疱疹病毒蛋白激酶,例如人巨细胞病毒(HCMV)的治疗相关pUL97,对病毒复制效率和发病机制都很重要,并代表关键的抗病毒药物靶标。HCMVpUL97是一种病毒细胞周期蛋白依赖性激酶(CDK)直系同源物,因为它与人类CDK共享功能和结构特性。最近,已经证明了vCDK/pUL97-cyclin复合物的形成以及多种病毒和细胞底物蛋白的磷酸化。遗传作图和结构建模方法帮助定义了两个pUL97接口,IF1和IF2,负责细胞周期蛋白结合。特别是,已经强调了vCDK/pUL97与宿主细胞周期蛋白以及CDK之间相互作用的调节重要性,既可以作为病毒复制的决定因素,也可以作为一种新型的药物靶向选择。这一方面通过发现细胞周期蛋白H型敲除后病毒复制受损而得到证实,并且这种针对宿主的干扰也会影响对现有疗法具有抗性的病毒。除了形成二元相互作用复合体之外,还描述了三元PUL97-细胞周期蛋白H-CDK7复合物,鉴于此,pUL97对CDK7活性的实验性反式刺激对于病毒-宿主共调控至关重要.根据这一认识,已经出现了几种新的抗病毒靶向选择。这些包括针对pUL97,宿主CDK的激酶抑制剂,和pUL97-cyclinH相互作用复合物。重要的是,最近报道了使用药理学相关CDK7和vCDK/pUL97抑制剂组合的抗病毒治疗方案具有统计学意义的药物协同作用。包括Maribavir.合并,这些发现为抗HCMV控制提供了更多的选择。这篇综述的重点是vCDK/pUL97与宿主细胞周期蛋白-CDK装置的调控相互作用,它解决了这些关键效应复合物与病毒复制和发病机理的功能相关性。在此基础上,定义了抗病毒药物靶向的新策略。
Herpesviral protein kinases, such as the therapy-relevant pUL97 of human cytomegalovirus (HCMV), are important for viral replication efficiency as well as pathogenesis, and represent key antiviral drug targets. HCMV pUL97 is a viral cyclin-dependent kinase (CDK) ortholog, as it shares functional and structural properties with human CDKs. Recently, the formation of vCDK/pUL97-cyclin complexes and the phosphorylation of a variety of viral and cellular substrate proteins has been demonstrated. Genetic mapping and structural modeling approaches helped to define two pUL97 interfaces, IF1 and IF2, responsible for cyclin binding. In particular, the regulatory importance of interactions between vCDK/pUL97 and host cyclins as well as CDKs has been highlighted, both as determinants of virus replication and as a novel drug-targeting option. This aspect was substantiated by the finding that virus replication was impaired upon cyclin type H knock-down, and that such host-directed interference also affected viruses resistant to existing therapies. Beyond the formation of binary interactive complexes, a ternary pUL97-cyclin H-CDK7 complex has also been described, and in light of this, an experimental trans-stimulation of CDK7 activity by pUL97 appeared crucial for virus-host coregulation. In accordance with this understanding, several novel antiviral targeting options have emerged. These include kinase inhibitors directed to pUL97, to host CDKs, and to the pUL97-cyclin H interactive complexes. Importantly, a statistically significant drug synergy has recently been reported for antiviral treatment schemes using combinations of pharmacologically relevant CDK7 and vCDK/pUL97 inhibitors, including maribavir. Combined, such findings provide increased options for anti-HCMV control. This review focuses on regulatory interactions of vCDK/pUL97 with the host cyclin-CDK apparatus, and it addresses the functional relevance of these key effector complexes for viral replication and pathogenesis. On this basis, novel strategies of antiviral drug targeting are defined.