Inhibitors of dual-specificity tyrosine phosphorylation-regulated kinases (DYRK) exert a strong anti-herpesviral activity
Inhibitors of dual-specificity tyrosine phosphorylation-regulated kinases (DYRK) exert a strong anti-herpesviral activity
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DOI：
10.1016/j.antiviral.2017.04.003
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发表时间：
2017-07-01
影响因子：
7.6
通讯作者：
Marschall, Manfred
中科院分区：
文献类型：
--
作者：
Hutterer, Corina;Milbradt, Jens;Marschall, Manfred
人巨细胞病毒（HCMV）感染是一个严重的医学问题，特别是在免疫功能低下的个体和新生儿中。（瓦尔）更昔洛韦治疗的成功受到药物相容性低和诱导病毒耐药性的阻碍。一种新的抗病毒治疗策略是基于对细胞定向信号的开发，即细胞信号转导。G.已知与致癌作用和肿瘤药物开发相关的途径。在这里，我们描述了一个推定的抗病毒药物的基础上靶向双特异性酪氨酸磷酸化调节激酶（DYRKs）的原则。DYRKs构成进化上保守的蛋白激酶家族，在控制细胞增殖和分化中具有关键作用。DYRK家族的成员能够磷酸化许多底物蛋白，包括细胞周期的调节剂，例如DYRK 1B可以诱导细胞周期停滞，这是调节HCMV复制的关键步骤。在这里，我们提供了DYRK在病毒复制过程中的关键作用和DYRK抑制剂（SC 84227，SC 97202和SC 97208，Harmine和AZ-191）的高抗病毒潜力的第一个证据。使用已建立的HCMV实验室和临床相关菌株的复制试验，获得浓度依赖性抑制曲线。平均抑制浓度（EC 50）为0.98 +/- 0.08 μ M/SC 84227、0.60 +/- 0.02 μ M/SC 97202、6.26 +/- 1.64 μ M/SC 97208，对于原代人成纤维细胞的感染，用HCMV株AD 169-GFP测定了0.71 +/- 0.019 μ M/骆驼蓬碱和0.63 +/- 0.23 μ M/AZ-191。抗病毒作用模式的首次分析表明，在HCMV基因表达的早期-晚期阻断病毒复制。此外，恒河猴巨细胞病毒（RhCMV），水痘-带状疱疹病毒（VZV）和单纯疱疹病毒（HSV-1）显示出类似的高敏感性，这些化合物。因此，我们得出结论，DYRK信号转导代表了一个有前途的目标途径的发展，新的抗疱疹病毒的战略。(C)2017 Elsevier B. V.版权所有。
Infection with human cytomegalovirus (HCMV) is a serious medical problem, particularly in immuno-compromised individuals and neonates. The success of (val)ganciclovir therapy is hampered by low drug compatibility and induction of viral resistance. A novel strategy of antiviral treatment is based on the exploitation of cell-directed signaling, e. g. pathways with a known relevance for carcinogenesis and tumor drug development. Here we describe a principle for putative antiviral drugs based on targeting dual-specificity tyrosine phosphorylation-regulated kinases (DYRKs). DYRKs constitute an evolutionarily conserved family of protein kinases with key roles in the control of cell proliferation and differentiation. Members of the DYRK family are capable of phosphorylating a number of substrate proteins, including regulators of the cell cycle, e.g. DYRK1B can induce cell cycle arrest, a critical step for the regulation of HCMV replication. Here we provide first evidence for a critical role of DYRKs during viral replication and the high antiviral potential of DYRK inhibitors (SC84227, SC97202 and SC97208, Harmine and AZ-191). Using established replication assays for laboratory and clinically relevant strains of HCMV, concentration dependent profiles of inhibition were obtained. Mean inhibitory concentrations (EC50) of 0.98 +/- 0.08 mu M/SC84227, 0.60 +/- 0.02 mu M/SC97202, 6.26 +/- 1.64 mu M/SC97208, 0.71 +/- 0.019 mu M/Harmine and 0.63 +/- 0.23 mu M/AZ-191 were determined with HCMV strain AD169-GFP for the infection of primary human fibroblasts. A first analysis of the mode of antiviral action suggested a block of viral replication at the early-late stage of HCMV gene expression. Moreover, rhesus macaque cytomegalovirus (RhCMV), varicella-zoster virus (VZV) and herpes simplex virus (HSV-1) showed a similarly high sensitivity to these compounds. Thus, we conclude that DYRK signaling represents a promising target pathway for the development of novel anti-herpesviral strategies. (C) 2017 Elsevier B.V. All rights reserved.