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Development of novel amyloid-beta aggregation inhibitors based on the constituents of Perilla frutescens var. crispa, and their mechanism of action

Research Project

Project/Area Number 16K01909
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Biomolecular chemistry
Research InstitutionMuroran Institute of Technology

Principal Investigator

UWAI KOJI  室蘭工業大学, 大学院工学研究科, 准教授 (80347905)

Research Collaborator TOKURAKU Kiyotaka  
HAYASHI Takafumi  
Project Period (FY) 2016-04-01 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2016: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Keywordsアルツハイマー病 / アミロイドβ / ロスマリン酸 / 凝集阻害 / シソ / 構造活性相関 / 核磁気共鳴法 / タンパク凝集 / シソ科植物 / シソ科 / ドッキングシミュレーション / 活性発現の分子機構 / 脳神経疾患 / アルツハイマー / アミロイド / 生物活性物質
Outline of Final Research Achievements

In this study, amyloid-beta aggregation inhibitory activities of stnthesized rosmarinic acid derivatives were evaluated by miclo-litter high-through put screening system (MSHTS) and ThT method, and docking simulation between Abeta and the derivatives were also studied. Results suggested that the compounds showed higer activity owned both lipophilic moiety and phenolic hydroxyls and their CLogP values were nearly equal to values of general drugs acted to central nervous system. Considering the difference of the activities obtained by two different methods (MSHTS and ThT), the derivatives showed the activity by two defferent mechanisms based on their chemical structure. The additional detailed biochemical and spectroscopic studies, the derivatives were devided to two groups: one was the compounds that inhibited the initial stage of the aggregation and another was the compounds that inhibited the aggregation between middle size aggregates.

Academic Significance and Societal Importance of the Research Achievements

アルツハイマー病 (AD) の原因の一つである患者の脳内でのアミロイドβ(Aβ)タンパクの凝集・蓄積を強く阻害するアオジソの,主要な活性成分の一つであるロスマリン酸をもとにした様々な誘導体を合成し,その凝集阻害機構を検討した.その結果,ロスマリン酸誘導体の構造の違いにより,凝集体の中でも脳の神経細胞に対して強い毒性を示す可溶性オリゴマーの形成に影響することが明らかになった.ADの患者数は世界的に増加し続け,その克服が喫緊の課題となっているが,現状では対症療法しかなく,根本的な治療法が求められている.本研究で得られた新しい物質はADの予防や治療,またAD発症の原因研究に有用であると考えられる.

Report

(4 results)
  • 2018 Annual Research Report   Final Research Report ( PDF )
  • 2017 Research-status Report
  • 2016 Research-status Report
  • Research Products

    (25 results)

All 2019 2018 2017 2016 Other

All Journal Article (3 results) (of which Peer Reviewed: 3 results,  Open Access: 2 results) Presentation (20 results) (of which Int'l Joint Research: 3 results,  Invited: 2 results) Remarks (1 results) Patent(Industrial Property Rights) (1 results)

  • [Journal Article] An automated microliter-scale high-throughput screening system (MSHTS) for real-time monitoring of protein aggregation using quantum-dot nanoprobes2019

    • Author(s)
      Sasaki Rina、Tainaka Reina、Ando Yuichi、Hashi Yurika、Deepak Hadya V.、Suga Yoshiko、Murai Yuta、Anetai Masaki、Monde Kenji、Ohta Kiminori、Ito Ikuko、Kikuchi Haruhisa、Oshima Yoshiteru、Endo Yasuyuki、Nakao Hitomi、Sakono Masafumi、Uwai Koji、Tokuraku Kiyotaka
    • Journal Title

      Scientific Reports

      Volume: 9 Issue: 1 Pages: 2587-2587

    • DOI

      10.1038/s41598-019-38958-0

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Rosmarinic acid is a novel inhibitor for Hepatitis B virus replication targeting viral epsilon RNA-polymerase interaction2018

    • Author(s)
      Tsukamoto Yuta、Ikeda Sotaro、Uwai Koji、Taguchi Riho、Chayama Kazuaki、Sakaguchi Takemasa、Narita Ryo、Yao Wan-Ling、Takeuchi Fumihiko、Otakaki Yukie、Watashi Koichi、Wakita Takaji、Kato Hiroki、Fujita Takashi
    • Journal Title

      PLOS ONE

      Volume: 13 Issue: 5 Pages: e0197664-e0197664

    • DOI

      10.1371/journal.pone.0197664

    • NAID

      120006649572

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Structure-activity relations of rosmarinic acid derivatives for the amyloid beta aggregation inhibition and antioxidant properties2017

