机器学习辅助的活小鼠通用蛋白激活，这一成果由北京大学陈鹏课题组经过不懈努力而取得。相关论文发表在2025年5月27日出版的《细胞》杂志上。
课题组在此报告CAGE-Proxvivo，这是一种计算机辅助的近端衰老策略，用于活体小鼠的按需蛋白质激活以及蛋白质-蛋白质相互作用调节。通过机器学习辅助进化所需的氨基酰基tRNA 合成酶（aaRSs），小组成功地将化学笼化的氨基酸纳入合理设计的“降解位点”，以暂时阻断靶蛋白的功能，并通过小分子触发的生物正交切割反应将其恢复原位。这种方法证明了广泛的适用性，从激活感兴趣的蛋白质到对生命系统中不同表型的细胞类型特异性调节。除了活性口袋老化之外，CAGE-Proxvivo还可以精确控制蛋白质之间的相互作用，例如，一种“门控”抗CD3抗体允许化学调节T细胞在肿瘤部位的募集和激活。总的来说，CAGE-Proxvivo提供了一个通用的平台，用于时间解决的生物学研究和生活条件下的按需治疗干预。
研究人员表示，在活体动物中精确控制蛋白质激活的通用策略对于蛋白质在体内环境下的功能获得研究至关重要。
附：英文原文
Title: Machine-learning-assisted universal protein activation in living mice
Author: Xin Wang, Yuan Liu, Zhenchao Wang, Xiangmei Zeng, William Shu Ching Ngai, Jie Wang, Heng Zhang, Xiao Xie, Rongfeng Zhu, Xinyuan Fan, Chu Wang, Peng R. Chen
Issue&Volume: 2025-05-27
Abstract: A universal strategy to precisely control protein activation in living animals is crucial for gain-of-function study of proteins under in vivo settings. We herein report CAGE-Proxvivo, a computer-aided proximal decaging strategy for on-demand protein activation as well as protein-protein interaction modulations in living mice. Through machine-learning-assisted evolution of desired aminoacyl-tRNA synthetases (aaRSs), we successfully incorporated chemically caged amino acids into rationally designed “decaging sites” to transiently block target proteins’ function, which can be restored in situ via a small-molecule-triggered bioorthogonal cleavage reaction. This method demonstrates broad applicability ranging from activating proteins of interest to cell-type-specific modulation of distinct phenotypes in living systems. Beyond the active-pocket decaging, CAGE-Proxvivo also enables precise control of protein-protein interactions, as exemplified by a “gated” anti-CD3 antibody that permits chemically regulated T cell recruitment and activation at tumor sites. Overall, CAGE-Proxvivo offers a universal platform for time-resolved biological studies and on-demand therapeutic interventions under living conditions.
DOI: 10.1016/j.cell.2025.05.006
Source: https://www.cell.com/cell/abstract/S0092-8674(25)00517-3