我们的前期研究发现新型DMARD药物艾拉莫德可选择性抑制IL-17信号从而改善小鼠胶原性关节炎，其机制与传统用药甲氨蝶呤、来氟米特等不同，初步证实其靶蛋白为IL-17信号中的接头蛋白Act1，但其详细作用机制仍不明，Act1的靶标属性亦有待确立。作为第1个Act1抑制剂，本项目拟深入阐明艾拉莫德与Act1结合的分子基础，包括用多种方法确证其结合，进一步借助计算机模拟、肽段截短和氨基酸突变等确定二者结合的结构功能域和位点。在此基础上考察艾拉莫德靶向Act1后对于Act1本身及Act1招募形成的复合体相关蛋白成员的影响。进一步借助艾拉莫德及其衍生物、Act1的siRNA或抗Act1抗体、靶向Act1特定功能域或位点的肽段等手段，探讨靶向Act1对治疗相关疾病的改善作用，从而揭示Act1在IL-17相关疾病中的关键靶标地位，为基于这种结构基础的药物设计和建立治疗免疫炎症相关疾病的新方法打下基础。

Our previous study has found that iguratimod, a novel disease-modifying antirheumatic drug, can ameliorate murine arthritis by blocking IL-17 signaling, which is distinct from methotrexate and leflunomide. The target protein of iguratimod has been proved to be Act1, the adaptor protein in IL-17 signaling. However, the unique mechanism has not been elucidated and the key position of Act1 has yet to be established. As the first small inhibitor of Act1, the structure basis for iguratimod induced interaction with Act1 will be further elucidated in this proposal. The binding of iguratimod to Act1 will be confirmed by varieties of methods. Then, we will identify the regions and amino residues required for Act1 to interact with iguratimod by using computer docking, truncation mutation and point mutation. And the effect of iguratimod on Act1 itself and Act1-adapted complex will also be examined. Finally, we will explore the improvement of iguratimod analogs, Act1 siRNA, Act1 antibodies, or small molecules which specifically target Act1 on IL-17 related diseases and reveal the key position of Act1 in these inflammatory diseases. The proposed research will provide insights into design of new drugs and discovery of novel approaches to the regulation of inmunoinflammation.