Nishimura, Takehiro

写真a

Affiliation

Faculty of Pharmacy, Department of Pharmacy Division of Natural Medicines ( Shiba-Kyoritsu )

Position

Research Associate/Assistant Professor/Instructor

Related Websites

Contact Address

1-5-30 Shibakoen, Minato-ku, Tokyo

External Links

Career 【 Display / hide 】

  • 2019.04
    -
    2022.03

    Next generation Natural Product Chemistry, Research & Development Dept., Senior Researcher

  • 2022.04
    -
    2022.06

    Keio Uninversity, Faculty of Pharmacy, 特任助教

  • 2022.07
    -
    Present

    Keio Uninversity, Faculty of Pharmacy, 助教

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Academic Background 【 Display / hide 】

  • 2010.04
    -
    2014.03

    Tohoku University, 薬学部, 創薬科学科

    University, Graduated

  • 2014.04
    -
    2016.03

    Tohoku University, 薬学研究科

    Graduate School, Completed, Master's course

  • 2016.04
    -
    2019.03

    Tohoku University, 薬学研究科

    Graduate School, Completed, Doctoral course

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Academic Degrees 【 Display / hide 】

  • 博士(薬科学）, Tohoku University, Coursework, 2019.03

    中員環天然化合物の構造を基盤としたアルカロイド型化合物ライブラリーの構築

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Research Areas 【 Display / hide 】

  • Life Science / Pharmaceutical chemistry and drug development sciences (Natural Product Chemistry, Medicinal Chemistry, Organic Chemistry)

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Papers 【 Display / hide 】

  • Ester derivatives of Dictyostelium differentiation-inducing factors exhibit antibacterial activity, possibly via a prodrug-like function

    Takahashi K., Kikuchi H., Nishimura T., Ishigaki H., Miura Y., Takahashi A., Kubohara Y.

    BMC Research Notes 18 ( 1 ) 40 2025.12

    　View Summary

    Objective: Dictyostelium differentiation-inducing factors 1 and 3 [DIF-1 (1) and DIF-3 (2), respectively], along with their derivatives, such as Ph-DIF-1 (3) and Bu-DIF-3 (4), demonstrate antibacterial activity in vitro against Gram-positive bacteria, including methicillin-sensitive Staphylococcus aureus (MSSA), methicillin-resistant S. aureus (MRSA), vancomycin-sensitive Enterococcus faecalis (VSE), and vancomycin-resistant Enterococcus faecium [VRE (VanA)]. This study investigates the therapeutic potential of DIF compounds against these Gram-positive bacteria. Results: In vitro tests revealed that the antibacterial activity of 3 and 4 was lost in the presence of human serum albumin (HSA), suggesting that HSA might inhibit their effectiveness. Further evaluation of less hydrophobic derivatives, DIF-1-NH2 (5) and NH2-Bu-DIF-3 (6), showed no antibacterial activity, even in the absence of HSA. However, ester derivatives Ph-DIF-1(AHA) (7) and Bu-DIF-3(2Ac) (8) exhibited antibacterial activity against the target bacteria in vitro, although this activity was also lost in the presence of HSA. We hypothesize that these ester derivatives may function as prodrugs, with their antibacterial activity possibly restored by hydrolysis through bacterial esterases. The results suggest that suitable ester modifications could enhance the in vivo antibacterial potential of DIF compounds, particularly if they can bypass HSA binding and be activated by bacterial enzymes.

  • JBIR-160–166 Obtained from the Heterologous Expression of a Cryptic Gene Cluster in Kitasatospora setae

    Takehiro Nishimura, Kei Kudo, Miho Izumikawa, Ikuko Kozone, Junko Hashimoto, Keita Amagai, Noritaka Kagaya, Yusuke Ogura, Hikaru Suenaga, Hirosato Takikawa, Shunji Takahashi, Haruo Ikeda, Kazuo Shin-ya

    Organic Letters (American Chemical Society)  27 ( 48 ) 13175 - 13180 2025.11

    Research paper (scientific journal), Joint Work, Lead author, Accepted

  • Analysis of compound–compound interactions between berberine and baicalin derivatives

    Takehiro Nishimura, Chihiro Iida, Haruhisa Kikuchi

    Journal of Natural Medicines ( the Springer Nature)   2025.11

    Research paper (scientific journal), Joint Work, Accepted

  • A new cannabigerolic acid derivative and its unprenylated precursor produced through the reconstitution of cannabinoid biosynthesis in Streptomyces

