合成ヒストンの模倣剤によって炎症を抑制する
Edwige Nicodeme1, Kate L Jeffrey, Uwe Schaefer
1Centre de Recherche GSK, 27 Avenue du Québec, 91140 Villebon Sur Yvette, France.
Nature
|November 12, 2010
まとめ
新しい合成化合物であるI-BETは,免疫細胞におけるヒストンの認識を妨害することによって,炎症性遺伝子発現を標的とする. このアプローチは,炎症性疾患と戦うために免疫調節薬の開発のための新しい戦略を提供します.
科学分野:
- 免疫学 免疫学とは
- 薬理学 薬理学とは
- 分子生物学は分子生物学である.
- エピジェネティクス エピジェネティクス
背景:
- 免疫細胞との病原体の相互作用は,炎症性遺伝子発現を誘発し,防御に不可欠ですが,過剰なタンパク質生産のためにしばしば有害です.
- 炎症反応の大きさは,上流のシグナル伝達タンパク質と,mRNA発現を調節するクロマチン複合体に依存する.
- 核タンパク質による翻訳後に改変されたヒストンの認識は,mRNAの転写と延長を開始するために重要である.
研究 の 目的:
- 炎症性遺伝子発現を標的とした新しい薬理学的戦略を提示する.
- ブロモドメインとエクストラターミナルドメイン (BET) タンパク質によるアセチルヒストンの認識の障害を調査する.
- 合成化合物 (I-BET) の免疫調節薬としての可能性を評価する.
主な方法:
- アセチル化ヒストンを模倣するように設計された合成化合物,I-BETの開発.
- I-BETの活性化マクロファージにおける炎症性遺伝子発現に関与するクロマチン複合体を破壊する能力をテストする.
- リポポリサッカリド誘発性エンド毒性ショックと細菌誘発性セプシスに対するI-BETの保護効果の評価 in vivo.
主要な成果:
- 合成化合物I-BETは,アセチル化ヒストンを効果的に真似し,BETタンパク質の認識に干渉する.
- I-BETはクロマチン複合体を破壊し,活性化マクロファージにおける主要な炎症性遺伝子の発現を大幅に減少させます.
- I-BETの投与は,実験モデルにおいて,内毒性ショックと細菌性セプシスに対する保護を与えました.
結論:
- 翻訳後に改変されたヒストンを認識するタンパク質をターゲットにすることは,新しい治療の道を示しています.
- I-BETのような合成化合物は,表遺伝子読者に干渉することによって,炎症性遺伝子発現を調節することができます.
- このアプローチは,炎症性疾患に対する新世代の免疫調節薬の開発に有望である.
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