Identification of the optimal structure required for a Shiga toxin neutralizer with oriented carbohydrates to function in the circulation
Identification of the optimal structure required for a Shiga toxin neutralizer with oriented carbohydrates to function in the circulation
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DOI：
10.1086/430388
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发表时间：
2005-06-15
影响因子：
6.4
通讯作者：
Natori, Y
中科院分区：
文献类型：
--
作者：
Nishikawa, K;Matsuoka, K;Natori, Y
滋贺毒素（Stx）是产Stx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，其树枝状聚合物结构中具有6个三羟甲基的globotriaosyl神经酰胺（Stx的受体）（称为“SUPER TWIG [ 1] 6”），以在循环中发挥作用。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，并确定了一种具有18个三联体的SUPER TWIG，SUPER TWIG（2）18，作为另一种有效的Stx中和剂。SUPER TWIGs（1）6和（2）18具有结构相似性，即哑铃形状，其中2个三聚体簇通过与疏水链的键连接。发现哑铃形状是与Stx形成复合物所需的，该复合物能够使Stx被巨噬细胞有效摄取和降解，因此，在循环中具有有效的Stx中和活性。我们还确定了SUPER TWIGs在Stx上的结合位点。
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, 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 determined the binding site of the SUPER TWIGs on Stx.