    Kei Kudo, Takehiro Nishimura, Kei Miyako, Hikaru Suenaga, Kazuo Shin-ya

    The Journal of Antibiotics (Nature Publishing Group)  78 ( 2 ) 126 - 130 2024.12

    Research paper (scientific journal), Joint Work, Accepted,  ISSN  00218820

    　View Summary

    A new derivative of cannabigerolic acid, designated as iso-cannabigerolic acid (iso-CBGA), a member of the cannabinoid family, and its precursor iso-olivetolic acid (iso-OA) were discovered from the culture of the engineered Streptomyces avermitilis heterologously expressing the genes responsible for cannabigerolic acid biosynthesis. Structural determination revealed an iso-pentyl moiety, which may arise from the biosynthetic precursor pool present in S. avermitilis. We describe herein the culture, isolation, structure determination and antibacterial activities of iso-CBGA and iso-OA.

  • Compound–compound interaction analysis of baicalin and berberine derivatives in aqueous solution

    Uekusa Y., Tanioka C., Nakamoto K., Tsutsumi R., Iida C., Enshu N., Nishimura T., Kiuchi F., Kikuchi H.

    Journal of Natural Medicines 78 ( 3 ) 590 - 598 2024.06

    ISSN  13403443

    　View Summary

    Baicalin and berberine are biologically active constituents of the crude drugs Scutellaria root and Coptis rhizome/Phellodendron bark, respectively. Baicalin and berberine are reported to combine together as a 1:1 complex that forms yellow precipitates by electrostatic interaction in decoctions of Kampo formulae containing these crude drugs. However, the structural basis and mechanism for the precipitate formation of this compound–compound interaction in aqueous solution remains unclarified. Herein, we searched for berberine derivatives in the Coptis rhizome that interact with baicalin and identified the chemical structures involved in the precipitation formation. Precipitation assays showed that baicalin formed precipitates with berberine and coptisine but not with palmatine and epiberberine. Thus, the 2,3-methylenedioxy structure may be crucial to the formation of the precipitates, and electrostatic interaction is necessary but is not sufficient. In this multicomponent system experiment, palmatine formed a dissociable complex with baicalin and may competitively inhibit the formation of berberine and coptisine precipitation with baicalin. Therefore, the precipitation formed by berberine and baicalin was considered to be caused by the aggregation of the berberine–baicalin complex, and the 2,3-methylenedioxy structure is likely crucial to the aggregation of the complex. Graphic abstract: (Figure presented.)

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Papers, etc., Registered in KOARA 【 Display / hide 】

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Reviews, Commentaries, etc. 【 Display / hide 】

  • Ester derivatives of Dictyostelium differentiation-inducing factors exhibit antibacterial activity, possibly via a prodrug-like function

    Katsunori Takahashi, Haruhisa Kikuchi, Takehiro Nishimura, Hirotaka Ishigaki, Yusuke Miura, Ayuko Takahashi, Yuzuru Kubohara

    BMC Research Notes 18 ( 1 ) 40 2025.01

    ISSN  1756-0500

    　View Summary

    Objective: Dictyostelium differentiation-inducing factors 1 and 3 [DIF-1 (1) and DIF-3 (2), respectively], along with their derivatives, such as Ph-DIF-1 (3) and Bu-DIF-3 (4), demonstrate antibacterial activity in vitro against Gram-positive bacteria, including methicillin-sensitive Staphylococcus aureus (MSSA), methicillin-resistant S. aureus (MRSA), vancomycin-sensitive Enterococcus faecalis (VSE), and vancomycin-resistant Enterococcus faecium [VRE (VanA)]. This study investigates the therapeutic potential of DIF compounds against these Gram-positive bacteria. Results: In vitro tests revealed that the antibacterial activity of 3 and 4 was lost in the presence of human serum albumin (HSA), suggesting that HSA might inhibit their effectiveness. Further evaluation of less hydrophobic derivatives, DIF-1-NH<inf>2</inf> (5) and NH<inf>2</inf>-Bu-DIF-3 (6), showed no antibacterial activity, even in the absence of HSA. However, ester derivatives Ph-DIF-1(AHA) (7) and Bu-DIF-3(2Ac) (8) exhibited antibacterial activity against the target bacteria in vitro, although this activity was also lost in the presence of HSA. We hypothesize that these ester derivatives may function as prodrugs, with their antibacterial activity possibly restored by hydrolysis through bacterial esterases. The results suggest that suitable ester modifications could enhance the in vivo antibacterial potential of DIF compounds, particularly if they can bypass HSA binding and be activated by bacterial enzymes.

