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非天然アミノ酸の導入を可能にする新型リボソーム翻訳系の構築

Research Project

Project/Area Number 18H02080
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Review Section Basic Section 37010:Bio-related chemistry
Research InstitutionThe University of Tokyo

Principal Investigator

加藤 敬行  東京大学, 大学院理学系研究科(理学部), 准教授 (90567760)

Project Period (FY) 2018-04-01 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
Budget Amount *help
¥17,160,000 (Direct Cost: ¥13,200,000、Indirect Cost: ¥3,960,000)
Fiscal Year 2021: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000)
Fiscal Year 2020: ¥6,630,000 (Direct Cost: ¥5,100,000、Indirect Cost: ¥1,530,000)
Fiscal Year 2019: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2018: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000)
Keywordsペプチド医薬 / 翻訳 / tRNA / 非天然アミノ酸 / リボソーム / 翻訳合成 / ペプチド創薬
Outline of Annual Research Achievements

本研究では、リボソーム翻訳系を人工的に改変することによりD-アミノ酸、β-アミノ酸、γ-アミノ酸、N-メチルアミノ酸等の特殊骨格を持つ非天然アミノ酸のペプチド鎖中への導入を目指した。今年度は、アミノアシル-tRNAのT-ステム領域の配列を最適化することにより、N-メチルアミノ酸の導入効率の向上に成功した。また、翻訳因子の1つであるEF-GがD-アミノ酸の連続導入の際にペプチドのトランケーションを生じさせることを明らかにし、D-アミノ酸導入において翻訳系中のEF-Gの濃度を最適化することが必要であることを示した。
さらに、環状β-アミノ酸の一種である2-aminobenzoic acidと3-aminothiophene-2-carboxylic acidおよび2種類のD-アミノ酸を導入した大環状ペプチドライブラリの構築に成功し、RaPID display法を用いて2種類の標的タンパク質(FXIIaおよびIFNGR1)に対する阻害剤ペプチドのセレクションを行った。その結果、FXIIaおよびIFNGR1に対する強力な阻害剤を取得することに成功した。いずれの阻害剤ペプチドにおいても2-aminobenzoic acidおよび3-aminothiophene-2-carboxylic acidが阻害活性に寄与しており、なおかつペプチドの血中安定性の向上にも寄与していることが確認された。これらのβ-アミノ酸は剛直な環状構造を持つことからペプチドのターン構造を強く誘起することが知られており、今後フォルダマーペプチドの新しいビルディングブロックとして活用できることが期待される。

Research Progress Status

令和3年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

令和3年度が最終年度であるため、記入しない。

Report

(4 results)
  • 2021 Annual Research Report
  • 2020 Annual Research Report
  • 2019 Annual Research Report
  • 2018 Annual Research Report

Research Products

(25 results)

All 2022 2021 2020 2019 2018 Other

All Int'l Joint Research (2 results) Journal Article (14 results) (of which Int'l Joint Research: 5 results,  Peer Reviewed: 14 results,  Open Access: 9 results) Presentation (9 results) (of which Int'l Joint Research: 5 results,  Invited: 2 results)

  • [Int'l Joint Research] IECB(フランス)

    • Related Report
      2021 Annual Research Report
  • [Int'l Joint Research] IECB(フランス)

    • Related Report
      2019 Annual Research Report
  • [Journal Article] Drop-off-reinitiation triggered by EF-G-driven mistranslocation and its alleviation by EF-P2022

    • Author(s)
      Tajima Kenya、Katoh Takayuki、Suga Hiroaki
    • Journal Title

      Nucleic Acids Research

      Volume: 50 Pages: 2736-2753

    • DOI

      10.1093/nar/gkac068

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] In Vitro Selection of Foldamer-Like Macrocyclic Peptides Containing 2-Aminobenzoic Acid and 3-Aminothiophene-2-Carboxylic Acid2022

    • Author(s)
      Katoh Takayuki、Suga Hiroaki
    • Journal Title

      Journal of the American Chemical Society

      Volume: 144 Pages: 2069-2072

    • DOI

      10.1021/jacs.1c12133

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Consecutive Ribosomal Incorporation of α-Aminoxy/α-Hydrazino Acids with D/L-Configurations into Nascent Peptide Chains2021

    • Author(s)
      Katoh Takayuki、Suga Hiroaki
    • Journal Title

      Journal of the American Chemical Society

      Volume: 143 Pages: 18844-18848

    • DOI

      10.1021/jacs.1c09270

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] In Vitro Selection of Thioether-Closed Macrocyclic Peptide by Means of the RaPID System2021

    • Author(s)
      Katoh Takayuki、Goto Yuki、Suga Hiroaki
    • Journal Title

      Methods in Molecular Biology

      Volume: 2371 Pages: 247-259

    • DOI

      10.1007/978-1-0716-1689-5_13

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Uniform affinity-tuning of N-methyl-aminoacyl-tRNAs to EF-Tu enhances their multiple incorporation2021

    • Author(s)
      Iwane Yoshihiko、Kimura Hiroyuki、Katoh Takayuki、Suga Hiroaki
    • Journal Title

      Nucleic Acids Research

      Volume: 49 Pages: 10807-10817

    • DOI

      10.1093/nar/gkab288

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Macrocyclic peptides exhibit antiviral effects against influenza virus HA and prevent pneumonia in animal models2021

    • Author(s)
      Saito, M Itoh Y, Yasui F, Munakata T, Yamane D, Ozawa M, Ito R, Katoh T, Ishigaki H, Nakayama M, Shichinohe S, Yamaji K, Yamamoto N, Ikejiri A, Honda T, Sanada T, Sakoda Y, Kida H, Le TH, Kawaoka Y, Ogasawara Tsukiyama-Kohara T, Suga H, & Kohara M
    • Journal Title

      Nat Commun.

