| Project/Area Number |
17390038
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Environmental pharmacy
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| Research Institution | International Medical Center of Japan |
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Principal Investigator |
NATORI Yasuhiro International Medical Center of Japan, Department of Clinical Pharmacology, Director (10164485)
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| Co-Investigator(Kenkyū-buntansha) |
NISHIKAWA Kiyotaka Doshisha University, Department of Molecular Life Sciences, Professor (40218128)
MATSUOKA Koji Saitama University, Department of Functional Materials Science, Associate Professor (40272281)
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| Project Period (FY) |
2005 – 2007
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| Project Status |
Completed (Fiscal Year 2007)
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| Budget Amount *help |
¥15,990,000 (Direct Cost: ¥14,700,000、Indirect Cost: ¥1,290,000)
Fiscal Year 2007: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000)
Fiscal Year 2006: ¥5,000,000 (Direct Cost: ¥5,000,000)
Fiscal Year 2005: ¥5,400,000 (Direct Cost: ¥5,400,000)
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| Keywords | Verotoxin / Enterohemorrhagic E.coli / Carbohydrate / Dendrimer / Toxin Neutralizer / Food Poisoning / Emerging Diseases / Shiga toxin-producing E.coil / 病原性大腸菌0157 |
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| Research Abstract |
Shiga toxin (Stx) is a major virulence factor of Stx-producing Escherichia coli. Recently, we developed a therapeutic Stx neutralizer with 6 trisaccharides of globotriaosyl ceramide (Gb3), a receptor for Stx, in its dendrimer structure (referred to as "SUPER TWIG [1]6") to function in the circulation. Here, we determined the optimal structure of SUPER TWIG for it to function in the circulation and identified a SUPER TWIG with 18 trisaccharides, SUPER TWIG (2) 18, as another potent Stx neutralizer. SUPER TWIGs (1) 6 and (2) 18 shared a structural similarity, a dumbbell shape in which 2 clusters of trisaccharides were connected via a linkage with a hydrophobic chain. The dumbbell shape was found to be required for formation of a complex with Stx that enables efficient uptake and degradation of Stx by macrophages and, consequently, for potent Stx-neutralizing activity in the circulation. We also previously developed linear polymers bearing clustered trisaccharides of Gb3 as orally applicable Stx neutralizers. Here, using a Gb3 polymer with a short spacer tethering the trisaccharide to the core, we found that shortening the spacer length markedly reduced the binding affinity for Stx2 but not Stx1. Moreover, mutational analysis revealed that the essential binding sites of the terminal trisaccharides were completely different between Stx1 and Stx2. Thus, we provided the information about the best structure for the therapeutic Stx neutralizer.
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