  • A new cannabigerolic acid derivative and its unprenylated precursor produced through the reconstitution of cannabinoid biosynthesis in Streptomyces.

    Kei Kudo, Takehiro Nishimura, Kei Miyako, Hikaru Suenaga, Kazuo Shin-Ya

    The Journal of antibiotics 78 ( 2 ) 126 - 130 2025.01

    ISSN  0021-8820

    　View Summary

    A new derivative of cannabigerolic acid, designated as iso-cannabigerolic acid (iso-CBGA), a member of the cannabinoid family, and its precursor iso-olivetolic acid (iso-OA) were discovered from the culture of the engineered Streptomyces avermitilis heterologously expressing the genes responsible for cannabigerolic acid biosynthesis. Structural determination revealed an iso-pentyl moiety, which may arise from the biosynthetic precursor pool present in S. avermitilis. We describe herein the culture, isolation, structure determination and antibacterial activities of iso-CBGA and iso-OA.

  • 設計図を書き換えて難培養微生物由来化合物の生産が可能に!

    西村 壮央

    ファルマシア (公益社団法人日本薬学会)  60 ( 10 ) 966 - 966 2024.10

    Article, review, commentary, editorial, etc. (scientific journal), Single Work, Lead author,  ISSN  0014-8601

    　View Summary

    植物から得られた生物活性分子のなかには，植物に共生する微生物が真の生産者である場合がある．このような微生物の多くは，特定の共生環境でのみ生育が可能で，一般的な実験室環境下では培養が困難であり，工業生産などへの応用が難しい．Kudoらは，in vitro Cas9反応とバクテリア人工染色体(bacterial artificial chromosome: BAC)上でのギブソンアセンブリーを応用し，相同性が高い配列が繰り返されるI型モジュール型ポリケチド合成酵素遺伝子の標的領域を制約なく編集できる革新的な技術「in vitroモジュール編集」を報告している．本技術を用いて天然物の設計図とも言える生合成遺伝子を編集し，異種発現ホストに発酵生産させることができれば，自由にデザインされた化合物の生産が可能になると期待できる．本稿では，培養困難な微生物由来化合物生産における課題の解決策の1つとして，in vitroモジュール編集を活用したFR900359の生産に関する文献を紹介する．

  • Synthesis of a Library of Terpenoid Alkaloid-like Compounds Containing Medium-sized Rings via Reconstruction of the Humulene Skeleton.

    Takehiro Nishimura, Kosuke Shiga, Mizuki Sekiya, Akihiro Sugawara, Takayuki Yonezawa, Haruhisa Kikuchi

    Chemistry (Weinheim an der Bergstrasse, Germany) 30 ( 48 ) e202402082 2024.08

    ISSN  09476539

    　View Summary

    The construction of a chemical library based on natural products is a promising method for the synthesis of natural product-like compounds. In this study, we synthesized a terpenoid alkaloid-like compound library based on the humulene skeleton. Our strategy, which enables access to diverse ring systems such as 11-membered monocyclic, oxabicyclic, and medium-sized aza ring-containing scaffolds, involves the introduction of a nitrogen atom, an intermolecular C-O bond formation via Lewis acid-mediated epoxide-opening transannulation, and a ring-reconstruction strategy based on olefin metathesis. A cheminformatics analysis based on their structural and physicochemical properties revealed that the synthesized compounds have high three-dimensionality and high natural product likeness scores but with structural novelty. The usefulness of the terpenoid alkaloid-like compound library for drug discovery and the accessibility to structure-activity relationship studies were validated by performing an assay for osteoclast-specific tartrate-resistant acid phosphatase activity, resulting in the identification of a lead compound for bone-resorptive diseases such as osteoporosis.

