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Toward overcoming drug resistance problem: Development of a novel system to evaluate inhibitor that interacts with protein backbone through hydrogen bonding

Research Project

Project/Area Number 19K15712
Research Category

Grant-in-Aid for Early-Career Scientists

Allocation TypeMulti-year Fund
Review Section Basic Section 37030:Chemical biology-related
Research InstitutionShizuoka University

Principal Investigator

Sato Kohei  静岡大学, 工学部, 助教 (30756705)

Project Period (FY) 2019-04-01 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
Budget Amount *help
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2021: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000)
Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2019: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Keywords難溶性ペプチド / タンパク質化学合成 / 水溶性タグ / HIV-1プロテアーゼ / ヒドラジド / ペプチド可溶化法 / ペプチドヒドラジド / 薬剤耐性 / 化学選択的反応
Outline of Research at the Start

タンパク質主鎖との水素結合を駆動力とする抗ウイルス薬は、耐性ウイルスにも薬効を示すとともに耐性株を生じにくい利点があるものの、水素結合を指標とする阻害剤評価系の開発は達成されていない。本評価系を実現するうえで、複数の同位体標識アミノ酸が導入されたタンパク質は有効なプローブとなり得るが、従来のタンパク質調製法では実現困難である。
そこで、研究代表者の合成技術を総動員して有効なタンパク質プローブを創製し、世界初となる阻害剤評価系へと応用する。

Outline of Final Research Achievements

In the field of treatment of viral infections, strategies for drug discovery are required to prevent the acquisition of drug resistance. Developing enzyme inhibitors that use hydrogen bonding with the protein backbones as a driving force is a practical approach to this problem. To establish an evaluation system of such types of inhibitors, a protein probe incorporating multiple isotopes labelling in a site-specific manner is essential, and the preparation of protein probes by chemical synthesis is required. In this study, we developed an efficient synthetic method for HIV-1 protease, one of the target enzymes of anti-HIV drugs.

Academic Significance and Societal Importance of the Research Achievements

特殊な修飾をもつタンパク質をつくる技術として、化学合成法が利用される。多くのタンパク質が化学的に合成されてきたが、原料や合成中間体が溶けない場合には合成を先に進めることが難しくなる。今回HIV-1プロテアーゼの化学合成を進める中で溶解性の問題に直面し、これを解決する新しい可溶化技術の開発に成功した。本技術は、HIV-1プロテアーゼに限らず溶解性が問題となる幅広いタンパク質合成に応用可能であり、これまで合成困難と考えられてきたタンパク質の化学合成を可能にする。

Report

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

    (47 results)

All 2022 2021 2020 2019 Other

All Journal Article (12 results) (of which Peer Reviewed: 11 results,  Open Access: 3 results) Presentation (32 results) (of which Int'l Joint Research: 10 results,  Invited: 1 results) Book (2 results) Remarks (1 results)

  • [Journal Article] Synthesis and Structural Characterization of β-Turn Mimics Containing (Z)-Chloroalkene Dipeptide Isosteres2022

    • Author(s)
      Kodama Yuki、Takeo Sayuri、Fujimoto Junko、Sato Kohei、Mase Nobuyuki、Narumi Tetsuo
    • Journal Title

      The Journal of Organic Chemistry

      Volume: 87 Issue: 5 Pages: 2167-2177

    • DOI

      10.1021/acs.joc.1c03115

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] β,γ-trans-selective γ-butyrolactone formation via homoenolate cross-annulation of enals and aldehydes catalyzed by sterically hindered N-heterocyclic carbene2021

    • Author(s)
      Kyan Ryuji、Kitagawa Yuya、Ide Ryuji、Sato Kohei、Mase Nobuyuki、Narumi Tetsuo
    • Journal Title

      Tetrahedron

      Volume: 91 Pages: 132191-132191

    • DOI

      10.1016/j.tet.2021.132191

    • NAID

      120007116803

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Stereoselective synthesis of highly functionalized (Z)-chloroalkene dipeptide isosteres containing an α,α-disubstituted amino acid2021

    • Author(s)
      Kodama Yuki、Imai Saki、Fujimoto Junko、Sato Kohei、Mase Nobuyuki、Narumi Tetsuo
    • Journal Title

