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New approaches for intracellular delivery of bioactive proteins

Research Project

Project/Area Number 18H04017
Research Category

Grant-in-Aid for Scientific Research (A)

Allocation TypeSingle-year Grants
Section一般
Review Section Medium-sized Section 47:Pharmaceutical sciences and related fields
Research InstitutionKyoto University

Principal Investigator

Shiroh Futaki  京都大学, 化学研究所, 教授 (50199402)

Project Period (FY) 2018-04-01 – 2021-03-31
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥45,500,000 (Direct Cost: ¥35,000,000、Indirect Cost: ¥10,500,000)
Fiscal Year 2020: ¥9,360,000 (Direct Cost: ¥7,200,000、Indirect Cost: ¥2,160,000)
Fiscal Year 2019: ¥9,360,000 (Direct Cost: ¥7,200,000、Indirect Cost: ¥2,160,000)
Fiscal Year 2018: ¥26,780,000 (Direct Cost: ¥20,600,000、Indirect Cost: ¥6,180,000)
Keywords抗体 / 細胞 / 薬物送達 / 細胞内送達 / エンドソーム不安定化 / エンドソーム脱出 / バイオ高分子 / エンドサイトーシス / ペプチド
Outline of Final Research Achievements

Considerable research efforts have been dedicated to the delivery of antibodies and other proteins having therapeutic potentials to cell interiors. However, there were certain rooms for improvement in the efficacy. Our laboratory developed a delivery peptide L17E capable of delivering antibodies into cells. In this study, we made structure-activity-relationship analyses of L17E to improve the efficacy. New delivery peptides were developed having ability of stimulating cellular uptake. Eventually, peptides having more than 10-fold delivery efficacy compared with L17E were developed. We found a potent macropinocytosis-inducing peptide SN21 and the analog P4A. Successful intracellular delivery of antibodies and other biomacromolecules was attained using the conjugates of these peptides with the LK15 membrane-lytic peptide.

Academic Significance and Societal Importance of the Research Achievements

更なる導入効率の向上や導入法の検討により、疾病に関連する細胞機能の異常とその修復に関する糸口を明らかにする新しい手法の開発が期待される。さらにこの原理に従い、新しい治療法に結びつく可能性もある。また、効率的な細胞内送達を可能にする細胞の取込機序に関しての知見も得られた。

Report

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

    (39 results)

All 2022 2021 2020 2019 2018 Other

All Int'l Joint Research (1 results) Journal Article (15 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 15 results,  Open Access: 6 results) Presentation (19 results) (of which Int'l Joint Research: 13 results,  Invited: 18 results) Patent(Industrial Property Rights) (4 results) (of which Overseas: 2 results)

  • [Int'l Joint Research] ストックホルム大学(スウェーデン)

    • Related Report
      2020 Annual Research Report
  • [Journal Article] Artificial Nanocage Formed via Self-Assembly of β-Annulus Peptide for Delivering Biofunctional Proteins into Cell Interiors2022

    • Author(s)
      Sakamoto Kentarou、Furukawa Hiroto、Arafiles Jan Vincent V.、Imanishi Miki、Matsuura Kazunori、Futaki Shiroh
    • Journal Title

      Bioconjugate Chemistry

      Volume: 33 Issue: 2 Pages: 311-320

    • DOI

      10.1021/acs.bioconjchem.1c00534

    • Related Report
      Products Report
    • Peer Reviewed / Open Access
  • [Journal Article] Stearylated Macropinocytosis-Inducing Peptides Facilitating the Cellular Uptake of Small Extracellular Vesicles2022

    • Author(s)
      Yuna Nakagawa, Jan Vincent V Arafiles, Yoshimasa Kawaguchi, Ikuhiko Nakase, Hisaaki Hirose, Shiroh Futaki
    • Journal Title

      Bioconjugate Chemistry

      Volume: - Issue: 5 Pages: 869-880

    • DOI

      10.1021/acs.bioconjchem.2c00113

    • Related Report
      Products Report
    • Peer Reviewed
  • [Journal Article] Potentiating the membrane interaction of an attenuated cationic amphiphilic lytic peptide for intracellular protein delivery by anchoring with pyrene moiety2021

