基于翻译后修饰的难靶蛋白质化学探针发现技术体系构建及化学干预

Chemical modulation of untargetable proteins is crucial for fundamental biomedical research as well as the mechanism study of diseases. On the basis of previous research, this project will comprehensively apply the interdisciplinary technology from computational biology, chemical biology, structural biology, and pharmacology for discovery and development of small-molecule inhibitors targeting untargetble proteins. Using an innovative strategy by mimicking the way how endogenous post-translational modifications regulate protein structure and function this project will discovery new targetable sites as well as chemical probes for untargetable proteins (such as the Ras superfamily, and autophagy related proteins). Chemical intervention study using the discovered probe in combination with genetic apoarches will be carried out to investigate into the dynamic regulation mechanism as well as novel functions of the proteins in diseases, from multi-dimension perspectives including molecular, cellular, tissue, and animal levels.The launch of this project will overcome the difficulties of developing chemical probes for untargetable proteins, and provide innovative research strategy and new paradigm for chemical biology research. It will also provide chemical probes for the study of dynamic modulation and the function of the target protein in diseases. Finally, the fulfillment of this project will bridge the gap of dynamic modification and targeted drug discovery, build a world-class research team of chemical biology for protein dynamic modifications, and lay the foundation of technology for the development of innovative drugs with independent intellectual property rights We expect to publish at least 10 high impact-factor papers on well-known international journals, and apply more than 5 patents.

难靶蛋白质动态修饰的化学调控研究，对于探索生物医学重大基础研究和疾病发病机制，有着非常重要的意义。本项目拟基于前期研究，综合运用计算生物学、化学生物学、结构生物学和药理学等多学科技术，以难靶蛋白质（如RAS超家族、自噬相关蛋白等）为切入点，基于蛋白翻译后修饰发现靶向难靶蛋白质的全新调控位点和化学探针，从分子、细胞、组织和动物等多维度开展对其动态修饰识别、调控及化学干预研究。项目的实施将为攻克难靶蛋白质化学探针开发困难这一瓶颈问题，提供创新性的研究策略和化学生物学研究新模式，为揭示难靶蛋白质的翻译后修饰功能、动态调控机制及其在疾病中的功能研究和临床应用提供化学探针，加速动态修饰调控与分子靶向药物发现之间的桥梁，建设一支国际一流的蛋白质动态修饰的化学生物学研究团队，为开发具有自主知识产权的创新药物奠定技术和活性物质基础。研究成果将发表高水平论文10篇以上，申请专利5项以上。

难靶蛋白质动态修饰的化学调控研究，对于探索生物医学重大基础研究和疾病发病机制，有着非常重要的意义。本项目综合运用计算生物学、结构生物学、化学生物学和分子生物学等多学科技术手段，通过蛋白翻译后的动态修饰，发现重点、热点难靶蛋白的全新化学干预位点和高效化学探针，构建高通量的靶向筛选平台，从分子、细胞、动物等多层次开展其动态修饰模式识别、活性调控和化学干预等研究。完成氯胺酮人源NMDA受体等重点难靶蛋白可修饰位点结构解析、全新甲基化修饰酶高通量筛选平台构建及化学探针开发、建立靶向翻译后修饰、开展先导化合物发现的计算和实验平台，靶向自噬标志蛋白LC3的乙酰化位点、RhoA和Src的磷酸化位点、转录因子TEAD3的棕梠酰化位点，发现其化学探针并开展化学干预研究。项目结题在Nature、Adv Sci、Nucleic Acids Res、Angew. Chem. Int. Ed、APSB、J Med Chem等杂志已发表接受本项目资助的通讯作者SCI论文致谢42篇，申请专利8项，培养研究生10名。