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 *help |
¥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.
|
Report
(4 results)
Research Products
(34 results)
-
-
-
-
-
-
-
-
-
[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
Related Report
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
Related Report
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
Related Report
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-acetylhexosaminidases2016
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
Related Report
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
Related Report
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
Related Report
Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
-
[Journal Article] Docking study and biological evaluation of pyrrolidine-based iminosugars as pharmacological chaperones for Gaucher disease2016
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
Related Report
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
Related Report
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
Related Report
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
Related Report
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
Related Report
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
Related Report
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
Related Report
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
Related Report
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
Related Report
Peer Reviewed / Acknowledgement Compliant
-
-
-
-
-
[Presentation] In silico study on the interaction of high affinity ligand calystegine B2 with β-glucocerebrosidase2015
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
Related Report
Int'l Joint Research
-
-
-
-
-
-