  • Compound–compound interaction analysis of baicalin and berberine derivatives in aqueous solution

    Yoshinori Uekusa, Chiharu Tanioka, Kenjiro Nakamoto, Riina Tsutsumi, Chihiro Iida, Naoto Enshu, Takehiro Nishimura, Fumiyuki Kiuchi, Haruhisa Kikuchi

    Journal of Natural Medicines (Springer Science and Business Media LLC)  78 ( 3 ) 590 - 598 2024.06

    ISSN  1340-3443

    　View Summary

    Baicalin and berberine are biologically active constituents of the crude drugs Scutellaria root and Coptis rhizome/Phellodendron bark, respectively. Baicalin and berberine are reported to combine together as a 1:1 complex that forms yellow precipitates by electrostatic interaction in decoctions of Kampo formulae containing these crude drugs. However, the structural basis and mechanism for the precipitate formation of this compound–compound interaction in aqueous solution remains unclarified. Herein, we searched for berberine derivatives in the Coptis rhizome that interact with baicalin and identified the chemical structures involved in the precipitation formation. Precipitation assays showed that baicalin formed precipitates with berberine and coptisine but not with palmatine and epiberberine. Thus, the 2,3-methylenedioxy structure may be crucial to the formation of the precipitates, and electrostatic interaction is necessary but is not sufficient. In this multicomponent system experiment, palmatine formed a dissociable complex with baicalin and may competitively inhibit the formation of berberine and coptisine precipitation with baicalin. Therefore, the precipitation formed by berberine and baicalin was considered to be caused by the aggregation of the berberine–baicalin complex, and the 2,3-methylenedioxy structure is likely crucial to the aggregation of the complex. Graphic abstract: (Figure presented.)

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Presentations 【 Display / hide 】

  • Construction of Middle-Molecule Chemical Library Based on the Ring-Reconsturuction Strategy of Cyclic Natural Products

    Takehiro Nishimura, Kosuke Shiga, Yuki Sato, Fumiaki Kobayashi, Haruhisa Kikuchi

    [International presentation]  Pacifichem2025, 

    2025.12
    , 

    Poster presentation

  • 多様性拡大抽出物を用いた非天然型モノテルペンインドールアルカロイドライブラリーの創出

    西村壮央, 鈴木佳英, 一戸佳祐, 菊地晴久

    [Domestic presentation]  第42回メディシナルケミストリーシンポジウム, 

    2025.11
    , 

    Poster presentation

  • 4連続不⻫中⼼を有するシクロペンタン—β-ラクトン含有天然化合物 JBIR-155 の合成研究

    吉田慶季, 西村壮央, 菊地晴久

    [Domestic presentation]  第51回反応と合成の進歩シンポジウム, 

    2025.11
    , 

    Poster presentation

  • 細胞性粘菌を用いた天然物化学研究

    西村　壮央, 菊地　晴久

    [Domestic presentation]  日本細胞性粘菌学会第15回例会, 

    2025.10
    , 

    Oral presentation (general)

  • エルサルバドル産植物を用いた抗トリパノソーマ活性を有する天然物の探索

    山内雄斗, 西村壮央, Marvin J. Núñez, 嶋田淳子, 菊地晴久

    [Domestic presentation]  第25回天然薬物の開発と応用シンポジウム, 

    2025.10
    , 

    Poster presentation

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Research Projects of Competitive Funds, etc. 【 Display / hide 】

  • 構造新規性と機能性を両立した中分子化合物群の創出

    2026.04
    -
    2027.03

    公益財団法人　上原記念生命科学財団, 研究奨励金, Principal investigator

  • 2023年度　武田科学振興財団　薬学系研究助成

    2023.08
    -
    2028.03

    武田科学振興財団, 薬学系研究助成, Research grant, Principal investigator

  • 伸長型テルペノイド-ポリケチドハイブリッド型中分子化合物の創出

    2023.04
    -
    2026.03

    日本学術振興会, Grants-in-Aid for Scientific Research, Grant-in-Aid for Early-Career Scientists, Principal investigator

