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Regulation of the immunostimulatory activity of CpG ODNs by G-quadruplex formation

Research Project

Project/Area Number 18K04858
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 27040:Biofunction and bioprocess engineering-related
Research InstitutionNational Institute for Materials Science

Principal Investigator

YAMAZAKI Tomohiko  国立研究開発法人物質・材料研究機構, 機能性材料研究拠点, 主幹研究員 (50419264)

Co-Investigator(Kenkyū-buntansha) 池袋 一典  東京農工大学, 工学(系)研究科(研究院), 卓越教授 (70251494)
Project Period (FY) 2018-04-01 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
Budget Amount *help
¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Keywordsトール様受容体9 / CpGオリゴデオキシヌクレオチド / グアニン四重鎖構造 / アジュバント / I型インターロイキン / オリゴ / 免疫細胞 / 抗体産出 / CpG ODN / Gカルテット構造 / 免疫活性化 / I型インターフェロン / インターロイキン / ワクチン / アジュバンド / NFカッパ B
Outline of Final Research Achievements

Toll-like receptor 9 activation by oligodeoxynucleotides (ODNs) containing unmethylated cytosine-phosphate-guanine (CpG) motifs triggers the innate immune system and establishes an adaptive immune response, and therefore these ODNs have been studied as vaccine adjuvants for infectious disease, or as therapeutic agents for allergies and cancer.
In this study, we aim to enhance immunostimulatory activity of CpG ODNs by forming guanine quadruplex (G4) structure. CpG ODNs forming G4 structure, exhibited a higher DNase stability, intracellular uptake. and immunostimulatory effect than do natural linear CpG ODNs. Additionally, we demonstrated that efficacy of the G4 CpG ODNs in activating TLR9 is defined by the number of CpG motifs and the number of nucleotides between the CpG motif and G-tracts. These findings suggest some hints for the rational design of highly potent G4 CpG ODNs for vaccine adjuvant applications.

Academic Significance and Societal Importance of the Research Achievements

本研究では、ワクチンに添加されている免疫賦活化剤(アジュバント)として利用することができる分子の開発を進めた。アジュバントはワクチンの効果を高める機能を持つ。CpGオリゴデオキシヌクレオチドは現在までにアジュバントとして使用されている水酸化アルミニウムと比較して、安全性が高く副作用が低いと考えられているが、安定性と機能が劣っていた。本研究では、核酸の立体構造を制御することにより天然核酸由来のCpGオリゴデオキシヌクレオチドの安定性と機能を向上させることを達成しており、成果は安全かつ効果の高いワクチンアジュバントの実用化に寄与する。

Report

(5 results)
  • 2021 Annual Research Report   Final Research Report ( PDF )
  • 2020 Research-status Report
  • 2019 Research-status Report
  • 2018 Research-status Report
  • Research Products

    (33 results)

All 2022 2021 2020 2019 Other

All Int'l Joint Research (10 results) Journal Article (6 results) (of which Int'l Joint Research: 4 results,  Peer Reviewed: 6 results,  Open Access: 4 results) Presentation (10 results) (of which Int'l Joint Research: 2 results,  Invited: 1 results) Remarks (6 results) Patent(Industrial Property Rights) (1 results)

  • [Int'l Joint Research] Lund大学(スウェーデン)

    • Related Report
      2021 Annual Research Report
  • [Int'l Joint Research] The University of North Carolina/North Carolina State University(米国)

    • Related Report
      2021 Annual Research Report
  • [Int'l Joint Research] Vietnam National University(ベトナム)

    • Related Report
      2021 Annual Research Report
  • [Int'l Joint Research] Institut Teknologi Bandung (ITB)(インドネシア)

    • Related Report
      2021 Annual Research Report
  • [Int'l Joint Research] Lund大学(スウェーデン)

    • Related Report
      2020 Research-status Report
  • [Int'l Joint Research] The University of North Carolina/North Carolina State University(米国)

    • Related Report
      2020 Research-status Report
  • [Int'l Joint Research] Lund大学(スウェーデン)

    • Related Report
      2019 Research-status Report
  • [Int'l Joint Research] The University of North Carolina/North Carolina State University(米国)

    • Related Report
      2019 Research-status Report
  • [Int'l Joint Research] The University of North carolina(米国)

    • Related Report
      2018 Research-status Report
  • [Int'l Joint Research] Universitas Indonesia(インドネシア)

