抗RNA病毒的表观遗传小分子抑制剂的筛选和分子机制研究

RIG-I信号通路在细胞抗RNA病毒过程中发挥着关键作用，但是其分子调控机制以及相关药物的研发尚有待深入研究。最新的研究成果发现表观遗传相关基因WDR5和WDR82参与调节RIG-I信号通路的激活，提示这类基因可能在这个信号通路中发挥着重要作用。我们通过对蛋白质甲基化酶siRNA文库和表观遗传药物的筛选，发现两个表观遗传相关的小分子抑制剂EFI1和EFI2有效地抑制RNA病毒在细胞内的增殖。同时初步的实验结果说明上述小分子所对应的蛋白酶EME1和EME2在敲低后增强SeV诱导的IFN-β的表达，说明EME1和EME2抑制RIG-I信号通路的激活。本项目将在此基础上研究EME1和EME2调控病毒激活的RIG-I信号通路的分子机制，探究小分子抑制剂EFI1和EFI2在抑制RNA病毒方面可能的应用前景。

RIG-I signaling pathway plays a key role in the cell response against RNA virus infection, but the detailed molecular mechanisms and related drug development still require extensive studies. The recent reports indicated that two epigenetic genes, WDR5 and WDR82, are involved in the activation of RIG-I pathway, which suggests epigenetic genes may have important functions in the pathway regulation. After screening of siRNA library for protein methylation and epigenetic chemicals, we identified two some molecules, EFI1 and EFI2, effectively inhibits the replication of RNA virus in the cell. Importantly, knockdown of EME1 or EME2, the responding enzymes for the two chemicals, enhanced IFN-β expression induced by SeV treatment, which indicated that EME1 and EME2 respectively repress pathway activation. Based on the above discoveries, the current project will further study the molecular mechanisms for RIG-I signaling pathway regulated by EME1 and EME2, and investigate the clinical potential of EFI1 and EFI2 in anti-viral treatment.