Design and synthesis of iminosugar-based pharmacological chaperone as a structure stabilizing agent for mutation enzyme

• Project/Area Number: 26460143
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Drug development chemistry
• Research Institution: University of Toyama
• Principal Investigator: Kato Atsushi 富山大学, 附属病院, 准教授 (60303236)
• Co-Investigator(Kenkyū-buntansha): 石井 達 大分大学, 医学部, 客員研究員 (00222935) ; 広野 修一 北里大学, 薬学部, 教授 (30146328) ; 足立 伊左雄 富山大学, 附属病院, 教授 (30151070)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2014: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• 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 / テイーサックス病 / テイ-サックス病

Outline of Final Research Achievements

We performed the computer modelling aided design and synthesis of Hex A inhibitors along with their applicability to Tay-Sachs disease treatment through biological evaluation in both an enzymatic and cellular setting. All 16 stereoisomeric N-methyl proline amides iminosugars have been synthesized from lactone saccessible from the enantiomers of glucuronolactone. All eight enantiomers with a (3R)-hydroxyl configuration are low micromolar to nanomolar inhibitors of a range of Hex A. Furthermore, its stereoisomers bearing a (2S,3R)-trans configuration are significantly more potent inhibitors than those with a (2R,3R)-cis motif. DMDP amide improved the thermostability of Hex A in vitro and increased intracellular Hex A activity by 15-fold in Tay-Sachs G269S fibroblasts after incubation for 5 days. These experimental results suggested that DMDP amide will be a good candidate for treatment of Tay-Sachs disease.

