ファージペプチド基板の探索:バイオアクティブなサイクルペプチドの選択的な生成のためのチロシナーゼ媒介サイクリング

Li-Wen Bai^1,2, Peng Cheng¹, Ting Dan¹

¹School of Pharmaceutical Sciences, South-Central Minzu University, Wuhan 430074, P. R. China.

Journal of the American Chemical Society

|August 27, 2025

まとめ

この研究は,サイクリックペプチドを作成するための新しいチロシナーゼ媒介ファグ表示プラットフォームを導入します. この効率的な方法は,治療目標のための強力なペプチド阻害剤の発見を可能にします.

科学分野:

バイオテクノロジー
分子生物学
薬物の発見

背景:

ファージ表示は,高親和性ペプチド結合剤の選択に有効です.
周期性ペプチドファグ表示のための既存の化学的方法は,しばしばファグの感染性を損なう.
酵素触媒は,ファグベースの周期性ペプチド表示に生物互換性があり,効率的な代替手段を提供します.

研究の目的:

効率的なサイクルペプチド生成のための新しいチロシナーゼ媒介ファグ表示プラットフォームを開発する.
酵素触媒を用いてファグの表示における化学的戦略の限界を克服する.
治療的に重要なタンパク質を標的とする生物活性マクロサイクルペプチドの発見を可能にします.

主な方法:

チロシナーゼ媒介のファグ表示システムの開発で,オキノン-システイン結合による1段階サイクリングが可能である.
酵素認識のためにタイロシン残基を選択的に表示するファグを設計する.
治療対象に対するマクロサイクルペプチド図書館の構築とスクリーニング.

主要な成果:

タイロシナーゼプラットフォームは,ファグの感染性を損なうことなく,効率的で生物互換性のある1段階サイクリングを証明しました.
タイロシナゼは,ネイティブをバイパスして,エンジニアリングされたタイロシン残基を選択的に認識しました.
PIP4K2AのACI1 (IC50 = 0. 93μM) とPTP1BのACP1 (IC50 = 1. 06μM) を含むマクロサイクルペプチド阻害剤が発見されました.

結論:

チロシナーゼ媒介のファグ表示は,生物活性サイクルペプチドの開発の一般的で効率的な戦略です.
このプラットフォームは,周期性ペプチド生成のための化学的方法の有望な代替手段を提供します.
発見された阻害剤は,このアプローチの治療応用の可能性を強調しています.

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