Guangzhou Jinan Biomedicine Research and Development Center, National Engineering Research Center of Genetic Medicine, Jinan University, Guangzhou, China; College of Life Science and Technology, Jinan University, Guangzhou, China.
Guangzhou Jinan Biomedicine Research and Development Center, National Engineering Research Center of Genetic Medicine, Jinan University, Guangzhou, China; College of pharmacy, Jinan University, Guangzhou, China.
Biochem Biophys Res Commun. 2014 Apr 18;446(4):990-6. doi: 10.1016/j.bbrc.2014.03.050. Epub 2014 Mar 19.
Herpes simplex virus type 1 (HSV-1) infection is very common worldwide and can cause significant health problems from periodic skin and corneal lesions to encephalitis. Appearance of drug-resistant viruses in clinical therapy has made exploring novel antiviral agents emergent. Here we show that chloride channel inhibitors, including tamoxifen and 5-nitro-2-(3-phenyl-propylamino) benzoic acid (NPPB), exhibited extensive antiviral activities toward HSV-1 and ACV-resistant HSV viruses. HSV-1 infection induced chloride ion influx while treatment with inhibitors reduced the increase of intracellular chloride ion concentration. Pretreatment or treatment of inhibitors at different time points during HSV-1 infection all suppressed viral RNA synthesis, protein expression and virus production. More detailed studies demonstrated that tamoxifen and NPPB acted as potent inhibitors of HSV-1 early entry step by preventing viral binding, penetration and nuclear translocation. Specifically the compounds appeared to affect viral fusion process by inhibiting virus binding to lipid rafts and interrupting calcium homeostasis. Taken together, the observation that tamoxifen and NPPB can block viral entry suggests a stronger potential for these compounds as well as other ion channel inhibitors in antiviral therapy against HSV-1, especially the compound tamoxifen is an immediately actionable drug that can be reused for treatment of HSV-1 infections.
单纯疱疹病毒 1 型（HSV-1）感染在全球范围内非常普遍，可导致周期性皮肤和角膜损伤，甚至脑炎等严重健康问题。临床治疗中出现耐药病毒，使得探索新型抗病毒药物成为当务之急。本研究表明，氯离子通道抑制剂如他莫昔芬和 5-硝基-2-(3-苯丙基氨基)苯甲酸（NPPB）对 HSV-1 和 ACV 耐药 HSV 病毒具有广泛的抗病毒活性。HSV-1 感染诱导氯离子内流，而抑制剂处理则降低了细胞内氯离子浓度的增加。在 HSV-1 感染的不同时间点进行抑制剂预处理或治疗均可抑制病毒 RNA 合成、蛋白表达和病毒产生。更详细的研究表明，他莫昔芬和 NPPB 可通过阻止病毒结合、渗透和核转位，作为 HSV-1 早期进入步骤的有效抑制剂发挥作用。具体而言，这些化合物似乎通过抑制病毒与脂筏的结合和中断钙稳态来影响病毒融合过程。总之，他莫昔芬和 NPPB 可阻断病毒进入的观察结果表明，这些化合物以及其他离子通道抑制剂在抗 HSV-1 的抗病毒治疗中具有更强的潜力，特别是化合物他莫昔芬是一种可立即使用的药物，可重复用于治疗 HSV-1 感染。
