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首页> 外文期刊>Molecular pharmacology. >Specific recognition of the bicyclic pyrimidine nucleoside analogs, a new class of highly potent and selective inhibitors of varicella-zoster virus (VZV), by the VZV-encoded thymidine kinase.
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Specific recognition of the bicyclic pyrimidine nucleoside analogs, a new class of highly potent and selective inhibitors of varicella-zoster virus (VZV), by the VZV-encoded thymidine kinase.

机译：VZV编码的胸苷激酶可特异性识别双环嘧啶核苷类似物，这是一类新型的高效有效的水痘带状疱疹病毒（VZV）抑制剂。

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摘要

Recently, an entirely new class of bicyclic nucleoside analogs (BCNAs) was found to display exquisite potency and selectivity as inhibitors of varicella-zoster virus (VZV) replication in cell culture. A striking difference in their ability to convert the BCNAs to their phosphorylated derivatives was observed between the VZV-encoded thymidine kinase (TK) and the very closely related herpes simplex virus type 1 (HSV-1) TK. Whereas VZV TK efficiently phosphorylated the BCNAs, HSV-1 TK was unable to do so. In addition, the thymidylate (dTMP) kinase activity of VZV TK further converted BCNA-5'-MP to BCNA-5'-DP. The BCNAs (or their phosphorylated derivatives) were not a substrate for cytosolic TK, mitochondrial TK, or cytosolic dTMP kinase. Human erythrocyte nucleoside diphosphate (NDP) kinase was unable to phosphorylate the BCNA 5'-diphosphates to BCNA 5'-triphosphates. Under the same experimental conditions, the anti-herpetic (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU) derivative was efficiently converted to BVDU-MP and BVDU-DP by both VZV TK and HSV-1 TK and further, into BVDU-TP, by NDP kinase. Our observations may account for the unprecedented specificity of BCNAs as anti-VZV agents.
机译：最近，发现一类全新的双环核苷类似物（BCNA）在细胞培养中作为水痘带状疱疹病毒（VZV）复制的抑制剂表现出出色的效能和选择性。在VZV编码的胸苷激酶（TK）和与之密切相关的单纯疱疹病毒1型（HSV-1）TK之间，观察到它们将BCNAs转化为其磷酸化衍生物的能力存在显着差异。 VZV TK有效地使BCNA磷酸化，而HSV-1 TK无法做到这一点。此外，VZV TK的胸苷酸（dTMP）激酶活性进一步将BCNA-5'-MP转换为BCNA-5'-DP。 BCNA（或其磷酸化衍生物）不是胞质TK，线粒体TK或胞质dTMP激酶的底物。人红细胞核苷二磷酸（NDP）激酶无法将BCNA 5'-二磷酸磷酸化为BCNA 5'-三磷酸。在相同的实验条件下，VZV TK和HSV-1 TK可将抗疱疹性（E）-5-（2-溴乙烯基）-2'-脱氧尿苷（BVDU）衍生物有效地转化为BVDU-MP和BVDU-DP通过NDP激酶进一步转化为BVDU-TP。我们的观察结果可能解释了BCNA作为抗VZV药物具有前所未有的特异性。

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