基于生物正交断键反应的蛋白质化学调控与功能解析

蛋白质是生命活动的物质基础，对活体环境下蛋白质功能的精准调控与动态解析是揭示生命过程、理解疾病机理等问题的重要途径，也是当今化学与生命科学交叉研究的前沿问题之一。本课题组长期致力于探索在活细胞内原位研究和调控蛋白质功能的新技术新方法，在国际上率先发展了生物正交断键反应，用以进行蛋白质侧链氨基酸的“化学脱笼”。基于这一概念，开发了一系列利用化学小分子调控蛋白功能的新方法，在蛋白质活性的在体、原位调控领域实现了一系列原始创新。在上述工作基础之上，本项目拟进一步提出蛋白质“活性中心”调控的新概念，获得调控蛋白质活性的一种通用策略，并将化学脱笼技术从特定氨基酸侧链拓展到任一蛋白质的活性中心，实现使用统一的小分子对任意蛋白进行精准调控与动态解析。在模型蛋白确证的基础之上，将在不同类型的蛋白体系上加以展示和应用。本项目的开展，将突破蛋白质在体研究的关键技术瓶颈，为蛋白质功能的在体调控提供普适性工具。

Comprehensive studies of proteins in living systems are the key to the answers of fundamental questions of biological processes and diseases, thus have been the frontier research topic in the interdisciplinary fields of chemistry and life sciences. Our group has long been exploring new technologies and methods on protein manipulations in living systems. A series of creative protein activation methods have been developed in our group by exploiting the bioorthogonal cleavage chemistry, greatly fueling the comprehensive studies of proteins in complex living systems. Inspired by our previous contributions on protein activations, we propose in this project a new concept: protein manipulations by regulating the protein active site instead of the single amino acid residue using bioorthogonal cleavage chemistry. This new concept will lead to the development of a simple universal protein manipulation method, which could control activity of any protein of interest in living systems by using only one single small molecule. The universal method will be confirmed by various type of proteins, and followed by exploring the biological processes and functions of several key proteins in living cells. The success of this project would emerge a universal and powerful tool for in situ protein manipulation, breaking through the key bottleneck in the research field of protein science.