    • Author(s)
      Taguchi Riho, Hatayama Koki, Takahashi Tomohito, Hayashi Takafumi, Sato Yuki, Sato Daisuke, Ohta Kiminori, Nakano Hiroto, Seki Chigusa, Endo Yasuyuki, Tokuraku Kiyotaka, Uwai Koji
    • Journal Title

      EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY

      Volume: 138 Pages: 1066-1075

    • DOI

      10.1016/j.ejmech.2017.07.026

    • Related Report
      2017 Research-status Report
    • Peer Reviewed
  • [Presentation] カフェ酸誘導体によるアミロイドβ可溶性オリゴマー形成阻害の分光学的解析2019

    • Author(s)
      上井幸司,久米田博之,坂本和,関千草,中野博人,馬渡康輝,徳樂清孝
    • Organizer
      化学系学協会北海道支部2019年冬季研究発表会
    • Related Report
      2018 Annual Research Report
  • [Presentation] Synergistic effects of inhibition of amyloid β aggregation and induction of brain-derived neurotrophic factor (BDNF) activity on mitigation of neurocytotoxicity by amyloid β2019

    • Author(s)
      Masahiro Kuragano, Mamoru Fukuchi, Koji Uwai, Kiyotaka Tokuraku
    • Organizer
      Joint Seminar on Environmental Science and Disaster Mitigation Research 2019
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Development of an automated microliter-scale highthroughput screening system with quantum-dot nanoprobes for amyloid aggregation inhibitors2019

    • Author(s)
      Rina Sasaki, Kenji Monde, Koji Uwai, Kiyotaka Tokuraku
    • Organizer
      Joint Seminar on Environmental Science and Disaster Mitigation Research 2019
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] アミロイド凝集阻害物質の自動スクリーニングシステムの開発と天然物および化合物ライブラリーの評価2019

    • Author(s)
      佐々木里奈、田井中玲奈、安藤雄一、太田公規、門出健次、上井幸司、徳樂清孝
    • Organizer
      2018年度日本生物物理学会北海道支部会
    • Related Report
      2018 Annual Research Report
  • [Presentation] ゲンノショウコ (Geranium thunbergii) のアミロイドβ凝集阻害物質2019

    • Author(s)
      上井幸司,久保研二,渡邉輝,関千草,中野博人,徳樂清孝
    • Organizer
      日本薬学会第139年会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 醤油に含まれるアミロイドβ凝集阻害物質の探索2018

    • Author(s)
      吉成航、上井幸司、徳楽清孝
    • Organizer
      日本食品化学学会第24回総会・学術大会
    • Related Report
      2018 Annual Research Report
  • [Presentation] アミロイドβ―カフェ酸誘導体複合体の分光学的解析2018

    • Author(s)
      坂本和,久米田博之,杉浦亜美,馬渡康輝,田口莉帆,関千草,中野博人,徳楽清孝,上井幸司
    • Organizer
      日本化学会北海道支部2018年夏季研究発表会
    • Related Report
      2018 Annual Research Report
  • [Presentation] A microliter-scale high-throughput screening system of amyloid-β aggregation inhibitors2018

    • Author(s)
      Kiyotaka Tokuraku, Koji Uwai
    • Organizer
      The 26th Annual Meeting of International Congress on Nutrition and Integrative Medicine (ICNIM 2018)
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] 北海道白糠町産植物からのAβ凝集阻害物質の探索と機能性評価2018

    • Author(s)
      渡邉輝、久保研二、杉村康司、大場慶司、上井幸司、徳樂清孝
    • Organizer
      第70回日本生物工学会大会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 量子ドットナノプローブを用いたアミロイド凝集阻害物質の自動化スクリーニングシステムの開発2018

    • Author(s)
      佐々木里奈、安藤雄一、上井幸司、徳楽清孝
    • Organizer
      第91回日本生化学会大会
    • Related Report
      2018 Annual Research Report
  • [Presentation] アミロイドβ凝集阻害機構のカフェ酸誘導体をツールとした分光学的解析2018

    • Author(s)
      上井幸司,久米田博之,坂本和,杉浦亜美,関千草,中野博人,徳樂清孝,馬渡康輝
    • Organizer
      第37回日本認知症学会学術集会
    • Related Report
      2018 Annual Research Report
  • [Presentation] アミロイドβ凝集阻害活性スクリーニングと活性物質の探索2018