      Chemical Communications

      Volume: 57 Issue: 56 Pages: 6915-6918

    • DOI

      10.1039/d1cc02952e

    • NAID

      120007116799

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Late-Stage Solubilization of Poorly Soluble Peptides Using Hydrazide Chemistry2021

    • Author(s)
      Sato Kohei、Tanaka Shoko、Wang Junzhen、Ishikawa Kenya、Tsuda Shugo、Narumi Tetsuo、Yoshiya Taku、Mase Nobuyuki
    • Journal Title

      Organic Letters

      Volume: 23 Issue: 5 Pages: 1653-1658

    • DOI

      10.1021/acs.orglett.1c00074

    • Related Report
      2020 Research-status Report
    • Peer Reviewed
  • [Journal Article] Pendant Alkoxy Groups on N‐Aryl Substitutions Drive the Efficiency of Imidazolylidene Catalysts for Homoenolate Annulation from Enal and Aldehyde2020

    • Author(s)
      Kyan Ryuji、Sato Kohei、Mase Nobuyuki、Narumi Tetsuo
    • Journal Title

      Angewandte Chemie International Edition

      Volume: 59 Issue: 43 Pages: 19031-19036

    • DOI

      10.1002/anie.202008631

    • NAID

      120006891194

    • Related Report
      2020 Research-status Report
    • Peer Reviewed
  • [Journal Article] Stereoselective synthesis of Gly-Gly-type (E)-methylalkene and (Z)-chloroalkene dipeptide isosteres and their application to 14-mer RGG peptidomimetics.2020

    • Author(s)
      Okita, H., Kato, Y., Masuzawa, T., Arai, K., Takeo, S., Sato, K., Mase, N., Oyoshi, T., Narumi, T.
    • Journal Title

      RSC Adv.

      Volume: 10 Issue: 49 Pages: 29373-29377

    • DOI

      10.1039/d0ra06554d

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Highly effective volatile organic compound dissolving strategy based on mist atomization for odorant biosensors2020

    • Author(s)
      Terutsuki Daigo、Mitsuno Hidefumi、Sato Kohei、Sakurai Takeshi、Mase Nobuyuki、Kanzaki Ryohei
    • Journal Title

      Analytica Chimica Acta

      Volume: 1139 Pages: 178-188

    • DOI

      10.1016/j.aca.2020.09.043

    • Related Report
      2020 Research-status Report
    • Peer Reviewed
  • [Journal Article] Fine-Bubble-Slug-Flow Hydrogenation of Multiple Bonds and Phenols2020

    • Author(s)
      Mase Nobuyuki、Iio Takuya、Nagai Kohei、Kozuka Tomoki、Sammi Akhtar Mst、Sato Kohei、Narumi Tetsuo
    • Journal Title

      Synlett

      Volume: 31 Issue: 19 Pages: 1919-1924

    • DOI

      10.1055/s-0040-1705948

    • NAID

      120006942488

    • Related Report
      2020 Research-status Report
    • Peer Reviewed
  • [Journal Article] Conversion of levoglucosan into glucose by the coordination of four enzymes through oxidation, elimination, hydration, and reduction2020

    • Author(s)
      Kuritani Yuya、Sato Kohei、Dohra Hideo、Umemura Seiichiro、Kitaoka Motomitsu、Fushinobu Shinya、Yoshida Nobuyuki
    • Journal Title

      Scientific Reports

      Volume: 10 Issue: 1 Pages: 20066-20066

    • DOI

      10.1038/s41598-020-77133-8

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Chemoselective Umpolung of Enals for Asymmetric Homoenolate Cross-Annulation of Enals and Aldehydes Catalyzed by N-Heterocyclic Carbene2019

    • Author(s)
      Ide Ryuji、Kyan Ryuji、Phuc Le Thien、Kitagawa Yuya、Sato Kohei、Mase Nobuyuki、Narumi Tetsuo
    • Journal Title

      Organic Letters

      Volume: 21 Issue: 22 Pages: 9119-9123

    • DOI

      10.1021/acs.orglett.9b03509

    • Related Report
      2019 Research-status Report
    • Peer Reviewed
  • [Journal Article] Epimerization-suppressed organocatalytic synthesis of poly-l-lactide in supercritical carbon dioxide under plasticizing conditions2019

    • Author(s)
      Mase Nobuyuki、Moniruzzaman、Yamamoto Shoji、Sato Kohei、Narumi Tetsuo、Yanai Hikaru
    • Journal Title

