权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Basic Research for development of new drug against Shiga-toxin producing E.Coli infection

抗产志贺毒素大肠杆菌感染新药开发的基础研究

基本信息

批准号：
17390038
负责人：
NATORI Yasuhiro
金额：
$ 10.23万
依托单位：
International Medical Center of Japan
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2007
项目状态：
已结题

项目摘要

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.

志贺毒素（Stx）是产生Stx的大肠杆菌的主要毒力因子。最近，我们开发了一种治疗性Stx中和剂，其树突结构（称为“SUPER TWIG[1]6”）中含有6种Stx受体globotriaosyl神经酰胺（Gb3）三糖，在循环中起作用。在这里，我们确定了SUPER TWIG的最佳结构，使其在循环中发挥作用，并鉴定了含有18个三糖的SUPER TWIG(2) 18，作为另一种有效的Stx中和剂。SUPER TWIGs(1) 6和(2)18在结构上具有相似性，两个三糖簇通过疏水链连接而成哑铃状。哑铃形状被发现是与Stx形成复合物所必需的，这种复合物使巨噬细胞能够有效地摄取和降解Stx，因此，在循环中具有强大的Stx中和活性。我们之前还开发了含有Gb3簇状三糖的线性聚合物，作为口服适用的Stx中和剂。在这里，我们使用具有短间隔的Gb3聚合物将三糖连接到核心，我们发现缩短间隔长度显著降低了Stx2的结合亲和力，而不是Stx1。此外，突变分析显示Stx1和Stx2的末端三糖的基本结合位点完全不同。因此，我们提供了治疗性Stx中和剂的最佳结构信息。

项目成果

期刊论文数量（0）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Type I platelet-activating factor acetylhydrolase catalyticsubunits over-expression induces pleiomorphic nuclei and centroso me amplification

I型血小板激活因子乙酰水解酶催化亚基过度表达诱导多形性核和中心体扩增

DOI：
发表时间：
2007
期刊：
Genes Cells 12
影响因子：
0
作者：
Yamaguchi N.;Koizumi H.;Aoki J.;Natori Y.;NishikawaK.;Natori Y.;Takanezawa Y.;and Arai H.
通讯作者：
and Arai H.

Structural analysis of the interaction between Shiga toxin B-subunits and linear polymers bearing clustered globotriose residues

志贺毒素 B 亚基与带有簇状球三糖残基的线性聚合物之间相互作用的结构分析

DOI：
发表时间：
2006
期刊：
Infect. Immun. 74
影响因子：
0
作者：
Watanabe M.;Igai K.;Matsuoka K.;Miyagawa A.;Watanabe T.;Yanoshita R.;Samejima Y.;Terunuma D.;Natori Y;and Nishikawa K.
通讯作者：
and Nishikawa K.

Identification of the optimal structure required for a Shiga toxin neutralizer with oriented carbohydrates to function in the circulation