翻訳後のOからCアシルシフトによるペプチド骨組み編集

Carly K Schissel¹, Helena Roberts-Mataric¹, Isaac J Garcia¹

¹Department of Chemistry, University of California, Berkeley, California 94720, United States.

Journal of the American Chemical Society

|February 11, 2025

まとめ

研究者は新しいペプチド・バックボーン編集戦略を開発しましたこの方法は,ペプチド内の炭素-炭素結合の形成を可能にし,組み込まれたヘテロサイクルの新しいタンパク質のような材料を作成します.

科学分野:

化学生物学
合成化学
生物化学

背景:

リボソームは,アミド,エステル,チオエステル結合のみを使用してペプチドを合成する.
脊髄に埋め込まれたC-C結合をペプチドに形成することは,合成生物学における重要な課題である.
既存の方法は,ペプチドの骨格内のサイト選択C-C結合形成のための戦略を欠いている.

研究の目的:

ペプチドバックボーン編集のための新しい非酵素戦略を開発する.
ペプチドの骨格内でC-C結合の形成を可能にします.
脊髄に埋め込まれたヘテロサイクルの多様なタンパク質のような物質を作り出します

主な方法:

リボソームまたは固体相合成によるペプチドへの脱水乳酸モチーフの導入.
モチーフを導入するためにα-ヒドロキシフェニルセレノシステインの酸化.
生理学的pHで自発的な異体化とアシルシフトの再配置.

主要な成果:

脱水乳酸モチーフを持つペプチドは,背骨に埋め込まれたα,γ-ディケトアミドを形成するために異体化します.
α,γ-ディケトアミド製品は,ヒドラジンやヒドロキシラミンなどの核愛素を用いて多様化することができる.
このプロセスは,ポリペプチドの骨格の中に埋め込まれたピラゾールとオキシムを生成します.

結論:

新しい非酵素ペプチド骨組み編集戦略が確立される.
この方法は,ペプチド骨格内のC-C結合形成の最初の例を提供します.
この戦略は生物活性な天然製品に似ている遺伝的にコードされた分子の発見を加速します

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