中国科学院机构知识库网格
Chinese Academy of Sciences Institutional Repositories Grid
首页 机构 成果 学者
  
  1. CAS IR Grid
  2. 上海药物研究所
  3. 中国科学院上海药物研究所
  4. 新药研究国家重点实验室
Proteome-Wide Data Guides the Discovery of Lysine-Targeting Covalent Inhibitors Using DNA-Encoded Chemical Libraries

文献类型：期刊论文

作者Wu, Xinyuan2,3; Li, Shunyao9; Liang, Ting7,8; Yu, Qing6,7,8; Zhang, Yiwei2,3; Liu, Jiaxiang3; Li, Kaige3,5; Liu, Zijian2,3; Cui, Mengqing3; Zhao, Yongchao4,7
刊名ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
出版日期2025-04-24
页码14
关键词Activity-based protein profiling data Covalent DNA-encoded chemical library Covalent ligand selection Lysine-targeting covalent inhibitors
DOI10.1002/anie.202505581
英文摘要Broadening the application of covalent inhibitors requires the exploration of nucleophilic residues beyond cysteine. The covalent DNA-encoded chemical library (CoDEL) represents an advanced technology for covalent drug discovery. However, its application in lysine-targeting inhibitors remains uncharted territory. Here, we report the utilization of CoDEL selection guided by proteome-wide data to identify lysine-targeting covalent inhibitors. A comprehensive assessment of activity-based protein profiling (ABPP) data on lysine distribution and ligandability reveals potential targets for selective covalent inhibition, including phosphoglycerate mutase 1 (PGAM1), bromodomain (BRD) family proteins, and ubiquitin-conjugating enzyme E2 N (UBE2N). The 10.7-million-member CoDELs, featuring diverse lysine-reactive warheads, enable the discovery of a series of covalent inhibitors, covering photo-covalent, reversible covalent, and irreversible covalent reaction mechanisms. In-depth characterization of binding sites and modes of action provides structural and functional insights. Notably, irreversible covalent inhibitors unveil a novel mechanism for regulating UBE2N-mediated ubiquitination by modulating the conformation of the protein complex. Our work adopts the ABPP-CoDEL strategy, offering an efficient and versatile selection method for the development of covalent inhibitors targeting functional lysines.
WOS关键词TO-ESTER SUBSTITUTION ; UBIQUITIN ; PROTEINS ; ENZYMES ; PERMEABILITY ; ALCOHOLS ; STRATEGY ; SIRT2
资助项目National Natural Science Foundation of China ; Institutional Technology Service Center of Shanghai Institute of Materia Medica, Chinese Academy of Sciences ; Shanghai Action Plan for Science, Technology and Innovation[23HC1401200] ; Shanghai Institute of Pharmaceutical Sciences independent research projects[SIMM0220233001] ; National Key R&D Program of China[2022YFC3401500] ; National Key R&D Program of China[2021YFA1101000] ; Shanghai Municipal Committee of Science and Technology[21TQ016] ; Zhejiang Provincial Natural Science Foundation of China[LD22H300003] ; Leading Innovative and Entrepreneur Team Introduction Program of Zhejiang[2022R01002] ; [92253203] ; [U22A20317]
WOS研究方向Chemistry
语种英语
WOS记录号WOS:001473325900001
出版者WILEY-V C H VERLAG GMBH
源URL[http://119.78.100.183/handle/2S10ELR8/317554]  
专题新药研究国家重点实验室
通讯作者Sun, Yi; Zhou, Lu; Lu, Xiaojie
作者单位1.Chinese Acad Sci, Zhongshan Inst Drug Discovery, Shanghai Inst Mat Med, Zhongshan 528400, Peoples R China
2.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
4.Zhejiang Univ, Sch Med, Affiliated Hosp 1, Dept Hepatobiliary & Pancreat Surg, Hangzhou 310003, Peoples R China
5.Nanjing Univ Chinese Med, Sch Chinese Mat Med, 138 Xianlin Rd, Nanjing 210023, Peoples R China
6.Chinese Acad Sci, Zhejiang Canc Hosp, Inst Basic Med & Canc IBMC, Dept Thyroid Surg, Hangzhou 310022, Peoples R China
7.Zhejiang Univ, Sch Med, Inst Translat Med, Hangzhou 310029, Peoples R China
8.Zhejiang Univ, China Natl Minist Educ, Key Lab Canc Prevent & Intervent, Canc Inst,Affiliated Hosp 2,Sch Med, Hangzhou 310029, Peoples R China
9.Fudan Univ, Sch Pharm, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Wu, Xinyuan,Li, Shunyao,Liang, Ting,et al. Proteome-Wide Data Guides the Discovery of Lysine-Targeting Covalent Inhibitors Using DNA-Encoded Chemical Libraries[J]. ANGEWANDTE CHEMIE-INTERNATIONAL EDITION,2025:14.
APA Wu, Xinyuan.,Li, Shunyao.,Liang, Ting.,Yu, Qing.,Zhang, Yiwei.,...&Lu, Xiaojie.(2025).Proteome-Wide Data Guides the Discovery of Lysine-Targeting Covalent Inhibitors Using DNA-Encoded Chemical Libraries.ANGEWANDTE CHEMIE-INTERNATIONAL EDITION,14.
MLA Wu, Xinyuan,et al."Proteome-Wide Data Guides the Discovery of Lysine-Targeting Covalent Inhibitors Using DNA-Encoded Chemical Libraries".ANGEWANDTE CHEMIE-INTERNATIONAL EDITION (2025):14.

入库方式： OAI收割

来源：上海药物研究所

浏览0
下载0
收藏0
其他版本

除非特别说明，本系统中所有内容都受版权保护，并保留所有权利。