申请人近年来一直致力于与钙离子通道有关的信号通路、光遗传学与免疫治疗的研究，详细阐明了STIM1和Orai蛋白共同调节钙库释放诱发的钙离子通道(CRAC)的分子机制，以第一作者或通讯作者身份在在Nat. Cell Biol.、Nat. Struct. Mol. Biol.、Nat. Commun.、eLife等著名学术期刊发表SCI论文19篇，其结果多次被作为热点研究进行专门推荐，被多家网络和新闻媒体所转载和评述。在本项目中，申请人和国内合作者拟对前期发现的1,2-萘醌类及异硫脲类化合物的结构进行全面分析，综合运用基于受体与配体的计算机辅助药物设计方法，分析先导化合物与CRAC通道的结合模式，结合传统的药物化学方法对其进行合理的结构优化设计与合成，并进一步在细胞水平及动物水平上评价其免疫调节活性，为开发具有自主知识产权的高活性CRAC通道阻滞剂类免疫调节剂提供理论依据。

The PI has been working on the signal transduction, optogenetics and immunotherapy study of Ca2+ release activated Ca2+ channel (CRAC) by disclosing the STIM1-Orai co-regulation mechanism of CRAC. In recent years, the applicant has published 19 papers as the first or corresponding author in many prestigious journals, including Nat. Cell Biol., Nat. Struct. Mol. Biol., Nat. Commun. and eLife, etc. These interesting results have been featured by many publishers, websites and media. In the current proposal, the PI and China co-PI will take an structural modification and optimization on the basis of naphthoquinone and isothiourea lead compounds. This project will use structure- and ligand-based durg design strategy to exmine the binding modes, to have a rational design and synthesis of derivatives, to evaluate these derivatives' immunomodulation activities on the cellular and animal level, as well as to lay a solid foundation for furthur CRAC blockers with own intellectual property.