文献类型：期刊文献

英文题名：Programmed Targeted Protein Degradation Via DNA Modularized Ligand

作者：Teng, Xuanming[1];Yang, Jingyi[1];Ren, Zhiyi[1];Yan, Sha[1];Zhai, Jiaxin[1];Hu, Xinyuan[1];Hou, Shule[2];Yang, Yangyang[1]

机构：[1]East China Univ Sci & Technol, Sch Pharm, Shanghai Key Lab Chem Biol, 130 Mei Long Rd, Shanghai 200237, Peoples R China;[2]Shanghai Jiao Tong Univ, Sch Med, Xinhua Hosp, Dept Otorhinolaryngol Head & Neck Surg, 1665 Kong Jiang Rd, Shanghai 200092, Peoples R China

年份：2025

卷号：20

期号：16

外文期刊名：CHEMMEDCHEM

收录：;WOS:【SCI-EXPANDED(收录号:WOS:001555743900009)】；

基金：This work was supported by National Key Research and Development Programs of China (grant nos. 2022YFD1700400 and 2023YFD1700300), Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, National Natural Science Foundation of China (grant no. 82371150 to S.L.H.).

语种：英文

外文关键词：DNA modulization; DNA self-assembly; PROTACs; targeted protein degradation

摘要：Proteolysis targeting chimera (PROTAC) technology holds great promise as a protein degradation modality in therapeutic development. However, there remain challenges, including complex chemical synthesis and linker screening. To address this, a proof-of-concept of a new modularized method by constructing DNA-PROTAC is presented by identifying the valid BRD4 and Sirt2 DNA-PROTACs. These findings may provide new approaches for linker design and ligand screening for PROTACs. Herein, a ligand modularization strategy is proposed that leverages the programmability of DNA to modulate the design and construction of PROTAC molecules to facilitate the programmatic discovery of new PROTAC molecules. The bromodomain-containing protein 4 (BRD4) is selected as a target for degradation to verify the effectiveness of DNA-PROTACs. The kinetics of BRD4 degradation were assessed by performing time-course experiments in HeLa cells. In addition, to evaluate the feasibility of the DNA-PROTAC strategy for degradation of other proteins, the silent mating type information regulation 2 homolog-2 (Sirt2) is selected as the degradation target. The design and synthesis procedures of BRD4 and Sirt2 DNA-PROTACs and their mechanisms of action, are systematically introduced, and the results may provide a new method for linker design and ligand screening of PROTACs.