Research Products

• [Int'l Joint Research] University of Oxford(英国)
• [Int'l Joint Research] Chinese Academy of Science(中国)
• [Int'l Joint Research] Universite de Poitiers(フランス)
• [Int'l Joint Research]
• [Int'l Joint Research] University of Oxford(英国)
• [Int'l Joint Research] Chinese Academy of Sciences(中国)
• [Int'l Joint Research] Universite de Poitiers(フランス)
• [Int'l Joint Research]
• [Journal Article] Epimerization of C5 of an N-hydroxypyrrolidine in the synthesis of swainsonine related iminosugars. (2016)
  • Author(s): Qian, B.-C., Kamori, A., Kinami, K., Kato, A., Li, Y.-X., Fleet, G. W. J., Yu, C-.Y.
  • Journal Title: Org. Biomol. Chem. Volume: 14(19) Issue: 19 Pages: 4488-4498
  • DOI: 10.1039/c6ob00531d
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Concise synthesis of calystegine B2 and B3 via intramolecular Nozaki-Hiyama-Kishi reaction. (2016)
  • Author(s): Wang, H.Y., Kato, A., Kinami, K., Li, Y.-X., Fleet, G.W.J., Yu, C.-Y.
  • Journal Title: Org. Biomol. Chem. Volume: 14 (21) Issue: 21 Pages: 4885-4896
  • DOI: 10.1039/c6ob00697c
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] First total synthesis of (+)-broussonetine W: Glycosisdase inhibitory activities of natural product & analogs. (2016)
  • Author(s): Song. Y.-Y., Kinami, K., Kato, A., Jia, Y.-M., Li, Y.-X., Fleet, G. W. J., Yu, C.-Y.
  • Journal Title: Org. Biomol. Chem. Volume: 14 (22) Issue: 22 Pages: 5157-5174
  • DOI: 10.1039/c6ob00720a
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] 3-Azidoazetidines as the first scaffolds for β-amino azetidine carboxylic acid peptidomimetics: azetidine iminosugars containing an acetamido group do not inhibit β-N-acetylhexosaminidases (2016)
  • Author(s): Liu, Z., Jenkinson, S. F., Kato, A., Nakagawa, S., Wormald, M. R., Yu, C.-Y., Fleet, G. W. J.
  • Journal Title: Tetrahedron Asymm. Volume: 27(17-18) Issue: 17-18 Pages: 872-881
  • DOI: 10.1016/j.tetasy.2016.08.001
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Structural essentials for β-N-acetylhexosaminidase inhibition by amides of prolines, pipecolic and azetidine carboxylic acids. (2016)
  • Author(s): Glawar, A. F. G., Martinez, R. F., Ayers, B. J., Hollas, M. A., Ngo, N. Nakagawa, S., Kato, A., Butters, T. D., Fleet, G. W. J., Jenkinson, S. F.
  • Journal Title: Org. Biomol. Chem. Volume: 14 (44) Issue: 44 Pages: 10371-10385
  • DOI: 10.1039/c6ob01549b
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Strategy for designing selective α-L-rhamnosidase inhibitors: Synthesis and biological evaluation of L-DMDP cyclic isothioureas. (2016)
  • Author(s): Miyawaki, S., Hirokami, Y., Kinami, K., Hoshino, M., Minehira, D., Miyamoto, D., Nash, R. J., Fleet, G. W. J., Adachi, I., Kato, A.
  • Journal Title: Bioorg. Med. Chem. Volume: 25 (1) Issue: 1 Pages: 107-115
  • DOI: 10.1016/j.bmc.2016.10.015
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Docking study and biological evaluation of pyrrolidine-based iminosugars as pharmacological chaperones for Gaucher disease (2016)
  • Author(s): Atsushi Kato, Izumi Nakagome, Kasumi Sato, Arisa Yamamoto, Isao Adachi, Robert J. Nash, George W. J. Fleet, Yoshihiro Natori, Yasuka Wasuka, Tatsushi Imahori, Yuichi Yoshimura, Hiroki Takahata and Shuichi Hirono
  • Journal Title: Org. Bio. Chem. Volume: 14 Issue: 3 Pages: 1039-1048
  • DOI: 10.1039/c5ob02223a
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Gem-difluoromethylated and trifluoromethylated derivatives of DMDP-related iminosugars: synthesis and glycosidase inhibition. (2016)
  • Author(s): Li, Y.-X., Kinami, K., Hirokami, Y., Kato, A., Su, J.-K., Jia, Y.-M., Fleet, G. W. J., Yu, C.-Y.
  • Journal Title: Org. Biomol. Chem. Volume: 14(7) Issue: 7 Pages: 2249-2263
  • DOI: 10.1039/c5ob02474a
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Fluorinated radicamine A and B: synthesis and glycosidase inhibition. (2016)
  • Author(s): Li, Y.-X., Iwaki, R., Kato, A., Jia, Y.-M., Fleet, G. W. J., Zhao, X., Xiao, M., Yu, C.-Y.
  • Journal Title: Eur. J. Org. Chem. Volume: 7 Issue: 7 Pages: 1429-1438
  • DOI: 10.1002/ejoc.201501453
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Synthesis and glycosidase inhibition of australine and its fluorinated derivatives. (2015)
  • Author(s): Li, Y.-X., Shimada, Y., Sato, K., Kato, A., Zhang, W., Jia, Y.-M., Fleet, G. W. J., Yu, C.-Y.
  • Journal Title: Org. Lett. Volume: 17(3) Issue: 3 Pages: 716-719
  • DOI: 10.1021/ol503728e
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Design and synthesis of labystegines, hybrid iminosugars from LAB and calystegine, as inhibitors of intestinal α-glucosidases: binding conformation and interaction for ntSI. (2015)
