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Covalent Attachment of Single Molecules for AFM-based Force Spectroscopy
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小分子共性阻害剤によるSTINGの標的化
Simone M Haag1, Muhammet F Gulen1, Luc Reymond2
1Global Health Institute, Swiss Federal Institute of Technology Lausanne (EPFL), Lausanne, Switzerland.
Nature
|July 6, 2018
まとめ
研究 者 たち は,先天 的 な 免疫 の 中 で 重要な 役割 を 果たす インターフェロン 遺伝子 (STING) の 刺激 タンパク質 を 阻害 する 小さな 分子 を 発見 し まし た. これらのSTING阻害剤は炎症を軽減し,自己炎症性疾患の治療の可能性を示しています.
科学分野:
- 免疫学
- 分子生物学
- 薬物の発見
背景:
- 異常な先天性免疫経路の活性化は様々な病気と関連しています
- 生まれつきの免疫に対する標的治療は有望ですが 開発は困難です
- インターフェロン遺伝子の刺激剤 (STING) タンパク質は細胞内DNAセンシングの重要な媒介です.
研究 の 目的:
- STINGタンパク質の新しい小分子抗体を発見し,特徴づけること.
- STING抗体がその機能を阻害するメカニズムを解明する.
- 自己炎症疾患のモデルにおけるSTING抑制の治療の可能性を評価する.
主な方法:
- 小分子STING抗薬の発見と特徴付け
- システイン91を標的とし,パルミトイレーションを阻害するなど,STING抑制メカニズムの調査.
- STING阻害剤がヒトとマウスの細胞におけるサイトカインの産生を抑制する効果の評価
- 自発炎症疾患のマウスモデルにおけるSTING抗薬の評価
主要な成果:
- 強力で選択的な小分子STING抗剤の特定
- これらの化合物が共性的にシステイン91を標的とし,STINGのパルミトイレーションを抑制することを示す.
- STINGのパルミトイロ化がマルチメリック複合体の組み立てと下流シグナル伝達に不可欠であるという証拠
- STING媒介の炎症性サイトカインの産生を in vitro で減少させる.
- 自己炎症性疾患のマウスモデルにおける病理学的特徴の弱化
結論:
- STINGのパルミトイレーションは,その機能に不可欠であり,薬学的に抑制することができます.
- 小分子STING抗薬は,自己炎症性疾患の有望な治療戦略です.
- この研究はSTING抑制と治療への応用のための新しいメカニズムを提供します.
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