Human Cytomegalovirus Inhibition by Cardiac Glycosides: Evidence for Involvement of the hERG Gene
Human Cytomegalovirus Inhibition by Cardiac Glycosides: Evidence for Involvement of the hERG Gene
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DOI：
10.1128/aac.00898-12
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发表时间：
2012-09-01
影响因子：
4.9
通讯作者：
Arav-Boger, Ravit
中科院分区：
文献类型：
--
作者：
Kapoor, Arun;Cai, Hongyi;Arav-Boger, Ravit
人巨细胞病毒（HCMV）感染仍然是孕妇和免疫功能低下人群的主要威胁。尽管有几种抗HCMV疗法可用，但高度期望开发新的抗HCMV剂。人们对鉴定可能通过调节细胞环境来抑制HCMV的化合物越来越感兴趣。对用于充血性心力衰竭患者的强心苷（CG）的兴趣已经增加，因为它们具有抗癌作用和抗病毒活性。我们报告说，几个CG-地高辛，洋地黄毒苷，哇巴因-是在nM浓度的HCMV的有效抑制剂。HCMV抑制发生在DNA复制之前，但在与其细胞受体结合之后。在CG处理的细胞中，即刻早期、早期和晚期病毒蛋白和细胞NF-κ B的水平显著降低。感染细胞中CG的活性与钾通道基因hERG的表达相关。CMV感染上调hERG，而CG显着下调其表达。感染小鼠CMV上调小鼠ERG（mERG），但治疗与CG没有抑制病毒复制或mERG转录。这些发现表明，CG可能通过调节与hERG相关的人类细胞靶点来抑制HCMV，这些化合物应研究其抗病毒活性。
Infection with human cytomegalovirus (HCMV) continues to be a major threat for pregnant women and the immunocompromised population. Although several anti-HCMV therapies are available, the development of new anti-HCMV agents is highly desired. There is growing interest in identifying compounds that might inhibit HCMV by modulating the cellular milieu. Interest in cardiac glycosides (CG), used in patients with congestive heart failure, has increased because of their established anticancer and their suggested antiviral activities. We report that the several CG-digoxin, digitoxin, and ouabain-are potent inhibitors of HCMV at nM concentrations. HCMV inhibition occurred prior to DNA replication, but following binding to its cellular receptors. The levels of immediate early, early, and late viral proteins and cellular NF-kappa B were significantly reduced in CG-treated cells. The activity of CG in infected cells correlated with the expression of the potassium channel gene, hERG. CMV infection upregulated hERG, whereas CG significantly downregulated its expression. Infection with mouse CMV upregulated mouse ERG (mERG), but treatment with CG did not inhibit virus replication or mERG transcription. These findings suggest that CG may inhibit HCMV by modulating human cellular targets associated with hERG and that these compounds should be studied for their antiviral activities.