      Volume: - Pages: 2654-2654

    • DOI

      10.1038/s41467-021-22964-w

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] In Vitro Selection of Macrocyclic <scp>d</scp>/<scp>l</scp>-Hybrid Peptides against Human EGFR2021

    • Author(s)
      Imanishi Sayaka、Katoh Takayuki、Yin Yizhen、Yamada Mituhiro、Kawai Marina、Suga Hiroaki
    • Journal Title

      Journal of the American Chemical Society

      Volume: 143 Pages: 5680-5684

    • DOI

      10.1021/jacs.1c02593

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Ribosomal synthesis and de novo discovery of bioactive foldamer peptides containing cyclic β-amino acids2020

    • Author(s)
      Katoh Takayuki、Sengoku Toru、Hirata Kunio、Ogata Kazuhiro、Suga Hiroaki
    • Journal Title

      Nature Chemistry

      Volume: 12 Pages: 1081-1088

    • DOI

      10.1038/s41557-020-0525-1

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Ribosomal Elongation of Aminobenzoic Acid Derivatives2020

    • Author(s)
      Katoh Takayuki、Suga Hiroaki
    • Journal Title

      Journal of the American Chemical Society

      Volume: 142 Pages: 16518-16522

    • DOI

      10.1021/jacs.0c05765

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Ribosomal Elongation of Cyclic γ-Amino Acids using a Reprogrammed Genetic Code2020

    • Author(s)
      Katoh Takayuki、Suga Hiroaki
    • Journal Title

      Journal of the American Chemical Society

      Volume: 142 Pages: 4965-4969

    • DOI

      10.1021/jacs.9b12280

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Flexizyme-catalyzed synthesis of 3'-aminoacyl-NH-tRNAs.2019

    • Author(s)
      Katoh T, Suga H.
    • Journal Title

      Nucleic Acids Research

      Volume: pii

    • DOI

      10.1093/nar/gkz143

    • Related Report
      2019 Annual Research Report 2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] In vitro expression of genetically encoded non-standard peptides consisting of exotic amino acid building blocks.2019

    • Author(s)
      Hirose H, Tsiamantas C, Katoh T, Suga H.
    • Journal Title

      Current Opinions in Biotechnology

      Volume: 58 Pages: 26-28

    • DOI

      10.1016/j.copbio.2018.10.012

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Engineering Translation Components Improve Incorporation of Exotic Amino Acids2019

    • Author(s)
      Katoh Takayuki、Suga Hiroaki
    • Journal Title

      International Journal of Molecular Sciences

      Volume: 20 Pages: 522-522

    • DOI

      10.3390/ijms20030522

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Ribosomal Incorporation of Consecutive beta-Amino Acids.2018

    • Author(s)
      Katoh T, Suga H.
    • Journal Title

      Journal of the American Chemical Society

      Volume: 140 Pages: 12159-12167

    • DOI

      10.1021/jacs.8b07247

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] 細胞膜透過型Helixペプチドライブラリーの構築とその薬剤候補探索への適用2022

    • Author(s)
      大城 裕亮・加藤 敬行・菅裕明
    • Organizer
      日本化学会
    • Related Report
      2021 Annual Research Report
  • [Presentation] In vitro selection of antibiotic peptides that inhibit the bacterial ribosome2022

    • Author(s)
      Rei Takahashi, Takayuki Katoh, Axel Innis, Hiroaki Suga
    • Organizer
      日本化学会
    • Related Report
      2021 Annual Research Report
  • [Presentation] 環状γ-アミノ酸含有特殊ペプチドライブラリの構築と薬剤候補探索への適用2020

    • Author(s)
      三浦敬、加藤敬行、菅裕明
    • Organizer
      日本化学会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 環状β-アミノ酸を含むヘリックスペプチドライブラリを用いた薬剤候補スクリーニング2020

    • Author(s)
      川合茉利奈、加藤敬行、菅裕明
    • Organizer
      日本化学会
    • Related Report
      2019 Annual Research Report
  • [Presentation] Ribosomal incorporation of consecutive D- and β-amino acids2019

    • Author(s)
      Katoh Takayuki、Suga Hiroaki
    • Organizer
      RNA 2019
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Ribosomal synthesis and de novo discovery of bioactive foldamer peptides containing β- and D-amino acids2019

    • Author(s)
      Takayuki Katoh
    • Organizer
      12th International Symposium on Aminoacyl-tRNA Synthetases
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Ribosomal incorporation of consecutive D- and β-amino acids2019

    • Author(s)
      Takayuki Katoh, Hiroaki Suga
    • Organizer
      Ribosome 2019
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Logical engineering of tRNA for incorporation of D- and β-amino acids into macrocyclic peptides2018

    • Author(s)
      Takayuki Katoh
    • Organizer
      4th International Conference on Circular Proteins and Peptides (ICCPP2018)
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Logical engineering of D-arm and T-stem of tRNA for incorporation of non-proteinogenic amino acids2018

    • Author(s)
      Takayuki Katoh, Hiroaki Suga
    • Organizer
      27th tRNA conference
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research

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Published: 2018-04-23   Modified: 2022-12-28  

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