    • Related Report
      2018 Research-status Report
  • [Journal Article] G-quadruplex-based CpG oligodeoxynucleotide/DOTAP complex strongly stimulates immunity in CpG motif-specific and loop-length-dependent manners2022

    • Author(s)
      Tu Anh Thi Tram、Hoshi Kazuaki、Shobo Miwako、Yamazaki Tomohiko
    • Journal Title

      Nanomedicine: Nanotechnology, Biology and Medicine

      Volume: 40 Pages: 102508-102508

    • DOI

      10.1016/j.nano.2021.102508

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Structural analysis of guanine quadruplex-forming oligonucleotides and their application to oligonucleotide therapeutics2021

    • Author(s)
      Yamazaki Tomohiko、TU Anh Ti Tram
    • Journal Title

      Drug Delivery System

      Volume: 36 Issue: 5 Pages: 360-368

    • DOI

      10.2745/dds.36.360

    • NAID

      130008163742

    • ISSN
      0913-5006, 1881-2732
    • Year and Date
      2021-11-25
    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Enhancement of the Immunostimulatory Effect of Phosphodiester CpG Oligodeoxynucleotides by an Antiparal-lel Guanine-Quadruplex Structural Scaffold.2021

    • Author(s)
      Safitri, F., Tu, A., Hoshi, K., Shobo, M., Zhao, D., Witarto, A., Sumarsono, S., Giri-Rachman, E., Tsukakoshi, K., Ikebukuro, K., and Yamazaki, T.
    • Journal Title

      Sensors (Basel)

      Volume: 11(11) Issue: 11 Pages: 1617-1617

    • DOI

      10.3390/biom11111617

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Monomeric G-Quadruplex-Based CpG Oligodeoxynucleotides as Potent Toll-Like Receptor 9 Agonists2020

    • Author(s)
      Tu Anh Thi Tram、Hoshi Kazuaki、Ikebukuro Kazunori、Hanagata Nobutaka、Yamazaki Tomohiko
    • Journal Title

      Biomacromolecules

      Volume: 21 Issue: 9 Pages: 3644-3657

    • DOI

      10.1021/acs.biomac.0c00679

    • Related Report
      2020 Research-status Report
    • Peer Reviewed
  • [Journal Article] G-Quadruplex Structure Improves the Immunostimulatory Effects of CpG Oligonucleotides2019

    • Author(s)
      Hoshi, Kazuaki; Yamazaki, Tomohiko; Sugiyama, Yuuki; Tsukakoshi, Kaori; Tsugawa, Wakako; Sode, Koji; Ikebukuro, Kazunori
    • Journal Title

      Nucleic acid therapeutics

      Volume: 29 (4) Issue: 4 Pages: 224-229

    • DOI

      10.1089/nat.2018.0761

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Preparation, characterization, and evaluation of chitosan-based nanoparticles as CpG ODN carriers2019

    • Author(s)
      Iswanti Febriana Catur、Nurulita Indah、Djauzi Samsuridjal、Sadikin Mohamad、Witarto Arief Budi、Yamazaki Tomohiko
    • Journal Title

      Biotechnology & Biotechnological Equipment

      Volume: - Issue: 1 Pages: 1-7

    • DOI

      10.1080/13102818.2019.1578690

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] ε-Poly-L-Lysine / Guanine-Quadruplexes CpG Oligodeoxynucleotide Complexes for Vaccine Adjuvant Applications2022

    • Author(s)
      ZHAO Dandan, TU Thi Tram Anh, YOSHIKAWA, Chiaki, YAMAZAKI, Tomohiko.
    • Organizer
      つくば医工連携フォーラム2022, つくばバイオマテリアル医工学研究会
    • Related Report
      2021 Annual Research Report
  • [Presentation] グアニン四重鎖構造を用いたDNAアジュバントの開発2021

    • Author(s)
      山崎 智彦, TU Thi Tram Anh, 星 和明, Safitri Fika Ayu, 塚越かおり, 池袋一典
    • Organizer
      日本核酸医薬学会第6回年会
    • Related Report
      2021 Annual Research Report
  • [Presentation] Development of functional oligonucleotides forming G-quadruplex structure by using topological structure evaluation based on CD spectrum analysis combined with principal component analysis2021

    • Author(s)
      塚越かおり, 鈴木仁子, 大山泰史, 佐藤星, TU Thi Tram Anh, 堀口靖夫, 永森浩司, 山崎 智彦, 池袋一典.
    • Organizer
      日本核酸医薬学会第6回年会
    • Related Report
      2021 Annual Research Report
  • [Presentation] Enhanced Immunostimulatory Activity of CpG Oligodeoxynucleotides by Forming Monomeric Guanine-Quadruplex Structure2020

