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Detection of particular structures using cyclic polyamides that selectively recognize G-quadruplex DNA and elucidation of their functions

Research Project

Project/Area Number 17J01932
Research Category

Grant-in-Aid for JSPS Fellows

Allocation TypeSingle-year Grants
Section国内
Research Field Chemical biology
Research InstitutionKyoto University

Principal Investigator

朝光 世煌  京都大学, 理学研究科, 特別研究員(DC2)

Project Period (FY) 2017-04-26 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥1,700,000 (Direct Cost: ¥1,700,000)
Fiscal Year 2018: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 2017: ¥900,000 (Direct Cost: ¥900,000)
KeywordsDNA結合性分子 / 抗ウイルス薬 / グアニン四重鎖DNA / グアニン四重鎖DNA結合性分子 / 二本鎖DNA結合性分子 / 選択的G4ターゲティング / 遺伝子発現制御 / 環状イミダゾール・リシンポリアミド
Outline of Annual Research Achievements

申請者は前年度までの研究テーマにおいて、グアニン四重鎖(G4)構造に特異的に結合するリガンド分子、環状イミダゾールリシンポリアミド(cIKP)と、ゲノム上の指定したG4構造のみを選択的にするようデザインした、二本鎖DNA結合分子付与型cIKPの開発を行い、一定の成果を報告した。今年度おける研究課題では、このcIKPの誘導体を設計・合成し、さらなる機能改善・機能開拓を目指した。インビトロ転写系におけるスクリーニングにより、cIKPのすべてのイミダゾールをピロールに置換した環状ピロール・リシンポリアミド(cPKP)が、高い遺伝子発現抑制効果と遺伝子選択性を示したことから、この化合物に対して詳細な検討を行った。その結果、種々の無細胞系のアッセイにより、cPKPのDNAに対する特殊な結合特性を導いた。この結果を踏まえて、cPKPがサイトメガウィルス(CMV)に対して選択的遺伝子転写抑制効果が期待できると考えて、抗ウイルス薬としての可能性を検討した。その結果、cPKPはCMVのコアプロモーター活性を選択的に減弱させることを見出した。さらにRNA-Seqによる網羅的遺伝子発現解析を実施し、高濃度(10 uM)においてもほとんどヒト遺伝子の発現プロファイルを変化させないことを確認した。これらの研究成果は、cPKPがヒトに対する副作用を抑えた抗ウイルス薬として発展する可能性を有する点で意義深い。申請者はこれらの研究成果を、XXIII INTERNATIONAL ROUNDTABLE ON NUCLEOSIDES, NUCLEOTIDES AND NUCLEIC ACIDSと日本化学第99春季年会で発表し、関連する論文を3報発表している。

Research Progress Status

平成30年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

平成30年度が最終年度であるため、記入しない。

Report

(2 results)
  • 2018 Annual Research Report
  • 2017 Annual Research Report
  • Research Products

    (14 results)

All 2019 2018 2017 Other

All Int'l Joint Research (4 results) Journal Article (5 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 5 results,  Open Access: 2 results) Presentation (5 results) (of which Int'l Joint Research: 3 results)

  • [Int'l Joint Research] Kent State University(米国)

    • Related Report
      2018 Annual Research Report
  • [Int'l Joint Research] Arizona University(米国)

    • Related Report
      2018 Annual Research Report
  • [Int'l Joint Research] Sogang University(韓国)

    • Related Report
      2018 Annual Research Report
  • [Int'l Joint Research] Nanyang Technological University(Singapore)

    • Related Report
      2017 Annual Research Report
  • [Journal Article] Orientation preferences of hairpin pyrrole-imidazole polyamides toward mCGG site2019

    • Author(s)
      Shinsuke Sato, Sefan Asamitsu, Toshikazu Bando, Hiroshi Sugiyama
    • Journal Title

      Bioorganic & Medicinal Chemistry

      Volume: 印刷中 Issue: 11 Pages: 2167-2171

    • DOI

      10.1016/j.bmc.2019.04.006

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Recent Progress of Targeted G-Quadruplex-Preferred Ligands Toward Cancer Therapy2019

    • Author(s)
      Sefan Asamitsu, Shunsuke Obata, Zutao Yu, Toshikazu Bando, Hiroshi Sugiyama
    • Journal Title

      Molecules

      Volume: 24 Issue: 3 Pages: 429-429

    • DOI

      10.3390/molecules24030429

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Ligand Design to Acquire Specificity to Intended G‐Quadruplex Structures2019

    • Author(s)
      Sefan Asamitsu, Toshikazu Bando, Hiroshi Sugiyama
    • Journal Title

      Chemistry A European Journal

      Volume: 25 Issue: 2 Pages: 417-430

    • DOI

      10.1002/chem.201802691

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Simultaneous Binding of Hybrid Molecules Constructed with Dual DNA-Binding Components to a G-Quadruplex and Its Proximal Duplex2018

    • Author(s)
      Asamitsu Sefan、Obata Shunsuke、Phan Anh Tu?n、Hashiya Kaori、Bando Toshikazu、Sugiyama Hiroshi
    • Journal Title

      Chemistry - A European Journal

      Volume: 24 Issue: 17 Pages: 4428-4435

    • DOI

      10.1002/chem.201705945

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] G-Quadruplex Induction by the Hairpin Pyrrole-Imidazole Polyamide Dimer2018

    • Author(s)
      Shunseke Obata, Sefan Asamitsu, Kaori Hashiya, Toshikazu Bando, Hiroshi Sugiyama
    • Journal Title

      Biochemistry

      Volume: 57 Issue: 5 Pages: 498-502

    • DOI

      10.1021/acs.biochem.7b01059

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed
  • [Presentation] Pyrrole-based oligoamide for specific DNA recognition2018

    • Author(s)
      Sefan Asamitsu, Toshikazu Bando, Hiroshi Sugiyama
    • Organizer
      日本化学第99春季年会
    • Related Report
      2018 Annual Research Report
  • [Presentation] Selective DNA recognition by Imidazole/Pyrrole-based cyclic oligopeptides2018

    • Author(s)
      Sefan Aasmitsu, Toshikazu Bando, Hiroshi Sugiyama
    • Organizer
      XXIII International Roundtable on Nucleosides, Nucletides and Nucleic acids
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Simultaneous recognition of G-quadruplex and its proximal duplex by hybrid molecules constructed with dual DNA-binding components2018

    • Author(s)
      Sefan Asamitsu, Shunsuke Obata, Anh Tuan Phan, Kaori Hashiya, Toshikazu Bando, Hiroshi Sugiyama
    • Organizer
      日本化学会第98春季年会 (2018)
    • Related Report
      2017 Annual Research Report
  • [Presentation] Simultaneous binding of hybrid molecules constructed with dual DNA-binding components to a G-quadruplex and its proximal duplex2018

    • Author(s)
      Sefan Asamitsu, Shunsuke Obata, Anh Tuan Phan, Kaori Hashiya, Toshikazu Bando, Hiroshi Sugiyama
    • Organizer
      The SPIRITS International Symposium - 2018
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Simultaneous binding of hybrid molecules constructed with dual DNA-binding components to quadruplex and its proximal duplex2017

    • Author(s)
      Sefan Asamitsu, Shunsuke Obata, Anh Tuan Phan, Kaori Hashiya, Toshikazu Bando, Hiroshi Sugiyama
    • Organizer
      The 44th International Symposium on Nucleic Acids Cemistry 2017
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research

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Published: 2017-05-25   Modified: 2024-03-26  

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