• Search Research Projects
  • Search Researchers
  • How to Use
  1. Back to previous page

Design of functional chaperone compounds based on structural stabilisation of mutant enzymes and their application in the treatment of Pompe disease

Research Project

Project/Area Number 21K06451
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 47010:Pharmaceutical chemistry and drug development sciences-related
Research InstitutionUniversity of Toyama

Principal Investigator

Kato Atsushi  富山大学, 学術研究部薬学・和漢系, 教授 (60303236)

Co-Investigator(Kenkyū-buntansha) 石井 達  大分大学, 医学部, 客員研究員 (00222935)
中込 泉  北里大学, 薬学部, 助教 (30237242)
名取 良浩  東北医科薬科大学, 薬学部, 講師 (50584455)
Project Period (FY) 2021-04-01 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2023: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2022: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Keywordsリソソーム病 / グリコシダーゼ / イミノ糖 / シャペロン / フォールディング / ポンペ病 / シャペロン療法 / 酵素補充療法
Outline of Research at the Start

ポンペ病は、リソソームに局在する酸性α-glucosidase (GAA)の遺伝的活性低下に起因する疾患であり、厚生労働省難治性疾患等政策研究事業の一つとなっている。本研究課題では、ポンペ病患者の変異タンパク質の立体構造に基づいた医薬分子設計、糖質生化学、創薬化学の研究手法を駆使して、ミューテーション部位に応じた「最適な低分子シャペロン」を創製し、ポンペ病の新しい治療薬の開発を待ち望んでいる患者に革新的な新薬を届けることを目的としている。

Outline of Final Research Achievements

This study provides the first example of a strategy to design a high affinity ligand toward lysosomal acid α-glucosidase (GAA) focusing on alkyl branches on 1-deoxynojirimycin (DNJ); 5-C-Heptyl-DNJ produced a nanomolar affinity for the GAA, with a Ki value of 0.0047 μM, which is 13-fold more potent than DNJ. The protein thermal shift assay revealed that 10 μM 5-C-heptyl-DNJ increased the midpoint of protein denaturation temperature (Tm) to 73.6 °C from 58.6 °C in the absence of the ligand, significantly improving the thermal stability of rhGAA. Furthermore, 5-C-heptyl-DNJ dose-dependency increased intracellular GAA activities in Pompe patient’s fibroblasts with the M519V mutation. The introduction of C5 alkyl branches on DNJ provides a new molecular strategy for pharmacological chaperone therapy for Pompe disease which may lead to the development of higher affinity and practically useful chaperones.

Academic Significance and Societal Importance of the Research Achievements

ポンペ病はGAAの 活性低下に起因する疾患であり、厚生労働省難治性疾患等政策研究事業対象の稀少疾患に指定されている。従来用いられてきた酵素補充療法は、抗体の産生や副作用の問題など克服すべき点が多くあった。本研究課題を通して既存のDNJに代わる新たな化合物デザインの提案に成功した。本化合物群とrhGAAの併用投与は、rhGAAに強く結合することで酵素の安定性と成熟度を高め、その結果、酵素の輸送効率を飛躍的に向上させ、より低用量で酵素補充療法が実施可能になることが期待される。更に、本成果は既存のDNJによるシャペロン療法が無効な変異を有するポンペ病患者にも新たな治療薬開発の指針を与えるものである。

Report

(4 results)
  • 2023 Annual Research Report   Final Research Report ( PDF )
  • 2022 Research-status Report
  • 2021 Research-status Report
  • Research Products

    (38 results)

All 2024 2023 2022 2021 Other

All Int'l Joint Research (9 results) Journal Article (12 results) (of which Int'l Joint Research: 12 results,  Peer Reviewed: 12 results,  Open Access: 1 results) Presentation (17 results) (of which Int'l Joint Research: 1 results)

  • [Int'l Joint Research] University of Oxford(英国)

    • Related Report
      2023 Annual Research Report
  • [Int'l Joint Research] Chinese Academy of Sciences(中国)

    • Related Report
      2023 Annual Research Report
  • [Int'l Joint Research] Universe de Poitiers(フランス)

    • Related Report
      2023 Annual Research Report
  • [Int'l Joint Research] University of Oxford(英国)

    • Related Report
      2022 Research-status Report
  • [Int'l Joint Research] Chinese Academy of Sciences(中国)

    • Related Report
      2022 Research-status Report
  • [Int'l Joint Research] Universe de Poitiers(フランス)

    • Related Report
      2022 Research-status Report
  • [Int'l Joint Research] University of Oxford(英国)

    • Related Report
      2021 Research-status Report
  • [Int'l Joint Research] Universite de Poitiers(フランス)