      Tetrahedron Letters

      Volume: 60 Issue: 34 Pages: 150987-150987

    • DOI

      10.1016/j.tetlet.2019.150987

    • NAID

      120006714473

    • Related Report
      2019 Research-status Report
    • Peer Reviewed
  • [Journal Article] マイクロ波グリーン有機化学 : デスクトッププラントを目指して2019

    • Author(s)
      間瀬暢之、武田和宏、佐藤浩平
    • Journal Title

      ケミカルエンジニヤリング

      Volume: 64 Pages: 395-402

    • Related Report
      2019 Research-status Report
  • [Presentation] ヒドラジドをカルボン酸保護体として利用する新規アスパルチミド形成抑制法の開発2022

    • Author(s)
      上村 春菜, 佐藤 浩平, 鳴海 哲夫, 間瀬 暢之
    • Organizer
      日本化学会第102春季年会
    • Related Report
      2021 Annual Research Report
  • [Presentation] ヒドラジド化学を利用したペプチド溶解法の開発とユビキチン合成への応用2022

    • Author(s)
      田中 晶子, 佐藤 浩平, 鳴海 哲夫, 間瀬 暢之
    • Organizer
      日本薬学会第142年会
    • Related Report
      2021 Annual Research Report
  • [Presentation] Chemoselective incorporation of hydrophilic tags to poorly soluble peptides using peptide hydrazides2021

    • Author(s)
      Shoko Tanaka, Kohei Sato, Tetsuo Narumi, Nobuyuki Mase
    • Organizer
      AIMESC2021
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Practical activation of peptide hydrazides in TFA enabling direct synthesis of N-terminal thiazolidine-containing peptide thioesters2021

    • Author(s)
      Kohei Sato, Shoko Tanaka, Tetsuo Narumi, Nobuyuki Mase
    • Organizer
      AIMESC2021
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research
  • [Presentation] ヒドラジド化学を基盤とした新規タンパク質合成戦略2021

    • Author(s)
      佐藤浩平
    • Organizer
      第52回 中部化学関係学協会支部連合秋季大会
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] Late-stage solubilization strategy to overcome solubility challenges using peptide hydrazide2021

    • Author(s)
      Kohei Sato, Shoko Tanaka, Shugo Tsuda, Tetsuo Narumi, Taku Yoshiya, Nobuyuki Mase
    • Organizer
      第58回ペプチド討論会
    • Related Report
      2021 Annual Research Report
  • [Presentation] Expanded late-stage solubilization of peptide hydrazide applicable to subsequent ligation2021

    • Author(s)
      Shoko Tanaka, Kohei Sato, Tetsuo Narumi, Nobuyuki Mase
    • Organizer
      第58回ペプチド討論会
    • Related Report
      2021 Annual Research Report
  • [Presentation] 共役ジエン構造を置換基修飾した凝集タウ標識分子PBB3化合物の光安定性評価および結合特性評価2021

    • Author(s)
      武田大、喜屋武龍二、佐藤浩平、間瀬暢之、鳴海哲夫
    • Organizer
      日本薬学会第141年会
    • Related Report
      2020 Research-status Report
  • [Presentation] 2型ニューロメジンU受容体選択的ペプチドアゴニストの分子内アシル転位反応の速度論的評価2021

    • Author(s)
      外山大地、新井康介、佐藤浩平、間瀬暢之、高山健太郎、鳴海哲夫
    • Organizer
      日本薬学会第141年会
    • Related Report
      2020 Research-status Report
  • [Presentation] アルケン型ペプチド結合等価体を基盤とする新規グアニン四重鎖結合ペプチド性化合物の探索2021

    • Author(s)
      竹尾沙優里、田畑舞子、加藤由奈、今井咲、佐藤浩平、間瀬暢之、大吉崇文、鳴海哲夫
    • Organizer
      日本薬学会第141年会
    • Related Report
      2020 Research-status Report
  • [Presentation] 化学的安定性の向上を指向したエステル連結型ユビキチン鎖アミド型アナログの化学合成2021

    • Author(s)
      田口佳紀、西澤拓真、竹内伶音、田中晶子、間瀬暢之、大竹史明、佐伯泰、佐藤浩平、鳴海哲夫
    • Organizer
      日本薬学会第141年会
    • Related Report
      2020 Research-status Report
  • [Presentation] グリーンものづくり:モノリス触媒を用いたフロー有機合成2021

