The synthesis of a photoactivatable alpha-GalCer derivative that maintains immunostimulative activty by evading anergy induction

2019 Fiscal Year Final Research Report

• Project/Area Number: 17K19194
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Research Field: Biomolecular chemistry and related fields
• Research Institution: Tokyo Institute of Technology
• Principal Investigator: YUASA HIDEYA 東京工業大学, 生命理工学院, 教授 (90261156)
• Project Period (FY): 2017-06-30 – 2020-03-31
• Keywords: 光免疫療法 / アナジー誘導 / ガラクトシルセラミド

Outline of Final Research Achievements

Galactosylceramide (GalCer) is recognized by the CD1d proteins on antigen-presenting cells at the ceramide moiety and the galactose moiety is presented to iNKT cells, which stimulates the immune responses. However, the immune suppression by repeated injection of GalCer has discouraged its development as an anti-cancer agent. To overcome the shortcoming by spatiotemporal restriction of its exposure, we synthesized the photochromic azobenzene-incorporated analogues and tested the photo-immunoregulation effect of in its binding to CD1d. FACS analyses indicated that some of these analogues enhanced the affinity to CD1d on photo-irradiation by about 20%. A docking simulation suggests that the photochromic molecule should be bulkier for a clearer discrimination between on and off states. We thus started the design and synthesis of bulkier azobenzene-incorporated analogues.

Free Research Field

生物有機化学

Academic Significance and Societal Importance of the Research Achievements

遠隔で薬品の活性を制御する方法論の開拓は近年始まった新しい学術領域の一つである。その中で、光異性化する化合物を生物活性調節に機能させる課題がある。本研究では、光異性化物質そのものをリガンド認識部位に取り込ませて制御しようとする試みを行い、一定の成果を得た。一般に光異性化物質は大きいので、認識部位に直接入り込めないが、本研究では、CD1dが脂質鎖全体を円形にして取り込むためにアゾベンゼンのシス体とフィットすることを利用した。この方法論をさらに進展させ、光異性化による完全な活性制御が可能となれば、時空間的に免疫系を制御する新しい方法論を構築するとともに、新たな抗癌治療につながる。