Development of bioactive peptides based on molecular design with conformational restriction
| Project/Area Number |
19K06965
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Review Section |
Basic Section 47010:Pharmaceutical chemistry and drug development sciences-related
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| Research Institution | Hokkaido University |
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Principal Investigator |
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| Project Period (FY) |
2019-04-01 – 2023-03-31
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| Project Status |
Completed (Fiscal Year 2022)
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| Budget Amount *help |
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2021: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
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| Keywords | ペプチド / フォルダマー / 三次元構造制御 / ヘリックス / 環状ペプチド / 配座制御 / 三次元構造 / 膜透過性 / ペプチドミメティクス |
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| Outline of Research at the Start |
本研究の最終目標は、細胞の中にある、疾病に関わるタンパク質同士の相互作用を制御可能な、新たなペプチド創薬方法論を確立することである。一般的に鎖状ペプチド分子は、構造的な自由度が高く、代謝安定性や膜透過性などに問題があることから、そのまま医薬ツール分子として用いることは難しい。そこで本研究では、ペプチド分子の主鎖骨格の形（＝三次元構造）を制御することによって、代謝安定性・膜透過性を備えた機能性ペプチド分子を創製する。
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| Outline of Final Research Achievements |
In this study, I aimed to establish a new methodology for bioactive peptide drugs that can target intracellular protein-protein interactions, and I worked on developing functionalized peptides by controlling the three-dimensional structure of the entire molecule. Specifically, I designed peptide foldamers that mimic the spatial arrangement of side-chain functional groups on the α-helix, which is essential for protein-protein interactions. Also, I developed cyclic peptides with high cell membrane permeability by using chiral cyclopropanes with highly controlled conformation as the key unit. As a result, I developed δ-peptide foldamers with an identical 14-helical structure in solution and crystals.
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| Academic Significance and Societal Importance of the Research Achievements |
ペプチドは新しい創薬モダリティとして注目されている。そのため、タンパク質間相互作用の制御を狙ったペプチドミメティクスの開発研究は盛んになされている。一方で、細胞内の相互作用を標的とした普遍的な方法論といえるものは未だにない。本研究は、細胞内タンパク質間相互作用に適用可能な一般性の高い新規ペプチドミメティクス開発方法論を提示・実践するものである。本研究の成果は、タンパク質間相互作用を標的としたペプチドミメティクス創薬の新たな基盤となりうる。
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Report
(5 results)
Research Products
(58 results)
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[Journal Article] Oxytocin Dynamics in the Body and Brain Regulated by the Receptor for Advanced Glycation End-Products, CD38, CD157, and Nicotinamide Riboside2022
Author(s)
H. Higashida, K. Furuhara, O. Lopatina, M. Gerasimenko, O. Hori, T. Hattori, Y. Hayashi, S. M. Cherepanov, A. A. Shabalova, A. B. Salmina, K. Minami, T. Yuhi, C. Tsuji, P. Y. Fu, Z. Liu, S. Luo, A. Zhang, S. Yokoyama, S. Shuto, M. Watanabe, K. Fujiwara, S. Munesue, A. Harashima, Y. Yamamoto
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Journal Title
Frontiers in Neuroscience
Volume: 16
Pages: 858070-858070
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Design and Synthesis of Cyclopropane Congeners of Resolvin E3, an Endogenous Pro-Resolving Lipid Mediator, as Its Stable Equivalents.2022
Author(s)
(2)Arai S, Fujiwara K, Kojima M, Aoki-Saito H, Yatomi M, Saito T, Koga Y, Fukuda H, Watanabe M, Matsunaga S, Hisada T, Shuto S
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Journal Title
The Journal of Organic Chemistry
Volume: 87(15)
Issue: 15
Pages: 10501-10508
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Delivering mRNA to Secondary Lymphoid Tissues by Phosphatidylserine‐Loaded Lipid Nanoparticles2022
Author(s)
Masaki Gomi, Yu Sakurai, Minami Sato, Hiroki Tanaka, Yumi Miyatake, Koichi Fujiwara, Mizuki Watanabe, Satoshi Shuto, Yuta Nakai, Kota Tange, Hiroto Hatakeyama, Hidetaka Akita
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Journal Title
Advanced Healthcare Materials
Volume: 12
Issue: 9
Pages: 2202528-2202528
DOI
Related Report
Peer Reviewed
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[Journal Article] Molecular Determinants and Pharmacological Analysis for a Class of Competitive Non-transported Bicyclic Inhibitors of the Betaine/GABA Transporter BGT12021
Author(s)
Petrine Wellendorph, Stefanie Kickinger, Maria EK Lie, Akihiro Suemasa, Anas Al-Khawaja, Koichi Fujiwara, Mizuki Watanabe, Kristine S Wilhelmsen, Christina B Falk-Petersen, Bente Frolund, Satoshi Shuto, Gerhard Franz Ecker
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Journal Title
Frontiers in Chemistry
Volume: 9
Pages: 736457-736457
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Development of a Highly Potent Analogue and a Long-Acting Analogue of Oxytocin for the Treatment of Social Impairment-Like Behaviors2019
Author(s)
Ichinose W, Cherepanov SM, Shabalova AA, Yokoyama S, Yuhi T, Yamaguchi H, Watanabe A, Yamamoto Y, Okamoto H, Horike S, Terakawa J, Daikoku T, Watanabe M, Mano N, Higashida H, Shuto S
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Journal Title
J Med Chem
Volume: -
Issue: 7
Pages: 3297-3310
DOI
Related Report
Peer Reviewed / Int'l Joint Research
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