    • Author(s)
      Kentarou Sakamoto, Junya Michibata, Yusuke Hirai, Akiko Ide, Asuka Ikitoh, Tomoka Takatani-Nakase and Shiroh Futaki
    • Journal Title

      Bioconjugate Chemistry

      Volume: - Issue: 5 Pages: 950-957

    • DOI

      10.1021/acs.bioconjchem.1c00101

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Use of homoarginine to obtain attenuated cationic membrane lytic peptides2021

    • Author(s)
      Sakamoto Kentarou、Akishiba Misao、Iwata Takahiro、Arafiles Jan Vincent V.、Imanishi Miki、Futaki Shiroh
    • Journal Title

      Bioorganic & Medicinal Chemistry Letters

      Volume: 40 Pages: 127925-127925

    • DOI

      10.1016/j.bmcl.2021.127925

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Discovery of a Macropinocytosis‐Inducing Peptide Potentiated by Medium‐Mediated Intramolecular Disulfide Formation2021

    • Author(s)
      Jan Vincent V. Arafiles, Hisaaki Hirose, Yusuke Hirai, Masashi Kuriyama, Maxwell M. Sakyiamah, Wataru Nomura, Kazuhiro Sonomura, Miki Imanishi, Akira Otaka, Hirokazu Tamamura, Shiroh Futaki
    • Journal Title

      Angewandte Chemie, International Edition

      Volume: 60 Issue: 21 Pages: 2-11

    • DOI

      10.1002/anie.202016754

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Protein Delivery to Cytosol by Cell-Penetrating Peptide Bearing Tandem Repeat Penetration-Accelerating Sequence2021

    • Author(s)
      Okuda Akiko、Futaki Shiroh
    • Journal Title

      Nethods in Molecular Biology

      Volume: 2383 Pages: 265-273

    • DOI

      10.1007/978-1-0716-1752-6_18

    • ISBN
      9781071617519, 9781071617526
    • Related Report
      Products Report
    • Peer Reviewed
  • [Journal Article] Design and Creation of Functional Membrane-Interacting Peptides2020

    • Author(s)
      Futaki Shiroh
    • Journal Title

      Journal of Synthetic Organic Chemistry, Japan

      Volume: 78 Issue: 11 Pages: 1058-1065

    • DOI

      10.5059/yukigoseikyokaishi.78.1058

    • NAID

      130007937276

    • ISSN
      0037-9980, 1883-6526
    • Year and Date
      2020-11-01
    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Optimizing Charge Switching in Membrane Lytic Peptides for Endosomal Release of Biomacromolecules2020

    • Author(s)
      Sakamoto Kentarou、Akishiba Misao、Iwata Takahiro、Murata Kazuya、Mizuno Seiya、Kawano Kenichi、Imanishi Miki、Sugiyama Fumihiro、Futaki Shiroh
    • Journal Title

      Angewandte Chemie International Edition

      Volume: 59 Issue: 45 Pages: 19990-19998

    • DOI

      10.1002/anie.202005887

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Improved cytosolic delivery of macromolecules through dimerization of attenuated lytic peptides2020

    • Author(s)
      Nomura Yohei、Sakamoto Kentarou、Akishiba Misao、Iwata Takahiro、Hirose Hisaaki、Futaki Shiroh
    • Journal Title

      Bioorganic & Medicinal Chemistry Letters

      Volume: 30 Issue: 17 Pages: 127362-127362

    • DOI

      10.1016/j.bmcl.2020.127362

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Rational Design Principles of Attenuated Cationic Lytic Peptides for Intracellular Delivery of Biomacromolecules2020

    • Author(s)
      Tamemoto Naoki、Akishiba Misao、Sakamoto Kentarou、Kawano Kenichi、Noguchi Hiroshi、Futaki Shiroh
    • Journal Title

