基于STING的“开放-闭合”动态激活构象发现、设计新型STING激动剂及其在肿瘤免疫治疗中的应用探索

干扰素基因刺激因子（STING）是固有免疫应答中的关键接头蛋白，激动STING可以从更广泛层面激活、增强人体免疫系统和适应性免疫功能。本项目以STING为研究对象，创新性的通过生物大分子体系的动态模拟，整合STING“开放”和“闭合”两种激活构象的结构属性，从差异化结构特征着手获得关键激活特征和微观作用机制，明晰小分子可结合口袋结构特征，采用基于关键结合位点的分子筛选和骨架重构策略指导激动剂的合理发现和设计，利用兼顾活性和成药性的优化策略提高分子性质，最终获得特异性非核苷酸类STING激动剂。同时利用高活性小分子激动剂探索激动STING是否可以作为肿瘤免疫治疗的新途径。本项目将蛋白质动态调控机制整合到药物发现过程，一方面为从肿瘤免疫角度为诊治肿瘤提供化学干预工具和药物靶点；另一方面为针对动态变化蛋白的化学干预提供了研究思路，可以进一步将基于蛋白动态机制驱动的药物研发思路实践于其他靶标。

Stimulator of interferon genes (STING) is a key adaptor protein in the innate immune response. Stimulating STING could broadly activate and enhance the immune system and adaptive immune ability. In this project, we focus on the development of STING agonist to regulate the tumor immune microenvironment. The method is to obtain the key activation characteristics and the pocket information by integrating the different structural properties of STING "open" and "closed" conformations with the help of dynamics simulation and molecular. Virtual screen and skeleton reconstruction strategy based on the key critical binding site are chosen as the main means to discover and design the nonnucleotide-like STING agonists with improved activity and druggability. After that, agonist was used to explore whether stimulating STING could be used as a new strategy for tumor immunotherapy. This project integrates the dynamic regulatory mechanisms of proteins into the drug discovery process. This research not only can provide new chemical tools and target for tumor immunotherapy, but also provides a new idea for chemical intervention against dynamically changing proteins, which can be applied to other targets.