Fine tuning Exo2, a small molecule inhibitor of secretion and retrograde trafficking pathways in mammalian cells.
Fine tuning Exo2, a small molecule inhibitor of secretion and retrograde trafficking pathways in mammalian cells.
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DOI：
10.1039/c0mb00035c
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发表时间：
2010-10
影响因子：
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通讯作者：
Lucie Guetzoyan;Robert A. Spooner;Frédéric Boal;David J. Stephens;J. Lord;Lynne M. Roberts;Guy J. Clarkson
中科院分区：
文献类型：
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作者：
Lucie Guetzoyan;Robert A. Spooner;Frédéric Boal;David J. Stephens;J. Lord;Lynne M. Roberts;Guy J. Clarkson
小分子4-羟基-3-甲氧基苯甲醛（5，6，7，8-四氢[1]苯并噻吩并[2，3-d]嘧啶-4-基）腙（Exo 2）刺激哺乳动物高尔基体和反式高尔基体网络的形态学变化，这些变化与布雷菲德菌素A诱导的变化几乎无法区分。布雷菲德菌素A和Exo 2都通过作用于在早期内体起作用的其他靶标来保护细胞免受滋贺（样）毒素的中毒，但这样做是以对靶细胞的高毒性为代价的。Exo 2的优点是，它更容易进行化学修饰，在这里，我们报告了一系列通过修饰四氢苯并噻吩并嘧啶核心，香草醛部分和连接这两个的腙键产生的Exo 2类似物。检查这些化合物在高尔基体堆叠、反式高尔基体网络和转铁蛋白受体阳性早期内体处刺激的形态学变化，并且这种活性与它们对细胞的蛋白质制造能力的固有毒性和它们对毒素攻击的保护作用相关。我们已经开发出可以分离细胞器形态、靶特异性、先天毒性和毒素保护的衍生物。我们的研究结果提供了独特的化合物，具有低毒性和增强的特异性，以解开膜运输网络的复杂性。
The small molecule 4-hydroxy-3-methoxybenzaldehyde (5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-yl)hydrazone (Exo2) stimulates morphological changes at the mammalian Golgi and trans-Golgi network that are virtually indistinguishable from those induced by brefeldin A. Both brefeldin A and Exo2 protect cells from intoxication by Shiga(-like) toxins by acting on other targets that operate at the early endosome, but do so at the cost of high toxicity to target cells. The advantage of Exo2 is that it is much more amenable to chemical modification and here we report a range of Exo2 analogues produced by modifying the tetrahydrobenzothienopyrimidine core, the vanillin moiety and the hydrazone bond that links these two. These compounds were examined for the morphological changes they stimulated at the Golgi stack, the trans-Golgi network and the transferrin receptor-positive early endosomes and this activity correlated with their inherent toxicity towards the protein manufacturing ability of the cell and their protective effect against toxin challenge. We have developed derivatives that can separate organelle morphology, target specificity, innate toxicity and toxin protection. Our results provide unique compounds with low toxicity and enhanced specificity to unpick the complexity of membrane trafficking networks.