オキソノルボナーディエンの反応剤からの分解性コンジュガット
Alexander A Kislukhin1, Cody J Higginson, Vu P Hong
1Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California 92037, USA.
Journal of the American Chemical Society
|March 30, 2012
まとめ
オキサノルボーンアディエネジカルボキシラート (OND) 反応剤は,血清アルブミン媒介体から薬物の制御された放出を可能にします. OND連結を修正することで,薬剤の放出速度を数分から数日に調整することができ,多用途の治療応用が可能です.
科学分野:
- 化学生物学 化学生物学とは
- 薬物の配達 薬物の配達
- バイオコンジュガーション 化学 化学
背景:
- 血清アルブミンは,薬物の投与のための主要なマクロ分子キャリアです.
- 効率的で制御可能な薬剤放出メカニズムの開発は,治療効果に不可欠です.
研究 の 目的:
- 血清アルブミンから薬物を結合および放出するためのオクソノルボナディエネジカルボキシラート (OND) 反応剤を調査する.
- アダクトの安定性と薬剤の放出運動に影響を与える修正を調査する.
主な方法:
- 30以上のモデルONDアダクトのチオールとアミンの合成と特徴付け.
- 牛の血清アルブミン (BSA) のシステインとアミン残留を含む反応運動学の研究.
- 様々な条件 (pH,温度) の下でのOND-アドクトの安定性の評価.
- 光貨物を用いた薬物放出プロフィールの評価.
主要な成果:
- OND反応剤は,BSAシステイン残基を,ミクロモラー濃度の中央で,数分以内に効率的に標識します.
- モデルシステムでは,アミンのラベリングよりもチオルの高い選択性 (>1000倍) が観察されましたが,タンパク質アミンのラベリングも実用的です.
- OND-アミンの添加物は,OND-チオルの添加物よりも最大15倍の安定性を示し,酸触媒による放出に敏感である.
- BSAの薬剤放出半減期は40分から7日であり,OND連結改変によって調整可能であった.
結論:
- OND反応剤は,タンパク質キャリアから調節可能な薬物放出システムを開発するための汎用的なプラットフォームを提供します.
- ONDリンクを改変することによって,放出率を制御する能力は,薬物投与アプリケーションに貴重なツールを提供します.
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