    • Author(s)
      久保研二,渡邉輝,関千草,中野博人,徳樂清孝,上井幸司
    • Organizer
      第36回メディシナルケミストリーシンポジウム
    • Related Report
      2018 Annual Research Report
  • [Presentation] アミロイドβとカフェ酸エステル誘導体型凝集阻害剤の核磁気共鳴法による相互作用解析2018

    • Author(s)
      杉浦 亜美、馬渡 康輝、田口 莉帆、関 千草、中野 博人、徳樂 清孝、上井 幸司
    • Organizer
      日本農芸化学会2018年度大会
    • Related Report
      2017 Research-status Report
  • [Presentation] ロスマリン酸誘導体によるアミロイドβ凝集阻害機構解明のためのNMR解析2018

    • Author(s)
      杉浦亜美・馬渡康輝・田口莉帆・関千草・中野博人・徳樂清孝・上井幸司
    • Organizer
      化学系学協会北海道支部2018年冬季研究会
    • Related Report
      2017 Research-status Report
  • [Presentation] ロスマリン酸誘導体をツールとしたアミロイドβ凝集阻害機構の解析2017

    • Author(s)
      上井幸司, 田口莉帆, 畑山晃輝, 高橋倫人, 太田公規, 橋友理香, 関千草, 中野博人, 遠藤泰之, 徳樂清孝
    • Organizer
      第36回日本認知症学会学術集会
    • Related Report
      2017 Research-status Report
  • [Presentation] アミロイドβ凝集阻害物質の探索とその構造活性相関に基づくメカニズムの研究2017

    • Author(s)
      上井幸司
    • Organizer
      日本化学会 北海道支部 北見地区化学講演会
    • Related Report
      2017 Research-status Report
    • Invited
  • [Presentation] メカニズムに着目したカフェイン酸誘導体のアミロイドβ凝集阻害活性評価2016

    • Author(s)
      田口莉帆、高橋倫人、畑山晃輝、太田公規、橋友理香、関千草、中野博人、遠藤泰之、徳樂清孝、上井幸司
    • Organizer
      第34回メディシナルケミストリーシンポジウム
    • Place of Presentation
      つくば国際会議場(茨城県・つくば市)
    • Year and Date
      2016-11-30
    • Related Report
      2016 Research-status Report
  • [Presentation] Presumption of amyloid-β aggregation mechanism based on the structure-activity relationships for aggregation inhibition and docking studies2016

    • Author(s)
      Riho TAGUCHI, Tomohito TAKAHASHI, Suguru KOSAKA, Kiyotaka TOKURAKU, Koji UWAI
    • Organizer
      The 44th symposium on structure-activity relationship and the 32st assembly for pesticide design research
    • Place of Presentation
      京都大学芝蘭会館(京都府・京都市)
    • Year and Date
      2016-11-16
    • Related Report
      2016 Research-status Report
  • [Presentation] ロスマリン酸誘導体をツールとしたアミロイドβ凝集阻害機構の解明2016

    • Author(s)
      田口莉帆、高橋倫人、畑山晃輝、橋友理香、関千草、中野博人、徳樂清孝、上井幸司
    • Organizer
      日本化学会北海道支部2016年夏季研究発表会
    • Place of Presentation
      室蘭工業大学(北海道・室蘭市)
    • Year and Date
      2016-07-23
    • Related Report
      2016 Research-status Report
  • [Presentation] アミロイドβ凝集阻害機構の解明を指向したロスマリン酸誘導体の構造活性相関2016

    • Author(s)
      田口莉帆、高橋倫人、畑山晃輝、橋 友理香、関 千草、中野博人、徳樂清孝、上井幸司
    • Organizer
      日本薬学会北海道支部第143回例会
    • Place of Presentation
      札幌コンベンションセンター(北海道・札幌市)
    • Year and Date
      2016-05-14
    • Related Report
      2016 Research-status Report
  • [Remarks] 室蘭工業大学  生命有機化学研究室のホームページ(申請者の研究室HP)

    • URL

      http://www3.muroran-it.ac.jp/biocat/Top.html

    • Related Report
      2018 Annual Research Report
  • [Patent(Industrial Property Rights)] アミロイド形成を評価する方法、装置及びプログラム2018

    • Inventor(s)
      徳楽清孝、上井幸司
    • Industrial Property Rights Holder
      室蘭工業大学
    • Industrial Property Rights Type
      特許
    • Industrial Property Number
      2018-242280
    • Filing Date
      2018
    • Related Report
      2018 Annual Research Report

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Published: 2016-04-21   Modified: 2020-03-30  

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