比較化学プロテオミクスによって特定された高度に選択的,可逆性阻害剤は,神経細胞におけるディアシルグリセロールリパース活性を調節する
Marc P Baggelaar1, Pascal J P Chameau2, Vasudev Kantae3
1†Department of Bioorganic Synthesis, Leiden Institute of Chemistry, Leiden University, Leiden 2300 RA, The Netherlands.
Journal of the American Chemical Society
|June 18, 2015
まとめ
研究者らは,ダイアシルグリセロールリパゼ (DAGL) -αおよび -β酵素に対する新しい選択性阻害剤,LEI105を開発しました. この発見は,エンドカンナビノイドシグナル伝達の研究を助け,2-AGの証拠を提供します.
科学分野:
- バイオケミストリー バイオケミストリー
- 神経科学は神経科学である.
- 薬理学 薬理学とは
背景:
- ディアシルグリセロールリパゼ (DAGL) -αと-βは,重要なエンドカンナビノイドである2-アラキドノイルグリセロール (2-AG) を合成する重要な酵素です.
- 選択的および可逆的阻害剤は,神経細胞におけるDAGL機能を調査するために必要です.
- 現在の阻害剤は,急性研究に必要な選択性と時間制御が欠けている.
研究 の 目的:
- DAGL-αとDAGL-βの高度選択的阻害剤を特定し,特徴づけること.
- 阻害剤発見と選択性プロファイリングのための構造誘導設計とキモプロテオミクスを活用する.
- DAGLの阻害による逆行シグナル伝達における2-AGの役割を調査する.
主な方法:
- 比較的および競争的活動ベースのタンパク質プロファイリング (ABPP) を組み合わせたキモプロテオミクス戦略を採用しました.
- ブロードスペクトルフッロフォスフォナートと特定のβ-ラクトンプローブを使用して,複雑なタンパク質の阻害物質を特定しました.
- 他のエンドカンナビノイド代謝酵素およびカンナビノイド受容体に対する有効な阻害剤選択性.
主要な成果:
- α-ケトヘテロサイクルのLEI105が,強力で,選択的で,可逆性のダブルDAGL-α/DAGL-β阻害体として発見されました.
- LEI105は,関連する酵素 (ABHD6,ABHD12,MAGL,FAAH) の抑制や,CB1受容体に対する親和性を示しませんでした.
- LEI105は,Neuro2A細胞における2 - AGのレベルを低下させ,マウスのヒポキャンパスのスライスにおけるCB1受容体媒介のシナプス可塑性を抑制しました.
結論:
- LEI105は,DAGL機能とエンドカンナビノイドシグナル伝達の研究に役立つ貴重な薬理学的ツールです.
- この発見は,逆行シグナル伝達における"オンデマンド"の2-AG生物合成の仮説を裏付けている.
- この研究は,ネイティブの生物システム内の選択性酵素阻害剤を発見するABPPの力を強調しています.
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