      Molecular Pharmaceutics

      Volume: 17 Issue: 6 Pages: 2175-2185

    • DOI

      10.1021/acs.molpharmaceut.0c00312

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Stimulating Macropinocytosis for Intracellular Nucleic Acid and Protein Delivery: A Combined Strategy with Membrane-Lytic Peptides To Facilitate Endosomal Escape2020

    • Author(s)
      Arafiles Jan Vincent V.、Hirose Hisaaki、Akishiba Misao、Tsuji Shogo、Imanishi Miki、Futaki Shiroh
    • Journal Title

      Bioconjugate Chemistry

      Volume: 31 Issue: 3 Pages: 547-553

    • DOI

      10.1021/acs.bioconjchem.0c00064

    • Related Report
      2020 Annual Research Report 2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Conversion of cationic amphiphilic lytic peptides to cell‐penetration peptides2020

    • Author(s)
      Yu Hao‐Hsin、Sakamoto Kentarou、Akishiba Misao、Tamemoto Naoki、Hirose Hisaaki、Nakase Ikuhiko、Imanishi Miki、Madani Fatemeh、Graslund Astrid、Futaki Shiroh
    • Journal Title

      Peptide Science

      Volume: 112 Issue: 1 Pages: 1-12

    • DOI

      10.1002/pep2.24144

    • Related Report
      2020 Annual Research Report 2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Peptide-assisted Intracellular Delivery of Biomacromolecules2020

    • Author(s)
      Futaki Shiroh、Arafiles Jan Vincent V.、Hirose Hisaaki
    • Journal Title

      Chemistry Letters

      Volume: 49 Issue: 9 Pages: 1088-1094

    • DOI

      10.1246/cl.200392

    • NAID

      130007897056

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Inducible Membrane Permeabilization by Attenuated Lytic Peptides: A New Concept for Accessing Cell Iinteriors through Ruffled Membranes2019

    • Author(s)
      Misao Akishiba, Shiroh Futaki
    • Journal Title

      Mol. Pharm.

      Volume: 16 Issue: 6 Pages: 2540-2548

    • DOI

      10.1021/acs.molpharmaceut.9b00156

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Modular Redesign of a Cationic Lytic Peptide to Promote the Endosomal Escape of Biomacromolecules2018

    • Author(s)
      Yusuke Azuma, Haruka Imai, Yoshimasa Kawaguchi, Ikuhiko Nakase, Hiroshi Kimura, Shiroh Futaki
    • Journal Title

      Angew. Chem. Int. Ed. Eng.

      Volume: 57 Issue: 39 Pages: 12771-12774

    • DOI

      10.1002/anie.201807534

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Presentation] Cytosolic Delivery of Biomacromolecules2021

    • Author(s)
      Shiroh Futaki
    • Organizer
      18th Akabori Conference
    • Related Report
      2020 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] 抗体・機能性タンパク質の細胞内送達に向けて2021

    • Author(s)
      二木史朗
    • Organizer
      (一財)バイオインダストリー協会 創薬モダリティ基盤研究会
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] Attenuated cationic lytic peptides for intracellular delivery2020

    • Author(s)
      Shiroh Futaki
    • Organizer
      CRS 2020 Annual Meeting & Exposition
    • Related Report
      2020 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] ペプチド・タンパク質の細胞内送達2020

    • Author(s)
      二木史朗
    • Organizer
      有機合成化学協会「ニューモダリティと有機合成化学」研究部会第3回勉強会
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] 生体膜を標的とする機能性ペプチドと細胞応答2020

    • Author(s)
      二木史朗
    • Organizer
      FBC特別シンポジウム2020
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] 抗体・機能性タンパク質の細胞内送達に向けて2020

    • Author(s)
      二木史朗
    • Organizer
      理研 星薬科大学 東北大学大学院薬学研究科シンポジウム
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] 生体膜を標的とする機能性ペプチド:分子設計と作用機序2020

    • Author(s)
      二木史朗
    • Organizer
      日本薬学会第140年会
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] Redesigning Cationic Lytic Peptides to Promote the Delivery of Biomacromolecules into Cell Interiors2019

