O-Cyanobenzaldehydes Irreversibly Modify Both Buried and Exposed Lysine Residues in Live Cells
文献类型：期刊论文
| 作者 | Ling, Huan1,9; Li, Lin1; Duan, Liping8; Huang, Weixue1; Zheng, Jiangnan7; Zhang, Shijie5,6; Li, Xinling7; Qiu, Xiaorong1; Zhou, Yang4; Ma, Nan2,3,8 |
| 刊名 | JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
 |
| 出版日期 | 2025-03-28 |
| 卷号 | 147期号:14页码:11955-11963 |
| ISSN号 | 0002-7863 |
| DOI | 10.1021/jacs.4c18006 |
| 英文摘要 | Lysine residue represents an attractive site for covalent drug development due to its high abundance (5.6%) and critical functions. However, very few lysines have been characterized to be accessible to covalent ligands and perturb the protein functions, owing to their protonation state and adjacent steric hindrance. Herein, we report a new lysine bioconjugation chemistry, O-cyanobenzaldehyde (CNBA), that enables selective modification of the lysine epsilon-amine to form iso-indolinones under physiological conditions. Activity-based proteome profiling enabled the mapping of 3451 lysine residues and 85 endogenous kinases in live cells, highlighting its potential for modifying hyper-reactive lysines within the proteome or buried catalytic lysines within the kinome. Further protein crystallography and mass spectrometry confirmed that K271_ABL1 and K162_AURKA are covalently targetable sites in kinases. Leveraging a structure-based drug design, we incorporated CNBA into the core structure of Nutlin-3 to irreversibly inhibit the MDM2-p53 interaction by targeting an exposed lysine K94 on the surface of murine double minute 2. Importantly, we have demonstrated the potential application of CNBA as a lysine-recognized bioconjugation agent for developing new antibody-drug conjugates. The results collectively validate CNBA as a new selective and efficient modifying agent with broad applications for both buried and exposed lysine residues in live cells. |
| WOS关键词 | PHASE-TRANSFER CATALYSIS ; DISCOVERY ; ACTIVATION ; INHIBITORS ; P53 ; ANTAGONISTS ; PROTEINS ; BINDING ; ASSAY ; MDM2 |
| 资助项目 | National Natural Science Foundation of China ; Shanghai Advanced Research Institute, Chinese Academy of Science, China ; Shanghai Advanced Research Institute, Chinese Academy of Sciences |
| WOS研究方向 | Chemistry |
| 语种 | 英语 |
| WOS记录号 | WOS:001455055500001 |
| 出版者 | AMER CHEMICAL SOC |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/316944]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Zhang, Zhi-Min; Ding, Ke |
| 作者单位 | 1.Chinese Acad Sci, Shanghai Inst Organ Chem, State Key Lab Chem Biol, Shanghai 200032, Peoples R China 2.Jinan Univ, Coll Pharm, Guangdong Hong Kong Macau Joint Lab Pharmacodynam, Guangzhou 510632, Guangdong, Peoples R China 3.Jinan Univ, Coll Pharm, Guangdong Basic Res Ctr Excellence Nat Bioact Mol, Guangzhou 510632, Peoples R China 4.Jinan Univ, Coll Pharm, Int Cooperat Lab Tradit Chinese Med Modernizat & I, Guangzhou City Key Lab Precis Chem Drug Dev, Guangzhou 511400, Peoples R China 5.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China 6.Chinese Acad Sci, State Key Lab Drug Res, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China 7.Southern Univ Sci & Technol, Dept Chem, Shenzhen 518055, Peoples R China 8.Jinan Univ, Sch Pharm, State Key Lab Bioact Mol & Draggabil Assessment, Guangzhou 511436, Peoples R China 9.Univ Chinese Acad Sci, Beijing 101408, Peoples R China |
| 推荐引用方式 GB/T 7714 | Ling, Huan,Li, Lin,Duan, Liping,et al. O-Cyanobenzaldehydes Irreversibly Modify Both Buried and Exposed Lysine Residues in Live Cells[J]. JOURNAL OF THE AMERICAN CHEMICAL SOCIETY,2025,147(14):11955-11963. |
| APA | Ling, Huan.,Li, Lin.,Duan, Liping.,Huang, Weixue.,Zheng, Jiangnan.,...&Ding, Ke.(2025).O-Cyanobenzaldehydes Irreversibly Modify Both Buried and Exposed Lysine Residues in Live Cells.JOURNAL OF THE AMERICAN CHEMICAL SOCIETY,147(14),11955-11963. |
| MLA | Ling, Huan,et al."O-Cyanobenzaldehydes Irreversibly Modify Both Buried and Exposed Lysine Residues in Live Cells".JOURNAL OF THE AMERICAN CHEMICAL SOCIETY 147.14(2025):11955-11963. |
入库方式： OAI收割
来源：上海药物研究所
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