炭素核愛体の様々なレドキソーム反応性プロファイル
Vinayak Gupta1, Jing Yang2, Daniel C Liebler3
1Department of Chemistry, The Scripps Research Institute , Jupiter, Florida 33458, United States.
Journal of the American Chemical Society
|March 31, 2017
まとめ
標的型共性阻害剤の発見のために 新種の炭素基の核粒子を開発しました これらの断片は酸化したシステイン残留物と反応し,薬物発見を"リドキソーム"に拡張し,リドキソーム調節に関する研究を支援します.
科学分野:
- 薬剤化学
- 化学生物学
- プロテオミクス
背景:
- 標的型共性阻害剤は薬剤発見において極めて重要であり,しばしば特定の疾患に関連する経路を標的とする.
- フラグメントベースのリガンド発見 (FBLD) は,結合可能なタンパク質の範囲を拡大した.
- 伝統的なFBLDはシステイン反応性断片に依存しますが,がんのような疾患におけるシステイン酸化は,このアプローチを制限します.
研究 の 目的:
- 酸化システイン残基を標的とした共性リガンド発見のための新しい方法を開発する.
- 結腸がん細胞のプロテオームに対して 炭素基の核性分子のライブラリをスクリーニングする
- 新しい共性リンガンドを特定し,その反応性と標的の好みを調査する.
主な方法:
- 炭素基の核愛素断片の新しいライブラリの開発
- これらの断片を,断片ベースの共性結合体発見を用いて結腸がん細胞タンパク質に対してスクリーニングする.
- 反応性プロファイルとターゲット偏好を含む,同定された共振性リガンド-タンパク質の相互作用の分析.
主要な成果:
- 薬効性および孤児タンパク質における1280以上のS-スルフェニル化システインの共性リガンドを特定した.
- 異なる反応性プロファイルと標的の偏好を明らかにした.
- 選択的にタンパク質チロシンファスファターゼを標的とするピロリジンジオンの核愛体を発見した.
結論:
- C-核愛素を用いた断片ベースの共性リンガンドの発見は,結合可能な"リドキソーム"の包括的な見方を提供する.
- このアプローチは,共性阻害剤の開発と疾患における酸化還元調節を理解する上で重要な意味を持つ.
- タンパク質の機能における酸化還元変異の役割を調査するための新しい化学的ツールを提供します.
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