艾芬地尔和Flavopiridol被全基因组RNA干扰筛选有效药物改善小鼠流感H5N1病毒感染后急性肺损伤。

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张秦张C,张Y, Y, Q,刘问,商D,卢H,李X,周C、F黄,金N,江C

艾芬地尔和Flavopiridol被全基因组RNA干扰筛选有效药物改善小鼠流感H5N1病毒感染后急性肺损伤。

mSystems。2019年12月10;4 (6)。pii: 4/6 / e00431-19。doi: 10.1128 / mSystems.00431-19。

PubMed ID
31822599 (在PubMed
]
文摘

由于有效的治疗方法的局限性,禽流感H5N1病毒是最致命的流感病毒株,导致严重的急性肺损伤(ALI)。开发有效的药物改善H5N1-induced阿里,我们探索一种核糖核酸干扰(RNAi)筛查的方法监测变化引起的细胞死亡的H5N1感染。我们执行RNAi筛查在A549肺上皮细胞和19424个基因检测H5N1感染引起的细胞死亡。这些屏幕识别1137击倒的宿主基因改变细胞生存能力20%以上。beplay体育安全吗DrugBank搜索这些1137年宿主基因确定146年制药与372年目标基因药物的候选人进行验证。我们获得了104与65年商用药物靶基因进行验证和检查了他们改进后的细胞生存能力的H5N1感染。我们发现了28个药物能明显恢复H5N1型病毒感染后细胞生存能力和测试10 H5N1-induced-ALI小鼠模型。神经艾芬地尔药物和抗癌药物flavopiridol明显减少白细胞浸润和肺损伤评分在肺部感染的老鼠,在感染小鼠肺组织明显改善水肿,显著提高感染h5n1病毒的小鼠的生存。艾芬地尔是一个对手的n -甲基- d -门冬氨酸受体,与炎症和肺损伤。Flavopiridol是一种细胞周期蛋白依赖性激酶抑制剂4(到),与白细胞迁移和肺损伤。 These results suggest that ifenprodil and flavopiridol represent novel remedies against potential H5N1 epidemics in addition to their proven indications. Furthermore, our strategy for identifying repurposable drugs could be a general approach for other diseases.IMPORTANCE Drug repurposing is a quick and economical strategy for developing new therapies with approved drugs. H5N1 is a highly pathogenic avian influenza virus subtype that can cause severe acute lung injury (ALI) and a high mortality rate due to limited treatments. The use of RNA interference (RNAi) is a reliable approach to identify essential genes in diseases. In most genomewide RNAi screenings, virus replication is the readout of interference. Since H5N1 virus infection could induce significant cell death and the percentage of cell death is associated with virus lethality, we designed a genomewide RNAi screening method to identify repurposable drugs against H5N1 virus with cell death as the readout. We discovered that the neurological drug ifenprodil and the anticancer drug flavopiridol could effectively ameliorate murine ALI after influenza A H5N1 virus infection, suggesting that they might be novel remedies for H5N1 virus-induced ALI in addition to the traditional indications.

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