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首页> 外文期刊>Journal of Molecular Biochemistry >N2-Phenyl-9-(hydroxyalkyl)guanines and related compounds are substrates for Herpes simplex thymidine kinases
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N2-Phenyl-9-(hydroxyalkyl)guanines and related compounds are substrates for Herpes simplex thymidine kinases

机译：N2-苯基-9-（羟烷基）鸟嘌呤和相关化合物是单纯疱疹胸苷激酶的底物

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Herpes simplex virus (HSV) types 1 and 2 thymidine kinases (TK) are responsible for phosphorylation of antiherpes acyclonucleosides such as acyclovir (ACV) and 9-(4-hydroxybutyl)guanine (HBG). Related compounds, the N2-phenyl-9-(hydroxyalkyl)guanines, are devoid of direct antiviral activity, but potently inhibit the viral TKs and block viral reactivation from latency in vivo. The similarity in structure between the acyclonucleosides and TK inhibitors raised the question of the relevance of phosphorylation of certain of the latter analogs in their mechanisms of action. Using recombinant TKs and HPLC analysis of reaction mixtures, we report that the lead TK inhibitor N2-phenyl-9-(4-hydroxybutyl)guanine (HBPG) and its pentyl homolog (HPnPG) are excellent substrates for the enzymes, approaching the efficiency with which the natural substrate thymidine is phosphorylated, and significantly better than ACV or HBG. Other 9-hydroxyalkyl congeners are substrates for the enzymes, but with much poorer efficiency. HBPG triphosphate was a poor inhibitor of HSV DNA polymerase, the target of acyclonucleoside triphosphates, suggesting that phosphorylation of HBPG is not important in its mechanism of blocking viral reactivation in vivo. The fact that HBPG is an efficient substrate is consistent, however, with its binding mode based both on molecular modeling studies and x-ray structure of the HBPG:TK complex.
机译：1型和2型单纯疱疹病毒（HSV）胸苷激酶（TK）负责抗疱疹无环核苷（例如无环鸟苷（ACV）和9-（4-羟丁基）鸟嘌呤（HBG））的磷酸化。相关化合物N2-苯基-9-（羟烷基）鸟嘌呤没有直接的抗病毒活性，但有效抑制病毒TK，并阻止病毒在体内潜伏期重新激活。无环核苷和TK抑制剂在结构上的相似性提出了一个问题，即后者某些类似物的磷酸化在其作用机理中的相关性。使用重组TK和反应混合物的HPLC分析，我们报告称主要TK抑制剂N2-苯基-9-（4-羟基丁基）鸟嘌呤（HBPG）及其戊基同系物（HPnPG）是酶的优良底物，接近于天然底物胸腺嘧啶核苷被磷酸化，明显优于ACV或HBG。其他9-羟烷基同源物是酶的底物，但效率较差。 HBPG三磷酸酯是HSV DNA聚合酶（无环核苷三磷酸酯的靶标）的弱抑制剂，这表明HBPG的磷酸化在其体内阻断病毒再激活的机制中并不重要。但是，HBPG是有效的底物这一事实与基于分子模型研究和HBPG：TK络合物的X射线结构的结合模式是一致的。

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