核受体RORgt的链接区域作为小分子干预靶点的研究

RORγt是调控TH17细胞发育分化和功能的关键转录因子，利用小分子干预RORγt的功能已经成为研发TH17细胞相关的自身免疫疾病和肿瘤治疗方法的重要手段。目前小分子的干预靶点主要为RORγt的配体结合域。但是现有化合物在抑制RORγt在TH17细胞中产生IL-17等细胞因子的同时，也破坏了RORγt对胸腺细胞发育的功能，因而产生严重毒副作用。本课题在前期工作中通过对全长RORγt蛋白的研究，发现了可选择性地抑制RORγt的产生IL-17的活性，但对胸腺细胞毒性极低的化合物。作用机制研究表明，此类化合物很可能作用于RORγt的链接区域。本项目将阐明此类化合物与RORγt的链接区域的结合机制，化合物干预RORγt转录蛋白复合物的作用机制，深入优化此类化合物的活性和水溶性，为研究新型选择性RORγt小分子干预手段提供研究基础和工具化合物。

RORγt is a type of transcription factor in T cells which takes vital roles in T cell maturation, differentiation and functions. Thereof, the intervene of RORγt activities by small molecules has been a promising therapeutic target for autoimmune diseases and cancers. Most of the currently available small molecules bind in the ligand binding domain (LBD) of RORγt. However, due to the functional limit of RORγt’s LBD, these small molecules cannot differentiate the activities RORγt in TH17 cells and the thymocytes, which lead to the serious side effects. In our preliminary research with full-length RORγt, we discovered small molecules specifically targeted on TH17 activity without insignificant effects on thymocyte. The mechanism study showed that these activities are related with Hinge domain of RORγt. This project will elucidate the working mechanism of the Hinge domain as the target of small molecules and optimize these compounds for selective activity and better water solubility, which will afford basis and tool compounds for chemical biology studies of RORγt.