    • Author(s)
      藤本准子、齋藤祐介、水上友人、佐藤浩平、鳴海哲夫、間瀬暢之
    • Organizer
      日本化学会第101春季年会
    • Related Report
      2020 Research-status Report
  • [Presentation] グリーンものづくり:グラジエント法によるフロー反応条件迅速最適化手法の開発2021

    • Author(s)
      宮下直己、佐藤浩平、鳴海哲夫、武田和宏、間瀬暢之
    • Organizer
      日本化学会第101春季年会
    • Related Report
      2020 Research-status Report
  • [Presentation] ファインバブル有機化学:エレメント積層型ミキサーによる気相-液相反応性評価2021

    • Author(s)
      小坂優太、小山祐未、佐藤浩平、鳴海哲夫、間瀬暢之
    • Organizer
      日本化学会第101春季年会
    • Related Report
      2020 Research-status Report
  • [Presentation] ファインバブル有機化学:化学反応性に対する気泡発生機構の効果2021

    • Author(s)
      小塚智貴、佐藤浩平、鳴海哲夫、間瀬暢之
    • Organizer
      日本化学会第101春季年会
    • Related Report
      2020 Research-status Report
  • [Presentation] マイクロ波フロー化学:機械学習による出口温度推算手法の開発2021

    • Author(s)
      磯部海志、佐藤浩平、鳴海哲夫、武田和宏、間瀬暢之
    • Organizer
      日本化学会第101春季年会
    • Related Report
      2020 Research-status Report
  • [Presentation] マイクロ波フロー化学:機械学習による反応条件迅速最適化手法の開発2021

    • Author(s)
      金拓哉、佐藤浩平、鳴海哲夫、武田和宏、間瀬暢之
    • Organizer
      日本化学会第101春季年会
    • Related Report
      2020 Research-status Report
  • [Presentation] 難溶解性ペプチドへの新規水溶性タグ導入法の開発とHIV-1プロテアーゼ合成への展開2021

    • Author(s)
      田中晶子、佐藤浩平、津田修吾、鳴海哲夫、吉矢拓、間瀬暢之
    • Organizer
      日本化学会第101春季年会
    • Related Report
      2020 Research-status Report
  • [Presentation] グリーンものづくり:植物成長調節剤フェアリー化合物のフロー合成による連続生産2021

    • Author(s)
      土居瑞希、佐藤浩平、鳴海哲夫、河岸洋和、間瀬暢之
    • Organizer
      日本化学会第101春季年会
    • Related Report
      2020 Research-status Report
  • [Presentation] Chemical synthesis of ubiquitin derivatives containing non-canonical unit2020

    • Author(s)
      Kohei Sato, Yoshinori Taguchi, Takuma Nishizawa, Sayuri, Takeo, Shoko Tanaka, Nobuyuki, Mase, Tetsuo Narumi
    • Organizer
      第57回ペプチド討論会
    • Related Report
      2020 Research-status Report
  • [Presentation] ペプチドヒドラジドを利用した新規水溶性タグ導入法の開発2020

    • Author(s)
      田中晶子、佐藤浩平、王俊真、石川賢哉、津田修吾、鳴海哲夫、吉矢拓、間瀬暢之
    • Organizer
      第10回CSJ化学フェスタ2020
    • Related Report
      2020 Research-status Report
  • [Presentation] マイクロウェーブ・ファインバブル・フロー手法の融合によるグリーン有機合成2019

    • Author(s)
      間瀬暢之、松尾圭哉、金拓哉、藤本准子、佐藤浩平、鳴海哲夫、武田和宏
    • Organizer
      第63回 香料・テルペンおよび精油化学に関する討論会
    • Related Report
      2019 Research-status Report
  • [Presentation] Chemical Synthesis of Protein for Protein-based Therapeutic2019

    • Author(s)
      Kohei Sato
    • Organizer
      The 2nd International Postgraduate Symposium in Biotechnology
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research
  • [Presentation] ENANTIOSELECTIVE SYNTHESIS OF 4,5-DISUBSTITUTED GAMMA-BUTYROLACTONES BY N-HETEROCYCLE CARBENE-CATALYZED HOMOENOLATE ANNULATION DIRECTLY FROM ENALS AND ALDEHYDES2019

