腫瘍性KRas (G12V) の全1種および全d種の化学合成と折り畳み

Adam M Levinson¹, John H McGee², Andrew G Roberts

¹Tri-Institutional PhD Program in Chemical Biology, Weill Cornell Medical College , New York, New York 10065, United States.

Journal of the American Chemical Society

|April 28, 2017

まとめ

研究者は,がんを誘発する Ras タンパク質 (KRas) の鏡像形式を合成しました. これらのエナチオメアタンパク質は分子を折りたたんで結合し難しいがん標的に対する新しい治療戦略を可能にします

科学分野:

生物化学
化学生物学
腫瘍学

背景:

ラスタンパク質は,細胞の成長と生存を調節する重要なGTPasesです.
変異したRasタンパク質はヒトの癌の約30%に関与し,制御不能の増殖を促しています.
ラスは生化学的性質のために治療的にターゲットにすることが歴史的に困難でした.

研究の目的:

腫瘍性KRas ((G12V) の全1および全dアミノ酸の化学合成を達成する.
これらのエナチオメリックRasタンパク質の生化学的性質と機能的能力を調査する.
腫瘍性Rasに対する新しい治療戦略の開発のための基盤を確立する.

主な方法:

Fmocベースの固相ペプチド合成がタンパク質構築に使用された.
原生化学結合とイソニトリル媒介活性化が組み立てに使用された.
合成され,生化学的に特徴づけられた.

主要な成果:

バイオチニル化KRas ((G12V) の全1および全dアミノ酸の合成に成功した.
KRas ((G12V) の両方のエナントオメアは,核酸基板を折り畳み,結合することが示された.
ヌクレオチド基板と結合相手の相互作用におけるエナチオディスクリミネーションが観察された.

結論:

エナティオメリックKRasの合成と機能的検証は,新しい生化学的ツールを提供します.
この作業により,オール-dペプチドリガンドを識別するためのミラー画像酵母表面表示が可能になる.
これらの発見は,腫瘍性KRasに対する治療薬の開発に有望な新しい道を示しています.

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