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ペプチドーペプトイド複合骨格をもつエピゲノム酵素阻害剤の発見

Research Project

Project/Area Number 11F01344
Research Category

Grant-in-Aid for JSPS Fellows

Allocation TypeSingle-year Grants
Section外国
Research Field Chemistry related to living body
Research InstitutionThe University of Tokyo

Principal Investigator

菅 裕明  東京大学, 大学院理学系研究科, 教授

Co-Investigator(Kenkyū-buntansha) HIPOLITO Christopher  東京大学, 大学院理学系研究科, 外国人特別研究員
HIPORITO CHRISTOPHER  東京大学, 大学院・理学系研究科, 外国人特別研究員
HIPOLITO CHRISTOPHER  東京大学, 大学院・理学系研究科, 外国人特別研究員
Project Period (FY) 2011 – 2013
Project Status Completed (Fiscal Year 2013)
Budget Amount *help
¥2,300,000 (Direct Cost: ¥2,300,000)
Fiscal Year 2013: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 2012: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 2011: ¥700,000 (Direct Cost: ¥700,000)
Keywords特殊ペプチド / 膜タンパク質 / エピゲノム / 翻訳 / non-standard amino acids / in vitro selection / flexizyme / co-crystallization peptide / enzyme inhibitor
Research Abstract

本研究は2つの研究計画を立てた。(1)細菌の薬剤放出ポンプタンパク質の一つであるPfMATE結合し、且つその高解像度の構造解析を達成しうる特殊ペプチドの創出と複合体の構造解析、(2)ヒトエピゲノム制御に関わる脱メチル化酵素群に属するLSD1とヒストンメチル化酵素SMYD3への特殊ペプチド阻害剤の発見、である。本研究を推進するに当たり、所属研究室で既に開発されたRaPID (Random non-standard Peptides Integrated)システムを駆使し、本目的の達成を試みる。
(1)のPfMATEに結合する特殊ペプチドの探索、およびその共結晶化による高解像度構造解析は成功し、2013年Nature誌に論文を発表するに至った。またコレラ菌MATEについては、特殊ペプチドの探索を終了し、現在構造解析を進めている。
(2)については、LSD1を標的とした阻害剤の探索にも成功したが、阻害活性が数μMと十分でなかった。Warheadを含んだ特殊ペプチドライブラリーを作成し再挑戦したが、これといって芳しい成果が上がらなかった。結論として、全長のLSD1を使って探索した場合、LSD1にアクセサリー領域が多いため、様々な部位との結合する特殊ペプチドが濃縮されることが、阻害剤として高活性の特殊ペプチドの獲得に至らなかったと考えた。現在は、LSD1の活性部位のみを発現したコンストラクトで、再々挑戦を進めている。

Current Status of Research Progress
Current Status of Research Progress

1: Research has progressed more than it was originally planned.

Reason

(抄録なし)

Strategy for Future Research Activity

(抄録なし)

Report

(3 results)
  • 2013 Annual Research Report
  • 2012 Annual Research Report
  • 2011 Annual Research Report
  • Research Products

    (14 results)

All 2014 2013 2012 2011

All Journal Article (5 results) (of which Peer Reviewed: 5 results) Presentation (7 results) Patent(Industrial Property Rights) (2 results) (of which Overseas: 1 results)

  • [Journal Article] Protein cocrystallization molecules originating from in vitro selected macrocyclic peptides2014

    • Author(s)
      C・J・ Hipolito, N・K・ Bashiru ddin H・Suga
    • Journal Title

      Current Opinion in Structural Biology

      Volume: (印刷中)

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] A macrocyclic peptide that serves as a cocrystallization ligand and inhibits the function of a MATE family transporte2013

    • Author(s)
      C・J・ Hipolito, Y・Tanaka, T・ Katoh, O・ Nureki, H・ Suga
    • Journal Title

      Molecules

      Volume: 18 Issue: 9 Pages: 10514-30

    • DOI

      10.3390/molecules180910514

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Structural basis for the drug extrusion mechanism by a MATE multidrug transporter2013

    • Author(s)
      Y・ Tanaka, C・J・ Hipolito, A・D・ Maturana, K・ Ito, T・ Kuroda, T・ Higuchi, T・ Katoh, H・E・ Kato, M・ Hattori, K・ Kumazaki, T・ Tsukazaki, R・ Ishitani, H・ Suga, O・ Nureki
    • Journal Title

