5つまたは6つ構成の構成的にロックされた2',4'-カルボサイクルリボチミジン:合成,構造,および生化学的研究
Puneet Srivastava1, Jharna Barman, Wimal Pathmasiri
1Department of Bioorganic Chemistry, Biomedical Center, Uppsala University, Uppsala, Sweden.
Journal of the American Chemical Society
|June 8, 2007
まとめ
ロックされた核酸 (LNA) とエNAの新しいカルボサイクリックアナログは,アンチセンセスのオリゴヌクレオチドの安定性と治療的可能性を高めます. これらの改変されたオリゴヌクレオチドは,潜在的薬剤開発のための改善された核酸抵抗性および薬物動態特性を示しています.
科学分野:
- 薬用化学 薬用化学について
- 核酸化学 核酸化学について
- オリゴヌクレオチドの治療薬
背景:
- アンチセンセオリゴヌクレオチド (AON) は有望な治療薬ですが,安定性や薬動性が悪いことがよくあります.
- ロックされた核酸 (LNA) とエNAの改変はAONの特性を高めますが,さらなる改善は望ましいです.
研究 の 目的:
- LNA (カルボサイクリック-LNA-T) とエNA (カルボサイクリック-ENA-T) の新しいカルボサイクリックアナログを合成する.
- これらの改変がアンチセンスオリゴヌクレオチド (AON) の性質に与える影響を評価する.
主な方法:
- カーボサイクリック-LNA-Tとカーボサイクリック-ENA-Tの合成,過激なサイクリング反応を用いて.
- 改造された核酸化物をAONs.に組み込む.
- 構造確認は,NMRスペクトロスコピー (HMBC,TOCSY,COSY,NOE) を用いたものです.
- ドプレックス安定性 (Tm),RNase H分裂率,および血清のヌクレアース安定性の評価.
主要な成果:
- 炭水化物-LNA-Tと炭水化物-ENA-Tは,高収量で合成されました.
- 改造されたAONは,ネイティブAONと比較して,二重溶解温度 (Tm) の上昇を示した.
- カーボサイクリック-LNAまたはカーボサイクリック-ENAを1回併用すると,血清の核酵素の安定性が著しく増加しました (>48時間).
- RNase H cleavage率は,ネイティブおよび他の改変されたAONと比較可能でした.
結論:
- カーボサイクリック-LNAおよびカーボサイクリック-ENAの改変は,AONsに顕著なヌクレアース抵抗性と安定性を与えます.
- これらの改変により,薬理学的な性質が向上し,必要な用量を減らす可能性があります.
- 炭水化物-LNA-Tと炭水化物-ENA-Tは,安定性と有効性のために,反感覚療法剤の有望な候補です.
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