人体先天免疫作用因子RNase L的抑制剂开发及作用机理研究

核糖核酸酶RNase L在人体抗病毒先天免疫中扮演重要角色。在病毒入侵人体时，RNase L通过降解病毒和宿主的单链RNA来阻止病毒的复制。前期研究发现，抗癌靶向药物舒尼替尼（Sunitinib）可以抑制RNase L从而增强溶瘤病毒对癌细胞的攻击效果。申请人拟研究Sunitinib与RNase L的作用机制，研究方法包括解析共晶结构，根据结构设计Sunitinib小分子结构类似物，并测试这些小分子对RNase L酶活力的影响。与此同时，申请人通过筛选，获得了一个RNase L的高活性小分子抑制剂。我们将使用结构生物学手段探索该抑制剂的作用机理，优化小分子结构并检测其在抗癌溶瘤病毒疗法中的效力。进一步地，为更好地理解RNase L对底物RNA识别和剪切的分子机制，我们将解析RNase L与底物RNA的复合物结构，为深入地理解人体先天免疫反应基本生物机制并设计创新性的调控小分子奠定基础。

RNase L, a ribonuclease, plays important physiological roles in human antiviral innate immunity. Upon viral invasion, RNase L will be activated and consequently cleaves both viral and host RNA in order to prevent viral replication. It has been reported that anticancer drug Sunitinib can inhibit RNase L and further enhance anticancer viral therapy. Therefore, we propose to investigate the interactions between Sunitinib and RNase L by solving the co-crystal structure of these two molecules. Based on the structural information, we will use structure-activity-relationship (SAR) to design Sunitinib analogs and test their potency. We have obtained another potent RNase L inhibitor by screening against a kinase focused small molecule library. We will employ structure based drug discovery to discover more potent and specific inhibitors for RNase L and test their efficacy in anticancer viral therapy. Finally, we propose the structure determination for the complex of RNase L and substrate RNA in order to understand the recognition and cleavage mechanisms of RNase L in human innate immunity and to design novel small molecule modulators.