    • Related Report
      2021 Research-status Report
  • [Int'l Joint Research] Chinese Academy of Sciences(中国)

    • Related Report
      2021 Research-status Report
  • [Journal Article] Nanomolar β-glucosidase and β-galactosidase inhibition by enantiomeric α-1-C-alkyl-1,4-dideoxy-1,4-imino-arabinitol derivatives2023

    • Author(s)
      Zi Dong、Song Ying-Ying、Lu Tian-Tian、Kise Maki、Kato Atsushi、Wang Jun-Zhe、Jia Yue-Mei、Li Yi-Xian、Fleet George W.J.、Yu Chu-Yi
    • Journal Title

      European Journal of Medicinal Chemistry

      Volume: 247 Pages: 115056-115056

    • DOI

      10.1016/j.ejmech.2022.115056

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Design, synthesis and glycosidase inhibition of DAB derivatives with C-4 peptide and dipeptide branches2023

    • Author(s)
      Zi Dong、Shimadate Yuna、Wang Jun-Zhe、Kato Atsushi、Li Yi-Xian、Jia Yue-Mei、Fleet George W. J.、Yu Chu-Yi
    • Journal Title

      Organic & Biomolecular Chemistry

      Volume: 21 Issue: 13 Pages: 2729-2741

    • DOI

      10.1039/d3ob00097d

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Design and synthesis of iso-allo-DNJ and L-isoDALDP derivatives: pursuit of potent and selective inhibitors of α-glucosidase2023

    • Author(s)
      Yang Lin-Feng、Zhang Ming、Shimadate Yuna、Kato Atsushi、Hou Tian-Yang Liu、Li Yi-Xian、Jia Yue-Mei、Fleet George W. J.、Yu Chu-Yi
    • Journal Title

      Organic & Biomolecular Chemistry

      Volume: 21 Issue: 16 Pages: 3453-3464

    • DOI

      10.1039/d3ob00404j

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Design and Pharmacological Chaperone Effects of N-(4′-Phenylbutyl)-DAB Derivatives Targeting the Lipophilic Pocket of Lysosomal Acid α-Glucosidase2023

    • Author(s)
      Kato Atsushi、Nakagome Izumi、Kise Maki、Yoshimura Kousuke、Tanaka Nobutada、Nash Robert J.、Fleet George W. J.、Kobayashi Yota、Ikeda Hayato、Okada Takuya、Toyooka Naoki
    • Journal Title

      Journal of Medicinal Chemistry

      Volume: 66 Issue: 13 Pages: 9023-9039

    • DOI

      10.1021/acs.jmedchem.3c00637

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Design, synthesis and glycosidase inhibition of C-4 branched LAB and DAB derivatives2022

    • Author(s)
      Wang Jun-Zhe、Cheng Bin、Kato Atsushi、Kise Maki、Shimadate Yuna、Jia Yue-Mei、Li Yi-Xian、Fleet George W.J.、Yu Chu-Yi
    • Journal Title

      European Journal of Medicinal Chemistry

      Volume: 233 Pages: 114230-114230

    • DOI

      10.1016/j.ejmech.2022.114230

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Diastereoselective Synthesis, Glycosidase Inhibition, and Docking Study of C-7-Fluorinated Casuarine and Australine Derivatives2022

    • Author(s)
      Li Yi-Xian、Wang Jun-Zhe、Shimadate Yuna、Kise Maki、Kato Atsushi、Jia Yue-Mei、Fleet George W. J.、Yu Chu-Yi
    • Journal Title

      The Journal of Organic Chemistry

      Volume: 87 Issue: 11 Pages: 7291-7307

    • DOI

      10.1021/acs.joc.2c00485

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] trans, trans-2-C-Aryl-3,4-dihydroxypyrrolidines as potent and selective β-glucosidase inhibitors: Pharmacological chaperones for Gaucher disease2022

    • Author(s)
      Wang Jun-Zhe、Shimadate Yuna、Kise Maki、Kato Atsushi、Jia Yue-Mei、Li Yi-Xian、Fleet George W.J.、Yu Chu-Yi
    • Journal Title

      European Journal of Medicinal Chemistry

      Volume: 238 Pages: 114499-114499

    • DOI

      10.1016/j.ejmech.2022.114499

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Introduction of C-alkyl branches to L-iminosugars changes their active site binding orientation2022

    • Author(s)
      Kato Atsushi、Nakagome Izumi、Yoshimura Kosuke、Kanekiyo Uta、Kishida Mana、Shinzawa Kenta、Lu Tian-Tian、Li Yi-Xian、Nash Robert J.、Fleet George W. J.、Tanaka Nobutada、Yu Chu-Yi
    • Journal Title

