Daikoku T, Yamamoto N, Saito S, Kitagawa M, Shimada N, Nishiyama Y
Research Institute for Disease Mechanism and Control, Nagoya University School of Medicine, Japan.
Biochem Biophys Res Commun. 1991 Apr 30;176(2):805-12. doi: 10.1016/s0006-291x(05)80257-8.
Oxetanocin G(9-(2-deoxy-2-hydroxymethyl-beta-D-erythro-oxetanosyl)guanine, OXT-G) is a potent and selective agent against human cytomegalovirus (HCMV). In this study we synthesized the triphosphate form of OXT-G, OXT-GTP, and examined its effect on the activities of HCMV DNA polymerase, herpes simplex type 2 (HSV-2) DNA polymerase and human DNA polymerase alpha. OXT-GTP was found to inhibit all these polymerases in a competitive manner with respect to dGTP. The Km for dGTP and the Ki for OXT-GTP of HCMV DNA polymerase were 0.86 and 0.53 mu M, respectively, while the corresponding values of DNA polymerase alpha were 2.2 and 3.6 mu M, respectively. HPLC analysis using [3H]OXT-G also revealed that OXT-G was converted to its triphosphate form 7- to 8-fold more efficiently in HCMV-infected cells than in uninfected cells. The results suggest that both the preferential phosphorylation of OXT-G in HCMV-infected cells and the preferential inhibition of HCMV DNA polymerase by OXT-GTP may contribute towards the selective activity of OXT-G against HCMV replication.
氧杂环丁烷胞苷G（9-(2-脱氧-2-羟甲基-β-D-赤式-氧杂环丁烷基)鸟嘌呤，OXT-G）是一种强效且选择性的抗人巨细胞病毒（HCMV）药物。在本研究中，我们合成了OXT-G的三磷酸形式OXT-GTP，并检测了其对HCMV DNA聚合酶、单纯疱疹病毒2型（HSV-2）DNA聚合酶和人DNA聚合酶α活性的影响。结果发现，OXT-GTP以与dGTP竞争的方式抑制所有这些聚合酶。HCMV DNA聚合酶的dGTP的Km值和OXT-GTP的Ki值分别为0.86和0.53 μM，而DNA聚合酶α的相应值分别为2.2和3.6 μM。使用[3H]OXT-G的HPLC分析还显示，与未感染细胞相比，OXT-G在HCMV感染细胞中转化为其三磷酸形式的效率要高7至8倍。结果表明，HCMV感染细胞中OXT-G的优先磷酸化以及OXT-GTP对HCMV DNA聚合酶的优先抑制可能共同促成了OXT-G对HCMV复制的选择性活性。
