Potent inhibition of tau fibrillization with a multivalent ligand
Potent inhibition of tau fibrillization with a multivalent ligand
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DOI：
10.1016/j.bbrc.2007.08.166
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发表时间：
2007-11-09
影响因子：
3.1
通讯作者：
Kuret, Jeff
中科院分区：
文献类型：
--
作者：
Honson, Nicolette S.;Jensen, Jordan R.;Kuret, Jeff
小分子的tau纤维化抑制剂正在研究中，作为询问tau聚集途径的工具，并作为阿尔茨海默病的潜在治疗药物。已建立的抑制剂包括thiacbocyanine染料，它可以在阴离子表面活性剂聚集诱导剂的存在下抑制重组tau蛋白的成纤维。为了提高抑制效能，合成了一个含有两个硫碳菁基团的环状双硫碳菁分子，并通过电子显微镜和吸光度光谱对其进行了抑制tau纤成活性和配体聚集状态的表征。结果表明，双硫碳菁染料的抑菌活性与单体菁染料的抑菌活性相似，但在80 nM左右的浓度下抑菌活性可达50%。在水溶液中测试的所有浓度下，双硫碳菁都坍塌形成封闭的翻盖结构。然而，tau蛋白的存在选择性地稳定了开放构象。这些结果表明，双硫胺素的抑制活性来自多价，并揭示了更有效的tau聚集抑制剂的途径。(C) 2007爱思唯尔公司版权所有。
Small-molecule inhibitors of tau fibrillization are under investigation as tools for interrogating the tau aggregation pathway and as potential therapeutic agents for Alzheimer's disease. Established inhibitors include thiacarbocyanine dyes, which can inhibit recombinant tau fibrillization in the presence of anionic surfactant aggregation inducers. In an effort to increase inhibitory potency, a cyclic bis-thiacarbocyanine molecule containing two thiacarbocyanine moieties was synthesized and characterized with respect to tau fibrillization inhibitory activity by electron microscopy and ligand aggregation state by absorbance spectroscopy. Results showed that the inhibitory activity of the bis-thiacarbocyanine was qualitatively similar to a monomeric cyanine dye, but was more potent with 50% inhibition achieved at similar to 80 nM concentration. At all concentrations tested in aqueous solution, the bis-thiacarbocyanine collapsed to form a closed clamshell structure. However, the presence of tau protein selectively stabilized the open conformation. These results suggest that the inhibitory activity of bis-thiacarbocyanine results from multivalency, and reveal a route to more potent tau aggregation inhibitors. (C) 2007 Elsevier Inc. All rights reserved.