形の形状によって駆動される大きなマクロサイクリックペプチドの膜浸透性
Justin H Faris1, Emel Adaligil2, Nataliya Popovych3
1Department of Chemistry and Biochemistry, University of California, Santa Cruz, California 95064, United States.
Journal of the American Chemical Society
|February 8, 2024
まとめ
細胞内タンパク質を標的とする重要な課題である 細胞膜の透過性のためにマクロサイクリックペプチドを最適化しました この研究は,難しい標的に対する薬剤発見のためのペプチド図書館の設計を強化します.
科学分野:
- 薬剤化学
- 薬物の発見
- 化学生物学
背景:
- 小さな分子を超えてリガンドを開発することは 難しいタンパク質標的を調節するために重要です
- mRNAディスプレイからのマクロサイクリックペプチドは高い親和性を示すが,膜の透過性が低下し,細胞外標的への使用を制限する.
研究 の 目的:
- マクロサイクリックペプチドの受動膜透過性を調査する.
- 細胞内標的のためのマクロサイクルペプチドライブラリの設計を改善する.
主な方法:
- 200マクロサイクリック10マー以上をチオエーテルサイクリングモチーフを用いてスクリーニングした.
- 循環性ペプチド-ペプチドハイブリッドの浸透性を最適に特定した.
- 浸透性に影響する形状の変化を分析した.
主要な成果:
- チオエーテルサイクリングされた10-メル・スキャファードにおける浸透性の向上のための最適な脂質性範囲を決定した.
- 骨幹の順番が 貫通性を維持することを示しました
- 単一のアミノ酸の変化により,背骨のNH群を隔離する高度に浸透性のある支架に新しいサドル状の折りたたみが見られた.
結論:
- 物理化学的な知識は,浸透性マクロサイクリックペプチドmRNAディスプレイライブラリの設計を導くことができます.
- このアプローチは,設計による透過性へのバイアスライブラリを可能にします.
- 薬のような 化学的空間の外に ジオメトリ的に多様で 透き通る構造があります
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