  • Author(s): Kato, A., Zhang, Z.-L., Wang, H.-Y., Jia, Y.-M., Yu, C.-Y., Kinami, K., Hirokami, Y., Tsuji, Y., Adachi, I., Nash, R. J., Fleet, G. W. J., Koseki, J., Nakagome, I., Hirono, S.
  • Journal Title: J. Org. Chem. Volume: 80(9) Issue: 9 Pages: 4501-4515
  • DOI: 10.1021/acs.joc.5b00342
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] 3-Fluoro-azetidine carboxylic acids and trans,trans-3,4-difluoroproline as peptide scaffolds: inhibition of pancreatic cancer cell growth by a fluoroazetidine iminosugar. (2015)
  • Author(s): Liu, Z., Jenkinson, S. F., Vermaas, T., Adachi, I., Wormald, M. R., Hata, U., Kurashima, Y., Kaji, A., Yu, C,-Y., Kato, A., Fleet, G. W. J.
  • Journal Title: J. Org. Chem. Volume: 80(9) Issue: 9 Pages: 4244-4258
  • DOI: 10.1021/acs.joc.5b00463
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Fluorinated and conformationally fixed derivatives of L-homoDMDP: synthesis and glycosidase inhibition. (2015)
  • Author(s): Li, Yi.-X., Shimada, Y., Adachi, I., Kato, A., Jia, Y.-M., Fleet, G. W. J., Xiao, M., Yu. C.-Y.
  • Journal Title: J. Org. Chem. Volume: 80(10) Issue: 10 Pages: 5151-5158
  • DOI: 10.1021/acs.joc.5b00571
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Synthesis of 1,2-trans-2-acetamido-2-deoxyhomoiminosugars. (2014)
  • Author(s): Bleriot, Y., Tran, A. T., Prencipe, G., Jagadeesh, Y., Auberger, N., Zhu, S., Gauthier, C., Zhang, Y., Desire;, J., Adachi, I., Kato, A., Sollogoub, M.
  • Journal Title: Org. Lett. Volume: 16 (21) Issue: 21 Pages: 5516-5519
  • DOI: 10.1021/ol502929h
  • Peer Reviewed
• [Journal Article] Isolation and SAR studies of bicyclic iminosugars from Castanospermum australe as glycosidase inhibitors. (2014)
  • Author(s): Kato, A., Hirokami, Y., Kinami, K., Tsuji, Y., Miyawaki, S., Adachi, I., Hollinshead, J., Nash, R. J. Kiappes, J. L., Zitzmann, N., Cha, J. K., Molyneux, R. J., Fleet, G. W. J., Asano, N.
  • Journal Title: Phytochemistry Volume: 111 Pages: 124-131
  • DOI: 10.1016/j.phytochem.2014.12.011
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] コンピュータリガンドドッキングと分子動力学シミュレーションによるHexosaminidase A―リガンド複合体の相互作用解析 (2017)
  • Author(s): 中込 泉、加藤 敦、山乙 教之、足立 伊左雄、広野 修一
  • Organizer: 日本薬学会第137年会
  • Place of Presentation: 仙台国際センター 他
  • Year and Date: 2017-03-25
• [Presentation] Hexosaminidase Aの高親和性リガンドに対するイン・シリコ相互作用解析 (2016)
  • Author(s): 中込 泉、加藤 敦、山乙 教之、足立伊佐雄、広野修一
  • Organizer: 第44回構造活性相関シンポジウム
  • Place of Presentation: 京都大学医学部創立百年記念施設
  • Year and Date: 2016-11-16
• [Presentation] イミノ糖を基盤としたGCase高親和性リガンドの創製とファーマコロジカルシャペロン効果について (2016)
  • Author(s): 加藤 敦、中込 泉、佐藤香純、山本亜里紗、足立伊佐雄、広野修一
  • Organizer: 第35回糖質学会年会
  • Place of Presentation: 高知市文化プラザ かるぽーと
  • Year and Date: 2016-09-01
• [Presentation] ピロリジン型イミノ糖を基盤とした新規GCase高親和性リガンドのデザインとファーマコロジカルシャペロン効果について (2016)
  • Author(s): 加藤 敦、山本亜里紗、友原啓介、足立伊佐雄、渡邊靖香、名取良浩、吉村祐一、中込 泉、広野修一
  • Organizer: 日本薬学会第136年会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2016-03-27
• [Presentation] In silico study on the interaction of high affinity ligand calystegine B2 with β-glucocerebrosidase (2015)
  • Author(s): Nakagome, I., Kato, A., Yoshida, T., Yamaotsu, N., Adachi, I., Hirono, S.
  • Organizer: Pacifichem2015
  • Place of Presentation: Honolulu, Hawaii, USA
  • Year and Date: 2015-12-15
  • Int'l Joint Research
• [Presentation] Catalytic asymmetric syntheses and biological evaluations of α-1-C-substituted L-iminofuranose derivatives as α-glucosidase inhibitor (2015)
  • Author(s): Natori, Y., Kato, A., Adachi, I., Yoshimura, Y.
  • Organizer: Pacifichem2015
  • Place of Presentation: Honolulu, Hawaii, USA
  • Year and Date: 2015-12-15
  • Int'l Joint Research
• [Presentation] 1-C-n-ブチル-L-イミノフラノース誘導体の触媒的不斉合成と酵素阻害活性評価 (2015)
  • Author(s): 佐久間俊嘉、名取良浩、中川進平、加藤 敦、足立伊佐雄、吉村祐一
  • Organizer: 第33回メディシナルケミストリーシンポジウム
  • Place of Presentation: 幕張国際研修センター
  • Year and Date: 2015-11-25
• [Presentation] Computational study of the interaction of α-1-C-alkyl derivatives of 1,4-dideoxy-1,4-imino-D-arabinitol with β-glucocerebrosidase (2015)
  • Author(s): 中込 泉、加藤 敦、山乙教之、吉田智喜、足立伊佐雄、広野修一
  • Organizer: 第43回構造活性相関シンポジウム
  • Place of Presentation: 新潟日報メディアシップ 日報ホール
  • Year and Date: 2015-09-27
• [Presentation] α-glucosidase 阻害剤 α-1-C-Butyl-LAB のイソマルターゼに対する結合様式解析 (2015)
  • Author(s): 中込 泉、小関 準、加藤 敦、山乙教之、足立伊佐雄、広野修一
  • Organizer: 日本薬学会第135年会
  • Place of Presentation: 神戸学院大学他
  • Year and Date: 2015-03-26 – 2015-03-28
• [Presentation] β-glucocerebrosidaseに対する高親和性リガンドcalystegine B2類縁体の計算化学的相互作用解析 (2014)
  • Author(s): 中込 泉、加藤 敦、山乙教之、足立伊佐雄、広野修一
  • Organizer: 第42回構造活性相関シンポジウム
  • Place of Presentation: くまもと森都心プラザ
  • Year and Date: 2014-11-13 – 2014-11-14
• [Presentation] GCase高親和性リガンドである1-N型イミノ糖の結合親和性とファーマコロジカルシャペロン効果について (2014)
  • Author(s): 加藤 敦、山本亜里紗、中川進平、足立伊佐雄、中込 泉、広野修一
  • Organizer: 第33回糖質学会年会
  • Place of Presentation: 名古屋大学豊田講堂
  • Year and Date: 2014-08-10 – 2014-08-12