    　View Summary

    既存の中分子化合物とは異なるケミカルスペースを有する化合物ライブラリーの構築は、医薬品シーズ探索に重要である。
    本研究では、天然ポリケチドの分解反応により多様なユニットを得た後に、これらを環状ジテルペンへの組み込みと環構造の再構築により新奇性の高い化合物群を創出する。
    得られた化合物を生物活性試験などにより評価し、天然化合物を基盤とした新たな中分子化合物ライブラリー構築の方法論を確立する。
    本研究課題では、天然物の構造を基盤として「伸長型テルペンーポリケチドハイブリッド化合物」の構築を目指した。「伸長型テルペンーポリケチドハイブリッド化合物」とは申請者が定義する言葉で、植物が産生する化合物に多く見られるテルペン、微生物が産生する構造に見られるポリケチドの両化合物の特徴を有する化合物のことである。このような化合物を植物や微生物から大量供給可能な天然物を用いて、適切な化学反応に供することで、複雑な化学構造と多様な官
    能基を持つ化合物の構築を行う。これにより、未踏のケミカルスペースを持つ化合物群が得られると期待できる。
    本年度は、適切な天然物の探索と誘導体化について検討を行い、植物由来成分としてアビエチン酸およびカンファー酸を選択した。アビエチン酸およびカンファー酸の構造を基盤とし、ポリケチドとのハイブリッド構造の構築に向け、まずはペプチドとの縮合および大環状化の検討を行うことで本研究計画の実現可能性を検討した。
    上記の検討の結果、既存のペプチドとは異なる構造的特徴を有する化合物ライブラリーの構築を行った。本研究により構築される化合物ライブラリーは、既存の医薬品や天然物、ペプチドライブラリーとは一線を画していると期待できる。このことは、得られる構造を基に作成したバーチャルライブラリーを用いた予備的なケモインフォマティクス解析により、明らかにされている。今後、実際の化合物を供給し、広い生物活性を指標にスクリーニングを行うことで、有用なリード化合物の発見につながると期待できる。
    本年度は、植物由来化合物であるアビエチン酸、カンファー酸を基盤とし、「伸長型テルペンーポリケチドハイブリッド化合物」の部分構造となる化合物を得た。これらのビルディングブロックは、それぞれ異なる分子構造を有していることから既存の合成試薬とは異なる三次元構造を有する化合物群の創出につながると期待できる。
    さらに、予備的な検討として、微生物から供給される、ブレフェルジンA、エリスロマイシンについてもビルディング化の検討を行った。ブレフェルジンAについては、ヒドロキシをアミノ基へと置換することで、2種類のビルディングブロックを得た。エリスロマイシンについては、文献既知の方法に従い、2つの糖の除去について検討を行った。
    以上の検討結果より、本研究計画はおおむね順調に進展していると考えている。
    今後は、より多様な化合物の創出のため使用する天然物を増やしていく。これまでの検討には使用してこなかった構造的特徴を有する化合物を利用することで、ケミカルスペースの拡大が可能であると期待できる。例えば、微生物が産生するポリエーテル型化合物であるモネンシンや、植物が多く生産するフラボノイドなどを検討の候補とする予定である。
    また、得られた化合物については、順次生物活性試験に供することで、生物活性を指向した構造展開も行う予定である。実際に、中南米地域で蔓延しているシャーガス病の原因となる、トリパノソーマ原虫に対するアッセイ試験法を確立しており、このような評価方法を併せて検討していく。

  • Construction of Mid-Size Molecule Library based on the Natural Product Re-Construction Strategy

    2022.08
    -
    2024.03

    MEXT,JSPS, Grant-in-Aid for Scientific Research, Nishimura Takehiro, Grant-in-Aid for Research Activity Start-up, Principal investigator

    　View Summary

    New modalities such as mid-molecular drugs and antibody-drug conjugates are attracting attention, but there is a lack of compound libraries other than peptides as a screening source for mid-molecular compounds. The applicant will construct a library of mid-molecular compounds by subjecting natural products to degradation reactions to create building blocks with complex structures and large molecular weights, followed by reconstructing natural product-like structures using these building blocks. A new methodology will be established for creating structurally unique compounds that have the characteristics of natural products. The constructed compound library will be evaluated using cheminformatic analysis and various biological activities to demonstrate the usefulness of the compound library constructed by this methodology.

  • ホクト生物科学振興財団　研究助成

    2022.04
    -
    2023.03

    ホクト生物科学振興財団, 研究助成, Research grant, Principal investigator

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Courses Taught 【 Display / hide 】

  • STUDY OF MAJOR FIELD: (NATURAL MEDICINES)

    2025

  • SEMINAR: (NATURAL MEDICINES)

    2025

  • RESEARCH FOR BACHELOR'S THESIS 1

    2025

  • PHARMACOGNOSY LABORATORY COURSE

    2025

  • PHARMACOGNOSY 2

    2025

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Memberships in Academic Societies 【 Display / hide 】

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