RNA構造要素の選択的小分子阻害
John A Howe1, Hao Wang1, Thierry O Fischmann1
1Merck Research Laboratories, Kenilworth, New Jersey 07033, USA.
Nature
|September 30, 2015
まとめ
研究者らは 細菌のリボフラビンリボスイッチを 選択的に標的とする新種の合成分子である リボシールを発見しました この化合物は遺伝子発現とバクテリアの増殖を阻害し,薬物標的の可能性を拡大するために天然のリガンドを模倣します.
科学分野:
- 分子生物学
- RNA 生物学
- 薬物の発見
背景:
- リボスイッチは,リガンドを結合することによって遺伝子発現を制御する規制RNA要素です.
- 薬の開発のためのリボスイッチをターゲットにすることは,抑制剤の限られた化学的多様性のために困難です.
- 既存の阻害剤は,しばしば抗代謝物質またはリガンド類に限定されます.
研究 の 目的:
- バクテリアのリボフラビンリボスイッチの新しい化学調節剤を発見し,特徴づけること.
- 合成小分子による非コーディングRNA構造を標的とする可能性を調査する.
- 選択性を高めるために,独特の化学構造を持つ阻害剤を特定する.
主な方法:
- フェノタイプのスクリーニングで,潜在的な変調剤を特定する.
- リボフラビンリボスイッチとの相互作用の特徴.
- ribB遺伝子発現とバクテリアの増殖に対するリボシルの影響を評価する.
主要な成果:
- バクテリアのリボフラビンリボスイッチの選択的化学調節剤であるリボシルの発見
- リボシルはフラビンモノヌクレオチドの合成模倣剤として作用する.
- リボシールはリボスイッチ媒介の ribB 遺伝子発現を抑制し,細菌の増殖を抑制する.
結論:
- 非コーディングRNAの構造要素は,これまで考えられていたより広い範囲の合成小分子によってターゲットにすることができます.
- リボシルは,細菌のリボフラビンリボスイッチを抑制する新種の薬です.
- この研究はリボスイッチ標的薬の発見の 化学的領域を広げています
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