44秋田 英万45Hidetaka AKITA大石 徹46Tohru OISHI多段階的な細胞内動態制御能とナノ環境依存的な崩壊能を１分子に搭載したマルチ創剤基盤材料の創成（2017採択）Development of intracellular environment-responsive malti-nanoDDS material designed for the control of trafficking and degradation (Project 2017)細胞内カルシウムイオン濃度を制御する生物活性分子の設計・合成・評価（2017採択）Design, Synthesis, and Evaluation of Bioactive Molecules Controlling Intracellular Calcium Ion Concentration(Project 2017)申請者はこれまで，生体膜バリアの突破能と自己崩壊を介した内封分子の放出能を搭載した脂質様材料（ssPalm）や，本材料を用いた『電荷的に中性』な微小ナノ粒子の調製法を開発してきた．本研究では，ssPalmの分子改変によりssPalmの機能性と崩壊能を追求する．特に，崩壊の促進に関しては，細胞内環境に応答し，ナノ粒子内で分解反応が進行するという新概念に基づき，新たなリンカー構造を挿入した．この新たな技術の導入や脂溶性足場構造の改変などをおこないながら，核酸（mRNA）をはじめとした医薬候補品に対するマルチ創剤基盤として発展させた．特に，ビタミンE足場型の核酸導入技術がDNA/RNAワクチン用途として有用であることを示した．To date, we have developed a SS-cleavable pH-Activated Lipid-like Material (ssPalm) that mounts the dual functional motifs to overcome the biological membrane and to trigger the collapse for the release of the car-gos. Also, we have established the methods to prepare the “charge-neutral” nanoparticle. In this study, we pursue the functionality and disintegration ability of ssPalm by molecular modification of ssPalm. In particu-lar, a new linker structure was inserted based on the new concept that the decomposition reaction proceeds in the nanoparticles in response to the intracellular environment. While introducing this new technology and modifying the fat-soluble scaffold structure, they were applied to the DDS technology for the pharmaceutical candidates such as nucleic acid (mRNA). Especially, it was shown that the vitamin E scaffold-type nucleic acid introduction technology is useful for DNA/RNA vaccine applications.マイトトキシン(MTX)は，疎水性部分と親水性部分を併せ持つ分子量3422の海洋天然物であり，強力な細胞内へのカルシウムイオン流入活性を示す．本研究では，MTXの作用機構解明を目指した化学合成に基づくMTXの構造活性相関研究の一環として，MTXのNOPQR(S)環部，LMNO環部，DEF環部，GHI環部およびWXYZ環部の合成を行った．MTXによって引き起こされるカルシウムイオン流入の阻害活性を評価した結果，これまでに合成したMTXの疎水性部分に比べ，親水性部分に相当するLMNO環部の阻害活性は弱く，疎水性部分と親水性部分の境界領域に相当するNOPQR(S)環部は阻害活性を示さないことが分かり，生物活性発現機構に関する重要な示唆が得られた．Maitotoxin (MTX) is a marine natural product (MW 3422) comprised of hydrophobic and hydrophilic re-gions, and it elicits potent calcium ion influx activity into cells. In this study, as a part of the structure activity relationship study based on the chemical synthesis of partial structures of MTX, the NOPQR(S), LMNO, DEF, GHI, and WXYZ ring systems were synthesized. The inhibitory activities of the synthesized com-pounds against the calcium ion influx induced by MTX were evaluated, and the LMNO ring corresponding to the hydrophilic region showed lower activity compared with those of the hydrophobic region, and the NOPQR(S) ring elicited no inhibition, suggesting important information on the mode-of-action of MTX.
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