高効率に細胞内移行するアルギニンペプチドの開発と消化管粘膜透過への応用

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  • 髙山 健太郎
    京都大学化学研究所生体機能設計化学研究領域 京都薬科大学薬学部薬剤学分野

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  • Development of an Oligoarginine Peptide Displaying Rapid Cell Penetration for Improved Intestinal Absorption
  • Symposium Review 高効率に細胞内移行するアルギニンペプチドの開発と消化管粘膜透過への応用
  • Symposium Review コウコウリツ ニ サイボウ ナイ イコウ スル アルギニンペプチド ノ カイハツ ト ショウカカン ネンマク トウカ エ ノ オウヨウ

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  Arginine-rich peptides, including oligoarginines (Rn, n=7-12) are cell penetrating peptides (CPPs) and are useful for the intracellular delivery of membrane-impermeable substances. Endocytosed arginine-rich peptides can become trapped in endosomes, and the avoidance of endosomal retention is necessary for achieving effective cytosolic translocation. Our group has succeeded in enhancing the cellular uptake of oligoarginines by introducing short hydrophobic penetration accelerating sequences (Pas). The effectiveness of a Pas segment in improving the oligoarginine-mediated intracellular delivery of a biofunctional peptide was demonstrated through the efficient inhibition of glioma cell growth by a p53 C-terminal-derived retro-inverso peptide. The CPPs were expected to increase the penetration efficiency of low-permeability drugs through the intestinal epithelial cell layer into blood. Drugs conjugated to oligoarginines via a chemically stable linker tend to be retained in the negatively charged intracellular compartment due to the strongly cationic peptides. Our group has proposed the use of a self-cleavable linker strategy that effectively releases the drugs from the oligoarginine peptide. Chemical-triggered self-cleavage produces the parent drug via intramolecular imide formation under physiological conditions. The designed model drug-oligoarginine conjugates were converted with the half-life (t1/2) values of 9-100 min. Conjugates possessing a short t1/2 of 9-10 min improved the transport rate of the parent model drug in a Caco-2 monolayer permeation assay. The Pas attachment to the oligoarginine was also found to be effective in this permeation assay. The Pas attachment may provide a new platform for facilitating arginine-rich CPP-mediated cargo transport.<br>

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  • 薬学雑誌

    薬学雑誌 134 (1), 55-61, 2014-01-01

    公益社団法人 日本薬学会

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