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タイトル: Rapid labelling and covalent inhibition of intracellular native proteins using ligand-directed N-acyl-N-alkyl sulfonamide
著者: Tamura, Tomonori
Ueda, Tsuyoshi
Goto, Taiki
Tsukidate, Taku
Shapira, Yonatan
Nishikawa, Yuki
Fujisawa, Alma
Hamachi, Itaru
著者名の別形: 田村, 朋則
上田, 毅
後藤, 大輝
月館, 拓
西川, 雄貴
藤沢, 有磨
濵地, 格
キーワード: Chaperones
Chemical modification
発行日: 14-May-2018
出版者: Springer Nature
誌名: Nature Communications
巻: 9
論文番号: 1870
抄録: Selective modification of native proteins in live cells is one of the central challenges in recent chemical biology. As a unique bioorthogonal approach, ligand-directed chemistry recently emerged, but the slow kinetics limits its scope. Here we successfully overcome this obstacle using N-acyl-N-alkyl sulfonamide as a reactive group. Quantitative kinetic analyses reveal that ligand-directed N-acyl-N-alkyl sulfonamide chemistry allows for rapid modification of a lysine residue proximal to the ligand binding site of a target protein, with a rate constant of ~104 M−1 s−1, comparable to the fastest bioorthogonal chemistry. Despite some off-target reactions, this method can selectively label both intracellular and membrane-bound endogenous proteins. Moreover, the unique reactivity of N-acyl-N-alkyl sulfonamide enables the rational design of a lysine-targeted covalent inhibitor that shows durable suppression of the activity of Hsp90 in cancer cells. This work provides possibilities to extend the covalent inhibition approach that is currently being reassessed in drug discovery.
記述: 細胞内の狙った天然タンパク質を迅速に化学修飾する分子技術を開発 --不可逆阻害剤開発のための新しい戦略--. 京都大学プレスリリース. 2018-05-16.
著作権等: © The Author(s) 2018. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
URI: http://hdl.handle.net/2433/231114
DOI(出版社版): 10.1038/s41467-018-04343-0
関連リンク: http://www.kyoto-u.ac.jp/ja/research/research_results/2018/180514_1.html
出現コレクション:学術雑誌掲載論文等

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