Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Antimicrob Agents Chemother. 2012 Sep;56(9):4891-9. doi: 10.1128/AAC.00898-12. Epub 2012 Jul 9.
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-κB 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.
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 的治疗方法，但人们非常希望开发新的抗 HCMV 药物。人们越来越关注寻找可能通过调节细胞环境来抑制 HCMV 的化合物。由于其已确立的抗癌作用和潜在的抗病毒活性，人们对强心苷（CG）的兴趣日益增加，强心苷用于充血性心力衰竭患者。我们报告几种 CG——地高辛、洋地黄毒苷和哇巴因——在纳摩尔浓度下是有效的 HCMV 抑制剂。HCMV 的抑制作用发生在 DNA 复制之前，但在与细胞受体结合之后。CG 处理的细胞中，早期、早期和晚期病毒蛋白和细胞 NF-κB 的水平显著降低。CG 在感染细胞中的活性与钾通道基因 hERG 的表达相关。CMV 感染上调 hERG，而 CG 显著下调其表达。鼠巨细胞病毒（mCMV）感染上调鼠 ERG（mERG），但 CG 处理不能抑制病毒复制或 mERG 转录。这些发现表明，CG 可能通过调节与 hERG 相关的人类细胞靶标来抑制 HCMV，并且应该研究这些化合物的抗病毒活性。