      Nature

      Volume: 496 Issue: 7444 Pages: 247-51

    • DOI

      10.1038/nature12014

    • Related Report
      2013 Annual Research Report 2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Towards the Combinatorial Selection of Chemically Modified DNAzyme RNase A Mimics Active Against all-RNA Substrates2013

    • Author(s)
      Hollenstein, M., Hipolito, C. J., et al.
    • Journal Title

      ACS Combinatorial Science

      Volume: 15(4) Issue: 4 Pages: 174-182

    • DOI

      10.1021/co3001378

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Ribosomal production and in vitro selection of natural product-like peptidomimetics : The FIT and RaPID systems2012

    • Author(s)
      Hipolito C.J., Suga H.
    • Journal Title

      Current Opinion in Chemical Biology

      Volume: 16 Issue: 1-2 Pages: 1-8

    • DOI

      10.1016/j.cbpa.2012.02.014

    • Related Report
      2011 Annual Research Report
    • Peer Reviewed
  • [Presentation] In vitro selected cyclic peptides for the cocrystallization and inhibition of a transmembrane multidrug transporte2013

    • Author(s)
      Chris Hipolito
    • Organizer
      9th International Symposium on Aminoacyl-tRNA Synthetases
    • Place of Presentation
      箱根、日本
    • Year and Date
      2013-10-07
    • Related Report
      2013 Annual Research Report
  • [Presentation] In Vitro Selection of Cyclic Peptides for Cocrystallization with a Multidrug and Toxic compound Extrusion Protein2013

    • Author(s)
      Chris Hipolito
    • Organizer
      10th Annual Australian Peptide Conference
    • Place of Presentation
      Penang, Malaysia
    • Year and Date
      2013-09-12
    • Related Report
      2013 Annual Research Report
  • [Presentation] In Vitro Selection of Cyclic Peptides for Cocrystallization with a Multidrug and Toxic compound Extrusion Protein2013

    • Author(s)
      Chris Hipolito
    • Organizer
      American Peptide Symposium 2013
    • Place of Presentation
      Hawaii, USA
    • Year and Date
      2013-06-24
    • Related Report
      2013 Annual Research Report
  • [Presentation] Discovery of cocrystallzation cyclic peptides using the RaPID system2012

    • Author(s)
      Hipolito, C. J., et al.
    • Organizer
      35^<th> Annual Meeting of the MBSJ 2012
    • Place of Presentation
      Fukuoka International Congress Center, Hakata, Fukuoka, Japan
    • Year and Date
      2012-12-13
    • Related Report
      2012 Annual Research Report
  • [Presentation] Modified DNAzymes and the effects of shortening functional group linker length2012

    • Author(s)
      Hipolito, C. J., et al.
    • Organizer
      International Symposium on Nucleic Acid Chemistry 2012
    • Place of Presentation
      Toyoda Auditorium, Nagoya University, Nagoya, Japan
    • Year and Date
      2012-11-15
    • Related Report
      2012 Annual Research Report
  • [Presentation] Discovery of cocrystallzation cyclic peptides using the RaPID system2012

    • Author(s)
      Hipolito, C. J., et al.
    • Organizer
      International Conference on Circular Proteins 2012
    • Place of Presentation
      Heron Island, Queensland, Australia
    • Year and Date
      2012-10-15
    • Related Report
      2012 Annual Research Report
  • [Presentation] A macrocyclic peptide co-crystallized with a transmembrane protein2011

    • Author(s)
      Hipolito C.J., et al
    • Organizer
      The 38<th> International Symposium on Nucleic Acid Chemistrv
    • Place of Presentation
      Sapporo
    • Related Report
      2011 Annual Research Report
  • [Patent(Industrial Property Rights)] MATE活性阻害ペプチド2013

    • Inventor(s)
      菅裕明、濡木理、クリストファー ジェイヒポライト、田中良樹
    • Industrial Property Rights Holder
      東京大学
    • Filing Date
      2013-07-03
    • Related Report
      2013 Annual Research Report
    • Overseas
  • [Patent(Industrial Property Rights)] anti-MATEペプチド2012

    • Inventor(s)
      菅 裕明, 濡木 理, Chris Hipolito, 田中 良樹
    • Industrial Property Rights Holder
      国立大学法人 東京大学
    • Filing Date
      2012-04-26
    • Related Report
      2012 Annual Research Report

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Published: 2011-12-22   Modified: 2024-03-26  

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