      Organic and Biomolecular Chemistry

      Volume: 20 Issue: 36 Pages: 7250-7260

    • DOI

      10.1039/d2ob01099b

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] C-6 fluorinated casuarines as highly potent and selective amyloglucosidase inhibitors: Synthesis and structure-activity relationship study2022

    • Author(s)
      Li Yi-Xian、Wang Jun-Zhe、Shimadate Yuna、Kise Maki、Kato Atsushi、Jia Yue-Mei、Fleet George W.J.、Yu Chu-Yi
    • Journal Title

      European Journal of Medicinal Chemistry

      Volume: 244 Pages: 114852-114852

    • DOI

      10.1016/j.ejmech.2022.114852

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] 5-<i>C</i>-Branched Deoxynojirimycin: Strategy for Designing a 1-Deoxynojirimycin-Based Pharmacological Chaperone with a Nanomolar Affinity for Pompe Disease2022

    • Author(s)
      Kato Atsushi、Nakagome Izumi、Kanekiyo Uta、Lu Tian-Tian、Li Yi-Xian、Yoshimura Kosuke、Kishida Mana、Shinzawa Kenta、Yoshida Tomoki、Tanaka Nobutada、Jia Yue-Mei、Nash Robert J.、Fleet George W. J.、Yu Chu-Yi
    • Journal Title

      Journal of Medicinal Chemistry

      Volume: 65 Issue: 3 Pages: 2329-2341

    • DOI

      10.1021/acs.jmedchem.1c01673

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Synthesis and glycosidase inhibition of 5-C-alkyl-DNJ and 5-C-alkyl-L-ido-DNJ derivatives.2021

    • Author(s)
      Lu, T.-T., Shimadate, Y., Cheng, B., Kanekiyo, U., Kato, A, Wang, J.-Z., Li, Y.-X., Jia, Y.-M., Fleet, G.W.J., Yu, C.-Y.
    • Journal Title

      Eur. J. Med. Chem.

      Volume: 224 Pages: 113716-113716

    • DOI

      10.1016/j.ejmech.2021.113716

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Stereocomplementary synthesis of casuarine and its 6-epi-, 7-epi-, and 6,7-diepi-stereoisomers.2021

    • Author(s)
      Li, Y.-X., Wang, J.-Z., Kato, A., Shimadate, Y., Kise, M., Jia, Y.-M., Fleet, G.W.J., Yu, C.-Y.
    • Journal Title

      Org. Biomol. Chem.

      Volume: 19 (43) Issue: 43 Pages: 9410-9420

    • DOI

      10.1039/d1ob01725j

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Presentation] GAA活性中心近傍に存在する疎水性ポケットの発見とポンペ病に対する選択的シャペロン化合物の創製2024

    • Author(s)
      加藤 敦、中込 泉、喜瀬 真妃、吉村 洸亮、岡田 卓哉、豊岡 尚樹、田中 信忠
    • Organizer
      日本薬学会第144年会
    • Related Report
      2023 Annual Research Report
  • [Presentation] ポンペ病標的酵素GAAに対する低分子シャペロン1,4-dideoxy-1,4-imino-D-arabinitolの疎水性置換基誘導体に対するイン・シリコ解析2024

    • Author(s)
      中込 泉、加藤 敦、吉村 洸亮、兼清 歌、吉田 智喜、山乙 教之、田中 信忠
    • Organizer
      日本薬学会第144年会
    • Related Report
      2023 Annual Research Report
  • [Presentation] 希少糖型イミノ糖の活用を指向した分岐型5-C-アルキル誘導体の創製とポンペ病患者細胞に対するシャペロン活性について2023

    • Author(s)
      加藤 敦、中込 泉、兼清 歌、吉村 洸亮、田中 信忠
    • Organizer
      第42回 日本糖質学会年会
    • Related Report
      2023 Annual Research Report
  • [Presentation] GAAの疎水性ポケットを標的とした新規シャペロン化合物の創製とポンペ病治療薬への応用2023

    • Author(s)
      加藤 敦、岡田卓哉、中込泉、喜瀬真妃、吉村洸亮、田中信忠、Robert J. Nash、George W. J. Fleet、小林陽太、池田隼人、豊岡尚樹
    • Organizer
      第40回メディシナルケミストリーシンポジウム
    • Related Report
      2023 Annual Research Report
  • [Presentation] Design and pharmacological chaperone effects of DAB derivatives targeting the lipophilic pocket of lysosomal acid α-glucosidase.2023

    • Author(s)
      Takuya Okada, Atsushi Kato, Izumi Nakagome, Maki Kise, Kousuke Yoshimura, Nobutada Tanaka, Robert J. Nash, George W. J. Fleet, Yota Kobayashi, Hayato Ikeda, Naoki Toyooka.
    • Organizer
      KCOC-15 (The 15th International Kyoto Conference on New Aspects of Organic Chemistry)
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research
  • [Presentation] リソソーム酸性α-グルコシダーゼに対するシャペロン化合物5-C-alkyl-L-ido-DNJのアルキル鎖長の違いが活性や結合配向を変化させる2023

