Xu Yan, Yuan Yi, Fu Ding-Qiang, Fu Yi, Zhou Shan, Yang Wan-Ting, Wang Xu-Yang, Li Guang-Xun, Dong Juan, Du Feng, Huang Xin, Wang Qi-Wei, Tang Zhuo
Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu, Sichuan 610041, PR China; Natural Products Research Center, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, Sichuan 610041, PR China; University of Chinese Academy of Sciences, Beijing 100049, PR China.
Natural Products Research Center, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, Sichuan 610041, PR China; University of Chinese Academy of Sciences, Beijing 100049, PR China.
Bioorg Med Chem. 2023 May 15;86:117299. doi: 10.1016/j.bmc.2023.117299. Epub 2023 Apr 27.
RNA-binding proteins (RBPs) dysfunction has been implicated in a number of diseases, and RBPs have traditionally been considered to be undruggable targets. Here, targeted degradation of RBPs is achieved based on the aptamer-based RNA-PROTAC, which consists of a genetically encoded RNA scaffold and a synthetic heterobifunctional molecule. The target RBPs can bind to their RNA consensus binding element (RCBE) on the RNA scaffold, while the small molecule can recruit E3 ubiquitin ligase to the RNA scaffold in a non-covalent manner, thereby inducing proximity-dependent ubiquitination and subsequent proteasome-mediated degradation of the target protein. Different RBPs targets, including LIN28A and RBFOX1, have been successfully degraded by simply replacing the RCBE module on the RNA scaffold. In addition, the simultaneous degradation of multiple target proteins has been realized by inserting more functional RNA oligonucleotides into the RNA scaffold.
RNA结合蛋白（RBPs）功能障碍与多种疾病有关，传统上RBPs被认为是不可成药的靶点。在此，基于适体的RNA-蛋白酶体靶向嵌合体实现了RBPs的靶向降解，其由基因编码的RNA支架和合成的异双功能分子组成。目标RBPs可与其在RNA支架上的RNA共有结合元件（RCBE）结合，而小分子能以非共价方式将E3泛素连接酶招募至RNA支架，从而诱导邻近依赖性泛素化以及随后蛋白酶体介导的目标蛋白降解。通过简单替换RNA支架上的RCBE模块，包括LIN28A和RBFOX1在内的不同RBPs靶点已成功被降解。此外，通过在RNA支架中插入更多功能性RNA寡核苷酸，实现了多种目标蛋白的同时降解。
