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Development of fluorescent probes with AND-logic gate response for HYPOXIA

Research Project

Project/Area Number 19K23816
Research Category

Grant-in-Aid for Research Activity Start-up

Allocation TypeMulti-year Fund
Review Section 0801:Pharmaceutical sciences and related fields
Research InstitutionKobe Pharmaceutical University

Principal Investigator

Takashima Ippei  神戸薬科大学, 薬学部, 特任助教 (50769742)

Project Period (FY) 2019-08-30 – 2021-03-31
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000)
Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Keywordsアンドロジック / 蛍光プローブ / 微量元素 / シグナル増強 / 低酸素環境 / がん微小環境 / ANDロジック / ドラッグデリバリー / ANDロジックゲート / Fluorescent probe / HYPOXIA / AND logic gate / Enzyme prodrug / Cancer therapy
Outline of Research at the Start

HYPOXIAは一時的な虚血状態(梗塞や創傷)や腫瘍深部で発生し、心筋梗塞や腫瘍の治療における重要な標的イベントである。そこでHYPOXIAを検出する分子プローブはこれら疾患の解析や治療で有用と思われるが、従来の分子設計では疎水性が高く肝臓などへの非特異吸着が問題であった。そこで本研究では、細胞内の還元的環境を標的とした従来の分子設計に加えて、HYPOXIAで発現増強している細胞表面マーカーを標的とした親水性の高い分子設計を組み合わせて、高い選択性でHYPOXIAを検出可能なANDロジックゲート型のプローブ分子を開発することを目指す。

Outline of Final Research Achievements

Our research goal is the development of an AND logic gate targeting tumor-localized enzymes with a conventional hypoxia-sensitive molecule. In this project, we found that the enzyme we had planned to use for this system quickly degrades under physiological conditions, but a chemical modification of the enzyme overcame this issue. In addition, the enzyme substrate was also found to be unstable under physiological conditions, and the structure optimization efforts is underway. Through these optimization studies, we fortuitously found functional molecules that react selectively with zinc. The molecules were further applied as fluorescent probes to give a bright fluorescent response by signal amplification. These studies are also in progress and a part of results has been published in an international journal.

Academic Significance and Societal Importance of the Research Achievements

研究に用いる酵素の安定性を増す化学修飾方法を開発することでケミカルバイオロジー研究での新たなツールとなることが期待される。また本研究では、偶然に亜鉛に対するシグナル増強型の蛍光プローブを創製した。従来のプローブ分子に比べて高感度であり、生体中での微量の亜鉛を蛍光解析するのに優れた機能を持つ。また本研究概念は他の微量元素や生体内分子の検出に拡張可能であると思われ、蛍光プローブの開発における新たな分子設計指針としても有効であることが期待される。

Report

(3 results)
  • 2020 Annual Research Report   Final Research Report ( PDF )
  • 2019 Research-status Report
  • Research Products

    (17 results)

All 2021 2020 2019 Other

All Journal Article (6 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 6 results) Presentation (5 results) (of which Int'l Joint Research: 1 results) Book (2 results) Remarks (2 results) Patent(Industrial Property Rights) (2 results) (of which Overseas: 1 results)

  • [Journal Article] Non-genetic cell-surface modification with a self-assembling molecular glue2021

    • Author(s)
      Hakariya, H., Takashima, I., Takemoto, M., Noda, N., Sato, S., Uesugi, M.
    • Journal Title

      Chem Commun.

      Volume: 57 Issue: 12 Pages: 1470-1473

    • DOI

      10.1039/d0cc07171d

    • NAID

      120007002689

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Total Synthesis of Antiausterity Agent (±)-Uvaridacol L by Regioselective Axial Diacylation of a myo-Inositol Orthoester2021

    • Author(s)
      Takagi Akira、Usuguchi Kazuki、Takashima Ippei、Okuda Kensuke
    • Journal Title

      Organic Letters

      Volume: - Issue: 11 Pages: 4083-4087

    • DOI

      10.1021/acs.orglett.1c00079

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Engineering of an archaeal phosphodiesterase to trigger aggregation-induced emission (AIE) of synthetic substrates2020

    • Author(s)
      Zhang Yunlong、Wu Zhiyuan、Takashima Ippei、Nguyen Kathy-Uyen、Matsumoto Nobuyuki、Lindsey Jonathan S.
    • Journal Title

      New Journal of Chemistry

      Volume: 44 Issue: 33 Pages: 14266-14277

    • DOI

      10.1039/d0nj03208e

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] A fluorogenic probe using a catalytic reaction for the detection of trace intracellular zinc2020

    • Author(s)
      Takashima Ippei、Inoue Yohei、Matsumoto Nobuyuki、Takagi Akira、Okuda Kensuke
    • Journal Title

      Chemical Communications

      Volume: 56 Issue: 87 Pages: 13327-13330

    • DOI

      10.1039/d0cc05315e

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Discovery of Self‐Assembling Small Molecules as Vaccine Adjuvants2020

