| 研究課題/領域番号 |
22KF0114
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| 補助金の研究課題番号 |
22F22334 (2022)
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| 研究種目 |
特別研究員奨励費
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| 配分区分 | 基金 (2023)
補助金 (2022) |
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| 応募区分 | 外国 |
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| 審査区分 |
小区分37010:生体関連化学
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| 研究機関 | 東京大学 |
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研究代表者 |
菅 裕明 東京大学, 大学院理学系研究科(理学部), 教授 (00361668)
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| 研究分担者 |
ZHANG YUE 東京大学, 大学院理学系研究科(理学部), 外国人特別研究員
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| 研究期間 (年度) |
2023-03-08 – 2025-03-31
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| 研究課題ステータス |
交付 (2023年度)
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| 配分額 *注記 |
2,200千円 (直接経費: 2,200千円)
2024年度: 500千円 (直接経費: 500千円)
2023年度: 1,100千円 (直接経費: 1,100千円)
2022年度: 600千円 (直接経費: 600千円)
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| キーワード | RaPID / peptide cyclization / OPA / mRNA display |
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| 研究開始時の研究の概要 |
We aim to develop OPA-based cyclic peptide libraries using the FIT system. These libraries will selectively release the free reactive moiety after the translation step for peptide cyclization or PTMs, which will be further applied in the RaPID system to identify potential drug molecules. Additionally, we plan to explore a chemoselective peptide cyclization method for post-translational modifications. Through this, we aim to contribute to the development of chemical biology studies and drug discovery efforts, aimed at identifying peptide candidates against various disease-related proteins.
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| 研究実績の概要 |
We successfully established an mRNA display-based in vitro bicyclic peptide construction platform using a flexible in vitro translation (FIT) system with novel o-phthalaldehyde amino acids that can toggle reactivity on and off during the translation process. This strategy has been demonstrated on the construction of over 20 different nonstandard peptides with various lengths and sequences in vitro, facilitating the rapid assembly of a bicyclic nonstandard peptide library with up to 10^12 unique peptide sequences.
Additionally, the applicant developed an optimized thiopeptide drug discovery platform that predominantly incorporates non-proteinogenic structural elements. This platform successfully produced natural product-like drug candidates that target the Traf2- and NCK-interacting kinase (TNIK); a protein implicated in several forms of cancer. These candidates not only demonstrate high affinity and inhibitory activity (best KD = 2.1 nM, best IC50 = 0.15 μM) but also significant metabolic stability human serum (half-life of up to 99 hours).
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| 現在までの達成度 (区分) |
現在までの達成度 (区分)
2: おおむね順調に進展している
理由
We are currently evaluating the cyclization limits of our strategy by analyzing various model peptide RNA sequences to determine the optimal cyclization sites and nearby amino acid combinations. Subsequently, we are applying this novel strategy to construct nonstandard peptide libraries, characterized by densely functionalized structures reminiscent of natural products. We will assemble and screen a large combinatorial library of bicyclic peptides against TNIK protein, and thymic stromal lymphopoietin (TSLP), which plays a crucial role in the pathogenesis of immediate-type allergy. Our goal is to identify a series of compounds that act as potent and selective inhibitors. Currently, we are focused on the novel library design and are nearing completion of the library assembly. We will commence the new phase of bicyclic nonstandard peptide drug discovery targeting these two proteins within few months.
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| 今後の研究の推進方策 |
1.Evaluation of Cyclization Limits: We will assess the cyclization efficiency of our established OPA-based in vitro bicyclic peptide construction strategy, which utilizes the flexible in vitro translation (FIT) system to synthesize OPA-based novel non-proteinogenic amino acid-containing peptides. These peptides spontaneously cyclize with internal cysteine and lysine residues to form stable bicyclic structures. Our goal is to determine the optimal cyclization sites for both cysteine and lysine residues across different peptide sequences and structures.
2.Construction of a Bicyclic Nonstandard Peptide Library: Utilizing the optimized OPA-based in vitro method, we aim to construct various libraries that feature complex, densely functionalized structures reminiscent of natural products. This approach enables the establishment of large numbers of nonstandard peptides (>10^12 unique compounds) for early-stage peptide drug discovery.
3.Affinity Selection Against Disease-Related Protein Targets: Leveraging the established OPA-based bicyclic peptide library in combination with the random nonstandard peptide integrated discovery (RaPID) system, our focus is on rapid early-stage drug discovery targeting both cancer and allergy-related proteins, specifically TNIK and TSLP proteins. These targets are crucial in the pathogenesis of various cancers and immediate-type allergies, respectively.
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