高級タンパク質連鎖により,親和性が強化され,in vivoの安定性を持つ人工抗体が生成される
Wen-Hao Wu1, Xilin Bai1, Yu Shao1
1Beijing National Laboratory for Molecular Sciences, Key Laboratory of Polymer Chemistry & Physics of Ministry of Education, Center for Soft Matter Science and Engineering, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, P. R. China.
Journal of the American Chemical Society
|October 19, 2021
まとめ
研究者は新しいペプチドモチーフを使用して複雑なタンパク質トポロジを設計し,タンパク質カテネンの作成を可能にしました. このトポロジー工学のアプローチは,治療用途のタンパク質の親和性と安定性を高めます.
科学分野:
- タンパク質工学
- 化学トポロジー
- バイオテクノロジー
背景:
- タンパク質工学における化学トポロジーの可能性はほとんど未知のものである.
- 既存のタンパク質工学の方法は,トポロジカルな多様性や構造の複雑さを十分に利用できていません.
研究 の 目的:
- 複雑なトポロジカルなタンパク質,特にタンパク質カテネンを細胞で合成するための一般的でモジュラーな方法を開発する.
- タンパク質のトポロジが親和性やin vivoの安定性などの機能特性に与える影響を調査する.
- トポロジー工学で作られたタンパク質の 治療薬としての可能性を証明するためです
主な方法:
- p53dimから派生した交絡ペプチドヘテロダイマーモチーフの合理的な設計.
- 特定の鎖の絡まりを直接するために静電相互作用を組み込む.
- 分割インテイン媒介結合および/またはSpyTag/SpyCatcher化学を用いて,タンパク質ヘテロカテナンおよび[n]カテナンをプログラム合成する.
- アフィボディをカテナンのスキャフォードに埋め込むことで人工抗体を開発する.
主要な成果:
- 細胞内のタンパク質ヘテロカテナンと [n]カテナンを含む複雑なトポロジカルタンパク質の成功バイオシンセシス.
- ターゲットのタンパク質の親和性およびin vivoの安定性の強化が証明され,循環時間が延長された.
- 野生型の抗体と比較して,より高い親和性と改善された薬理学プロファイルを持つ人工抗体を開発した.
結論:
- トポロジー・エンジニアリングは 複雑なタンパク質の構造を作るための 強力で汎用的な戦略を提供します
- エンジニアリングされたタンパク質カテネンは,治療用タンパク質開発の有意な可能性を示唆する機能的特性を改善しています.
- このアプローチは,特異な性質を持つ新しいタンパク質を設計するためのモジュール化されたプラットフォームを提供します.
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