    • Author(s)
      Jin Shuyu、Vu Hue Thi、Hioki Kou、Noda Naotaka、Yoshida Hiroki、Shimane Toru、Ishizuka Shigenari、Takashima Ippei、Mizuhata Yoshiyuki、Beverly Pe Kathleen、Ogawa Tetsuya、Nishimura Naoya、Packwood Daniel、Tokitoh Norihiro、Kurata Hiroki、Yamasaki Sho、Ishii Ken J.、Uesugi Motonari
    • Journal Title

      Angewandte Chemie International Edition

      Volume: 60 Issue: 2 Pages: 961-969

    • DOI

      10.1002/anie.202011604

    • NAID

      120006958092

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Multifunctionalization of Cells with a Self-Assembling Molecule to Enhance Cell Engraftment2019

    • Author(s)
      Takashima Ippei、Kusamori Kosuke、Hakariya Hayase、Takashima Megumi、Vu Thi Hue、Mizukami Yuya、Noda Naotaka、Takayama Yukiya、Katsuda Yousuke、Sato Shin-ichi、Takakura Yoshinobu、Nishikawa Makiya、Uesugi Motonari
    • Journal Title

      ACS Chemical Biology

      Volume: 14 Issue: 4 Pages: 775-783

    • DOI

      10.1021/acschembio.9b00109

    • Related Report
      2019 Research-status Report
    • Peer Reviewed
  • [Presentation] 位置選択的ジベンゾイル化による(±)-uvaridacol Lの効率的合成2021

    • Author(s)
      臼口 和希、高木 晃、高嶋 一平、奥田 健介
    • Organizer
      日本薬学会第141年会(広島)(オンライン)
    • Related Report
      2020 Annual Research Report
  • [Presentation] がんの栄養飢餓耐性解除に着目したグルコース誘導体の構造活性相関研究2021

    • Author(s)
      高木 晃、田坂 今日子、津田 智英美、高嶋 一平、奥田 健介
    • Organizer
      日本薬学会第141年会(広島)(オンライン)
    • Related Report
      2020 Annual Research Report
  • [Presentation] Signal amplification method for the detection of intracellular zinc2020

    • Author(s)
      Ippei Takashima, Yohei Inoue, Nobuyuki Matsumoto, Akira Takagi, Eiji Nakata, and Kensuke Okuda
    • Organizer
      第11回エネルギー理工学研究所国際シンポジウム(オンライン)
    • Related Report
      2020 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 亜鉛触媒反応を応用した細胞内亜鉛イオンの 高感度検出プローブの開発2020

    • Author(s)
      井上 陽平,高嶋 一平、松本 信之,奥田 健介
    • Organizer
      第70回日本薬学会関西支部大会(オンライン)
    • Related Report
      2020 Annual Research Report
  • [Presentation] 細胞内亜鉛イオンの高感度検出プローブの開発2020

    • Author(s)
      高嶋 一平,井上 陽平,松本 信之,高木 晃,奥田 健介
    • Organizer
      生命金属に関する合同年会 (Conmetal2020)(オンライン)
    • Related Report
      2020 Annual Research Report
  • [Book] カレントレビュー36:生体分子反応を制御する、14章 (p128-134)2020

    • Author(s)
      高嶋一平、上杉志成
    • Total Pages
      7
    • Publisher
      化学同人
    • ISBN
      9784759813968
    • Related Report
      2020 Annual Research Report
  • [Book] CSJカレントレビュー2020

    • Author(s)
      高嶋一平、上杉志成
    • Total Pages
      212
    • Publisher
      化学同人
    • ISBN
      9784759813968
    • Related Report
      2019 Research-status Report
  • [Remarks] 【プレスリリース】シグナル増強システムを用いた亜鉛の高感度検出プローブの創製(薬化学研究室)

    • URL

      https://www.kobepharma-u.ac.jp/news/005389.html

    • Related Report
      2020 Annual Research Report
  • [Remarks] コニカミノルタ画像科学奨励賞(令和2年度)

    • URL

      https://www.konicaminolta.jp/about/csr/contribution/corporation/research/foundation/prize.html

    • Related Report
      2020 Annual Research Report
  • [Patent(Industrial Property Rights)] 新規化合物及び該化合物を含有する亜鉛検出用蛍光プローブ2020

    • Inventor(s)
      奥田健介、高嶋一平
    • Industrial Property Rights Holder
      神戸薬科大学
    • Industrial Property Rights Type
      特許
    • Industrial Property Number
      2020-135407
    • Filing Date
      2020
    • Related Report
      2020 Annual Research Report
  • [Patent(Industrial Property Rights)] 細胞移植を効率化する化合物2019

    • Inventor(s)
      上杉志成、高嶋一平、西川元也
    • Industrial Property Rights Holder
      上杉志成、高嶋一平、西川元也
    • Industrial Property Rights Type
      特許
    • Filing Date
      2019
    • Related Report
      2019 Research-status Report
    • Overseas

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Published: 2019-09-03   Modified: 2024-01-30  

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