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P7C3神経保護化学物質は,NAD回収の速度制限酵素を活性化することによって機能します

Gelin Wang¹, Ting Han¹, Deepak Nijhawan²

¹Department of Biochemistry, UT Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9152, USA.

|September 13, 2014

まとめ

神経保護性P7C3化学物質は,ニコチナミドアデニン・ディヌクレオチド (NAD) レベルを上昇させることで,神経細胞の生存を高めます. これは,NAMPT酵素を活性化することで達成され,神経変性疾患に対する新しい治療戦略を提供します.

科学分野:

神経科学は神経科学である.
バイオケミストリーバイオケミストリー
薬理学薬理学とは

背景:

P7C3クラスの化学物質は,神経変性モデルのニューロン生存を促進します.
P7C3神経保護の正確なメカニズムはまだ解明されていない.

研究の目的:

P7C3化合物が神経保護効果を発揮する分子機構を決定する.
活性P7C3誘導体の特定の細胞標的を特定するために.

主な方法:

フォトクロスリンク (ベンゾフェノン) とクリック化学 (アルキン) の機能を持つ活性P7C3誘導体の化学改変.
結合パートナーを特定するために,親和に基づくタンパク質識別.
精製されたニコチナミド・フォスフォリボシルトランスフェラーゼ (NAMPT) を使用した酵素活性アッセイ.
細胞ベースの測定は,NADレベルとドクソルビシン誘発の毒性に対する保護を評価するためのものです.

主要な成果:

改変されたP7C3誘導体が合成され,その結合標的を特定するために使用されました.
P7C3誘導体は,ニコチナミド・フォスフォリボシルトランスフェラーゼ (NAMPT) と結合することが判明し,これはNADの回収における鍵となる酵素である.
P7C3投与は,ドクソルビシンによって枯渇したNADレベルを回復させ,細胞を毒性から保護しました.
活性P7C3変種は,浄化されたNAMPT酵素の活性を増強した.

結論:

P7C3神経保護は,NAMPTの活性化によって媒介され,細胞内NADレベルが上昇します.
このメカニズムは,NADの枯渇によって特徴づけられる神経変性疾患に対する新しい治療アプローチを提供します.
NAMPT救済経路をターゲットにすることは,神経の回復力を高める有望な戦略です.

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