    • Author(s)
      Tetsuo Narumi, Ryuji Ide, Kohei Sato, Nobuyuki Mase
    • Organizer
      12th Asian Federation for Medicinal Chemistry (AFMC) International Medicinal Chemistry Symposium (AIMECS 2019)
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research
  • [Presentation] N-Aryl Effect on the Enhanced Catalytic Activity of Imidazolium-Salt Derived NHCs2019

    • Author(s)
      Ryuji Kyan, Kohei Sato, Nobuyuki Mase, Tetsuo Narumi
    • Organizer
      27th International Society of Heterocyclic Chemistry Congress
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research
  • [Presentation] One-Pot Synthesis of Highly Functionalized 2-Chloroaziridines for Stereoselective Synthesis of (Z)-Chloroalkene Dipeptide Isosteres Containing a,a-Disubstituted Amino Acids2019

    • Author(s)
      Saki Imai, Yuki Kodama, Kohei Sato, Nobuyuki Mase, Tetsuo Narumi
    • Organizer
      27th International Society of Heterocyclic Chemistry Congress
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research
  • [Presentation] CSTR Synthesis of Fairy Chemicals Using Fine Bubble and Flow Optimization Method2019

    • Author(s)
      Nobuyuki Mase, Keiya Matsuo, Takuya Kon, Junko Fujimoto, Kohei Sato, Tetsuo Narumi, Kazuhiro Takeda
    • Organizer
      27th International Society of Heterocyclic Chemistry Congress
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research
  • [Presentation] Post-treatment Free Synthesis of Fairy Chemicals Using Fine Bubble and Flow Optimization Method2019

    • Author(s)
      Keiya Matsuo, Kohei Sato, Tetsuo Narumi, Nobuyuki Mase
    • Organizer
      the 4th International Symposium on Process Chemistry (ISPC 2019)
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research
  • [Presentation] Reaction Optimization Using Microwave-Assisted Continuous Flow Reactor with In-Line Analysis2019

    • Author(s)
      Takuya Kon, Kohei Sato, Tetsuo Narumi, Kazuhiro Takeda, Nobuyuki Mase
    • Organizer
      the 4th International Symposium on Process Chemistry (ISPC 2019)
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research
  • [Presentation] Synthesis of GM2 activator protein segment through direct synthesis of N-terminal thiazolidine-containing peptide thioester from peptide hydrazides2019

    • Author(s)
      Shoko Tanaka, Tetsuo Narumi, Kohji Itoh, Akira Otaka, Nobuyuki Mase, Kohei Sato
    • Organizer
      23rd Korean Peptide and Protein Society Symposium
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research
  • [Presentation] ファインバブル-テレスコーピング法によるフェアリー化合物の合成2019

    • Author(s)
      松尾 圭哉, 佐藤 浩平, 鳴海 哲夫, 間瀬 暢之
    • Organizer
      第8回JACI/GSCシンポジウム
    • Related Report
      2019 Research-status Report
  • [Presentation] 効率的タンパク質化学合成を指向した固相ライゲーション法の開発2019

    • Author(s)
      佐藤浩平、津田修吾、王俊真、鳴海哲夫、吉矢拓、間瀬暢之
    • Organizer
      日本ケミカルバイオロジー学会 第14回年会
    • Related Report
      2019 Research-status Report
  • [Book] マイクロリアクター/フロー合成による反応条件を最適化した導入と目的に応じた実生産への適用 ~事例をふまえた現状と課題/不具合を避けるための設備設計~2020

    • Author(s)
      間瀬暢之,武田和宏,佐藤浩平
    • Total Pages
      270
    • Publisher
      サイエンス&テクノロジー株式会社
    • Related Report
      2020 Research-status Report
  • [Book] In Green Science and Technology; Chapter 5, Catalytic Green Organic Synthesis in Unique Reaction Environments2019

    • Author(s)
      Mase Nobuyuki、Sato Kohei
    • Total Pages
      344
    • Publisher
      CRC Press
    • ISBN
      9781000767995
    • Related Report
      2019 Research-status Report
  • [Remarks] 静岡大学工学部佐藤研究グループホームページ

    • URL

      https://wwp.shizuoka.ac.jp/sato-kohei/

    • Related Report
      2021 Annual Research Report 2020 Research-status Report 2019 Research-status Report

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Published: 2019-04-18   Modified: 2023-01-30  

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