYDROXYMETHYL)ETHOXY]METHYL)GUANINE - A SELECTIVE INHIBITOR OF HERPES GROUP VIRUS-REPLICATION
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DOI：
10.1073/pnas.80.13.4139
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发表时间：
1983-01-01
期刊：
影响因子：
--
通讯作者：
TOLMAN, RL
中科院分区：
文献类型：
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作者：
FIELD, AK;DAVIES, ME;TOLMAN, RL
9-{2-羟基-1-（羟甲基）乙氧基]甲基}鸟嘌呤（2“-去甲-2”-脱氧鸟苷; 2“NDG）选择性抑制疱疹病毒组的复制。在细胞培养研究中，2“NDG在抑制人巨细胞病毒复制和EB病毒诱导的淋巴细胞转化方面的效力至少是无环鸟苷（ACV）的10倍，在抑制单纯疱疹病毒（HSV）1型和2型以及水痘带状疱疹病毒方面的效力与ACV大致相同。口服2“NDG治疗小鼠全身或局部HSV-1感染或HSV-2阴道感染的有效性是ACV的6- 50倍。2“NDG的作用模式似乎涉及单纯疱疹病毒胸苷激酶的磷酸化和随后细胞激酶的磷酸化，以产生2”NDG三磷酸，这是疱疹病毒DNA聚合酶的有效抑制剂。与ACV相比，2 '' NDG是HSV-1胸苷激酶的更有效底物（2 '' NDG的Vmax/Km比ACV高30倍）; 2 '' NDG单磷酸是GMP激酶的更有效底物（2 '' NDG单磷酸的Vmax/Km比ACV单磷酸高492倍）。结合的效果是从2“NDG比从ACV更快地产生抑制性三磷酸。
9-{2-Hydroxy-1-(hydroxymethyl)ethoxy]methyl}guanine (2''-nor-2''-deoxyguanosine; 2''NDG) selectively inhibits the replication of herpes group viruses. In cell culture studies 2''NDG was at least 10-fold more potent than acyclovir (ACV) in inhibition of human cytomegalovirus replication and Epstein-Barr virus-induced lymphocyte transformation and was about as effective as ACV in inhibition of herpes simplex virus (HSV) types 1 and 2 and varicella zoster virus. Orally administered 2''NDG was 6- to 50-fold more efficacious than ACV in treating systemic or local HSV-1 infection or HSV-2 intravaginal infection in mice. The mode of action of 2''NDG appears to involve phosphorylation by herpes simplex virus thymidine kinase and subsequent phosphorylations by cellular kinases to produce 2''NDG triphosphate, which is a potent inhibitor of herpes virus DNA polymerase. Compared to ACV, 2''NDG was a more efficient substrate for HSV-1 thymidine kinase (Vmax/Km for 2''NDG 30-fold higher than that for ACV); 2''NDG monophosphate is a more efficient substrate for GMP kinase (Vmax/Km for 2''NDG monophosphate 492-fold higher than that for ACV monophosphate). The combined effect is more rapid production of the inhibitory triphosphate from 2''NDG than from ACV.