u TAOK3 phosphorylates the methylenecyclopropane nucleoside MBX 2168 to its monophosphate
u TAOK3 phosphorylates the methylenecyclopropane nucleoside MBX 2168 to its monophosphate
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DOI：
10.1016/j.antiviral.2015.04.001
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发表时间：
2015-07-01
影响因子：
7.6
通讯作者：
Bowlin, Terry L.
中科院分区：
文献类型：
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作者：
Komazin-Meredith, Gloria;Cardinale, Steven C.;Bowlin, Terry L.
在6-位具有醚或硫醚取代基的单羟甲基亚甲基环丙烷核苷（MCPNs）显示出作为广谱疱疹病毒抑制剂的前景。他们提出的作用机制涉及连续磷酸化为三磷酸，然后可以抑制病毒DNA聚合酶。这些化合物对单纯疱疹病毒（HSV）的抑制不依赖于病毒胸苷激酶（TK），已知TK磷酸化阿昔洛韦（ACV），阿昔洛韦是HSV感染的标准治疗。先前关于这些化合物对人巨细胞病毒（HCMV）的作用机制的研究表明，除了HCMV UL 97激酶之外，宿主激酶也参与了初始磷酸化。在使用基于活性的分级分离首先消除其他候选HSV-1编码的激酶（UL 13和US 3）以及潜在的宿主核苷激酶之后，我们现在已经鉴定了宿主丝氨酸-苏氨酸蛋白激酶TAOK 3作为负责将代表性单羟甲基MCPN类似物MBX 2168转化为其单磷酸的激酶。(C)2015爱思唯尔B. V.保留所有权利。
Monohydroxymethyl methylenecyclopropane nucleosides (MCPNs) with ether or thioether substituents at the 6-position show promise as broad-spectrum herpes virus inhibitors. Their proposed mechanism of action involves sequential phosphorylation to a triphosphate, which can then inhibit viral DNA polymerase. The inhibition of herpes simplex virus (HSV) by these compounds is not dependent on the viral thymidine kinase (TK), which is known to phosphorylate acyclovir (ACV), a standard treatment for HSV infections. Previous studies on the mechanism of action of these compounds against human cytomegalovirus (HCMV) implicated a host kinase in addition to HCMV UL97 kinase in performing the initial phosphorylation. After first eliminating other candidate HSV-1 encoded kinases (UL13 and US3) as well as potential host nucleoside kinases, using activity-based fractionation, we have now identified the host serine-threonine protein kinase TAOK3 as the kinase responsible for transforming the representative monohydroxymethyl MCPN analog MBX 2168 to its monophosphate. (C) 2015 Elsevier B.V. All rights reserved.