    • Author(s)
      Anh Thi Tram TU, Kazuaki Hoshi, Kazunori Ikebukuro, Nobutaka Hanagata, Tomohiko Yamazaki
    • Organizer
      16th Annual Meeting of the Oligonucleotide Therapeutics Society
    • Related Report
      2020 Research-status Report
    • Int'l Joint Research
  • [Presentation] Forming Monomeric Guanine-Quadruplex Structure for enhancing CpG oligodeoxynucleotides-mediated immunostimulatory properties.2020

    • Author(s)
      ツ チ トラム アン,星 和明, 池袋 一典, 山崎 智彦
    • Organizer
      第15回ナノ・バイオメディカル学会年会
    • Related Report
      2020 Research-status Report
  • [Presentation] Tuning of the immunostimulatory effect of G-quadruplex based CpG Oligodeoxynucleotides2020

    • Author(s)
      Anh Thi Tram TU, Kazuaki Hoshi, Kazunori Ikebukuro, Tomohiko Yamazaki
    • Organizer
      MANA International Symposium 2020 jointly with ICYS
    • Related Report
      2019 Research-status Report
  • [Presentation] Improvement of the immunostimulatory effects of CpG ODNs by forming G-quadruplex structure2019

    • Author(s)
      Kazuaki Hoshi, Anh Thi Tram TU, Kaori Tsukakoshi, Wakako Tsugawa, Koji Sode, Kazunori Ikebukuro, Tomohiko Yamazaki
    • Organizer
      46th International Symposium on Nucleic Acids Chemistry
    • Related Report
      2019 Research-status Report
  • [Presentation] Immunostimulatory properties of CpG ODNs forming G-quadruplex structure2019

    • Author(s)
      Anh Thi Tram TU, Kazuaki Hoshi, Kazunori Ikebukuro, Tomohiko Yamazaki
    • Organizer
      46th International Symposium on Nucleic Acids Chemistry
    • Related Report
      2019 Research-status Report
  • [Presentation] Gカルテット構造によるCpG ODNの免疫活性化能の向上2019

    • Author(s)
      山崎 智彦、星 和明、ツ チ トラム アン、塚越かおり、津川若子、早出広司、池袋一典
    • Organizer
      第71回日本生物工学会大会
    • Related Report
      2019 Research-status Report
  • [Presentation] Development of novel immunostimulators, as potent vaccine adjuvants2019

    • Author(s)
      Tomohiko YAMAZAKI
    • Organizer
      CSIRO-NIMS SYMPOSIUM
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research / Invited
  • [Remarks] 物質・材料研究機構 研究者紹介

    • URL

      https://samurai.nims.go.jp/profiles/yamazaki_tomohiko

    • Related Report
      2021 Annual Research Report 2020 Research-status Report
  • [Remarks] 北海道大学フロンティア生命材料科学研究室 研究室ホームページ

    • URL

      https://life.sci.hokudai.ac.jp/tl/lab/frontier-biomaterials-science

    • Related Report
      2021 Annual Research Report 2020 Research-status Report 2019 Research-status Report
  • [Remarks] 物質・材料研究機構 研究者紹介

    • URL

      http://samurai.nims.go.jp/YAMAZAKI_Tomohiko-j.html

    • Related Report
      2019 Research-status Report
  • [Remarks] 研究者総覧「SAMURAI」

    • URL

      https://samurai.nims.go.jp/profiles/YAMAZAKI_Tomohiko?locale=ja

    • Related Report
      2018 Research-status Report
  • [Remarks] 物質・材料研究機構 ナノメディシングループ ホームページ

    • URL

      https://www.nims.go.jp/group/nanomedicine/

    • Related Report
      2018 Research-status Report
  • [Remarks] 北大生命科学院 フロンティア生命材料科学研究室

    • URL

      https://life.sci.hokudai.ac.jp/tl/lab/frontier-biomaterials-science

    • Related Report
      2018 Research-status Report
  • [Patent(Industrial Property Rights)] 免疫刺激オリゴヌクレオチド2020

    • Inventor(s)
      山崎智彦
    • Industrial Property Rights Holder
      物質・材料研究機構
    • Industrial Property Rights Type
      特許
    • Industrial Property Number
      2020-143071
    • Filing Date
      2020
    • Related Report
      2020 Research-status Report

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Published: 2018-04-23   Modified: 2023-12-25  

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