    • Author(s)
      Shiroh Futaki
    • Organizer
      26th American Peptide Symposium/11th International Peptide Symposium
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Modulating Lipid Packing of Cell Membranes for the Access to Cell Interiors2019

    • Author(s)
      Shiroh Futaki
    • Organizer
      Chemistry and Biology of Peptides 2019
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Redesigning cationic lytic peptides to promote the delivery of biomacromolecules into cell interiors2019

    • Author(s)
      Shiroh Fuaki
    • Organizer
      ACS Fall 2019 National Meeting & Exposition
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Peptide-based approaches for delivering exogenous molecules into cells2019

    • Author(s)
      Shiroh Futaki
    • Organizer
      Hungarian Academy of Sciences
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Cytosolic Delivery of Biomacromolecules2019

    • Author(s)
      Shiroh Futaki
    • Organizer
      7th Indian Peptide Symposium
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] ペプチドを用いた生理活性分子の細胞内送達2018

    • Author(s)
      二木史朗
    • Organizer
      日本ケミカルバイオロジー学会第13回年会
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] Peptide-mediated Delivery of Biomacromolecules into Cells2018

    • Author(s)
      Shiroh Futaki
    • Organizer
      22th Korean Peptide Protein Society (KPPS) Symposium
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Cytosolic Delivery of Biomacromolecules2018

    • Author(s)
      Shiroh Futaki
    • Organizer
      15th Chinese International Peptide Symposium
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Peptide-mediated Delivery of Biomacromolecules into Cells2018

    • Author(s)
      Shiroh Futaki
    • Organizer
      Frontiers in Delivery of Therapeutics
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Peptide-mediated delivery of antibodies and bioactive proteins into cells2018

    • Author(s)
      Shiroh Futaki
    • Organizer
      2018 MDO/JSSX in Kanazawa (日本薬物動態学会第33回年会/MDO国際合同学会)
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Lipid-sensitive amphiphilic peptides for intracellular delivery of biomacromolecules2018

    • Author(s)
      Shiroh Futaki
    • Organizer
      8th Peptide Engineering Meeting (PEM8-2018)
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Lipid-sensitive amphiphilic peptides for intracellular delivery of biomacromolecules2018

    • Author(s)
      Shiroh Futaki
    • Organizer
      10th International Peptide Symposium/55th Japanese Peptide Symposium
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research / Invited
  • [Patent(Industrial Property Rights)] 細胞質送達ペプチド2022

    • Inventor(s)
      二木史朗、坂本健太郎、秋柴美沙穂
    • Industrial Property Rights Holder
      国立大学法人京都大学
    • Industrial Property Rights Type
      特許
    • Acquisition Date
      2022
    • Related Report
      Products Report
    • Overseas
  • [Patent(Industrial Property Rights)] 細胞質送達ペプチド2021

    • Inventor(s)
      二木史朗、坂本健太郎、秋柴美沙穂
    • Industrial Property Rights Holder
      国立大学法人京都大学
    • Acquisition Date
      2021
    • Related Report
      Products Report
  • [Patent(Industrial Property Rights)] 細胞質送達ペプチド2019

    • Inventor(s)
      二木史朗、ジャン・ヴィンセント・アラフィレス、秋柴美沙穂
    • Industrial Property Rights Holder
      国立大学法人京都大学
    • Industrial Property Rights Type
      特許
    • Industrial Property Number
      2019-139068
    • Filing Date
      2019
    • Related Report
      2019 Annual Research Report
  • [Patent(Industrial Property Rights)] 細胞質送達ペプチド2018

    • Inventor(s)
      二木史朗、坂本健太郎、秋柴美沙穂
    • Industrial Property Rights Holder
      二木史朗、坂本健太郎、秋柴美沙穂
    • Industrial Property Rights Type
      特許
    • Filing Date
      2018
    • Related Report
      2018 Annual Research Report
    • Overseas

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Published: 2018-04-23   Modified: 2023-03-30  

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