    • Author(s)
      中込 泉、加藤 敦、吉村 洸亮、兼清 歌、山乙 教之、田中 信忠
    • Organizer
      第51回構造活性相関シンポジウム
    • Related Report
      2023 Annual Research Report
  • [Presentation] 新たなグリコシダーゼ阻害剤デザインの提案と難病ポンペ病治療薬への応用2023

    • Author(s)
      岡田卓哉、加藤 敦、中込 泉、喜瀬真妃、田中信忠、Robert J. Nash、George W. J. Fleet、小林陽太、池田隼人、豊岡尚樹
    • Organizer
      第51回構造活性相関シンポジウム
    • Related Report
      2023 Annual Research Report
  • [Presentation] イミノ糖を用いたファーマコロジカルシャペロン創薬の可能性と今後の展望2023

    • Author(s)
      加藤 敦
    • Organizer
      日本薬学会第143年会
    • Related Report
      2022 Research-status Report
  • [Presentation] ポンペ病原因酵素リソソーム酸性α-グルコシダーゼに対する低分子シャペロン5-C-alkyl-L-ido-DNJのアルキル鎖長が活性や結合配向に及ぼす影響2023

    • Author(s)
      中込 泉、加藤 敦、吉村 洸亮、兼清 歌、山乙 教之、田中 信忠
    • Organizer
      日本薬学会第143年会
    • Related Report
      2022 Research-status Report
  • [Presentation] 6-Fluoro-casuarine誘導体の各種グリコシダーゼに対する阻害活性と構造活性相関2023

    • Author(s)
      島立 優奈、喜瀬 真妃、新澤 健太、加藤 敦
    • Organizer
      日本薬学会第143年会
    • Related Report
      2022 Research-status Report
  • [Presentation] ポンペ病の原因酵素酸性α-glucosidaseを標的とした高親和性シャペロン化合物の創製2023

    • Author(s)
      吉村 洸亮、中込 泉、兼清 歌、新澤 健太、吉田 智喜、田中 信忠、加藤 敦
    • Organizer
      日本薬学会第143年会
    • Related Report
      2022 Research-status Report
  • [Presentation] 水和サイト解析を用いたGAA高親和性アロステリックシャペロンのバーチャルスクリーニング2023

    • Author(s)
      吉田 智喜、三河 なつみ、中込 泉、加藤 敦、田中 信忠
    • Organizer
      日本薬学会第143年会
    • Related Report
      2022 Research-status Report
  • [Presentation] 5-C-分岐型デオキシノジリマイシンを基盤としたGAA高親和性シャペロンのデザイン研究2022

    • Author(s)
      加藤 敦、中込 泉、兼清 歌、吉村 洸亮、岸田 真奈、新澤 健太、吉田 智喜、田中 信忠
    • Organizer
      第41回日本糖質学会年会
    • Related Report
      2022 Research-status Report
  • [Presentation] Search for allosteric chaperones for lysosomal acid α-glucosidase2022

    • Author(s)
      山崎 真奈美、中込 泉、田中信忠、島立優奈、加藤 敦
    • Organizer
      CBI学会2022年大会
    • Related Report
      2022 Research-status Report
  • [Presentation] In silico解析と親和性測定に基づいたlysosomal acid α-glucosidase (GAA)選択特性を有するイミノ糖のデザイン研究2022

    • Author(s)
      加藤 敦、中込 泉、畑 瑞希、新澤 健太、名取 良浩、吉村 祐一、田中 信忠
    • Organizer
      日本薬学会第141年会
    • Related Report
      2021 Research-status Report
  • [Presentation] Casuarine誘導体の各種グリコシダーゼに対する阻害活性と構造活性相関2022

    • Author(s)
      島立 優奈、喜瀬 真妃、新澤 健太、加藤 敦
    • Organizer
      日本薬学会第141年会
    • Related Report
      2021 Research-status Report
  • [Presentation] イミノ糖を基盤とした酸性α-グルコシダーゼに対する選択的阻害剤のデザイン研究2021

    • Author(s)
      加藤 敦、中込 泉、畑 瑞希、吉村 洸亮、名取 良浩、吉村 祐一、広野 修一
    • Organizer
      第40回日本糖質学会年会
    • Related Report
      2021 Research-status Report

URL: 

Published: 2021-04-28   Modified: 2025-01-30  

Information User Guide FAQ News Terms of Use Attribution of KAKENHI

Powered by NII kakenhi