The sulfated triphenyl methane derivative acid fuchsin is a potent inhibitor of amyloid formation by human islet amyloid polypeptide and protects against the toxic effects of amyloid formation.
The sulfated triphenyl methane derivative acid fuchsin is a potent inhibitor of amyloid formation by human islet amyloid polypeptide and protects against the toxic effects of amyloid formation.
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DOI：
10.1016/j.jmb.2010.05.001
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发表时间：
2010-07-16
影响因子：
5.6
通讯作者：
Raleigh DP
中科院分区：
文献类型：
--
作者：
Meng F;Abedini A;Plesner A;Middleton CT;Potter KJ;Zanni MT;Verchere CB;Raleigh DP
胰岛淀粉样多肽（IAPP），也称为胰淀素，是2型糖尿病中淀粉样蛋白形成的原因。胰岛淀粉样蛋白的形成被认为通过杀死β细胞而促成疾病的病理学，并且其还可能促成胰岛移植失败。淀粉样蛋白形成抑制剂的设计是一个活跃的研究领域，但与Aβ的大量工作相比，对IAPP抑制剂的关注相对较少，并且大多数IAPP淀粉样蛋白的小分子抑制剂通常仅在显著摩尔过量时才有效。在这里，我们表明，简单的磺化三苯甲烷衍生物酸性品红，（3-（1-（4-氨基-3-甲基-5-磺酸基苯基）-1-（4-氨基-3-磺酸基苯基）亚甲基）环己-1，4-二烯磺酸），是一种有效的抑制剂，在体外淀粉样蛋白形成的IAPP在亚化学计量水平和保护培养的大鼠INS-1细胞对人类IAPP的毒性作用。荧光检测的硫磺素-T结合测定、光散射、圆二色性、二维IR和TEM测量证实该化合物防止淀粉样蛋白原纤维形成。离子强度依赖的研究表明，介导的影响部分静电相互作用。在淀粉样蛋白形成的滞后期的不同时间点加入该化合物的实验已经开始，表明它通过捕获中间物质来阻止淀粉样蛋白的形成。该化合物对Aβ肽的有效性较低，表明其通过IAPP抑制淀粉样蛋白形成的特异性。这里报道的工作提供了一个新的IAPP淀粉样蛋白抑制剂的结构类别，并展示了二维IR表征淀粉样蛋白抑制剂相互作用的能力。
Islet amyloid polypeptide (IAPP), also known as amylin, is responsible for amyloid formation in type 2 diabetes. The formation of islet amyloid is believed to contribute to the pathology of the disease by killing β-cells and it may also contribute to islet transplant failure. The design of inhibitors of amyloid formation is an active area of research, but comparatively little attention has been paid to inhibitors of IAPP in contrast to the large body of work on Aβ and most small molecule inhibitors of IAPP amyloid are generally effective only when used at a significant molar excess. Here we show that the simple sulphonated triphenyl methane derivative acid fuchsin, (3-(1-(4-Amino-3-methyl-5-sulphonatophenyl)-1-(4-amino-3-sulphonatophenyl) methylene) cyclohexa-1,4-dienesulphonic acid), is a potent inhibitor of in vitro amyloid formation by IAPP at substoichiometric levels and protects cultured rat INS-1 cells against the toxic effects of human IAPP. Fluorescence detected thioflavin-T binding assays, light scattering, circular dichroism, two dimensional IR and TEM measurements confirm that the compound prevents amyloid fibril formation. Ionic strength dependent studies show that the effects are mediated in part by electrostatic interactions. Experiments in which the compound is added at different time points during the lag phase of amyloid formation have commenced reveal that it arrests amyloid formation by trapping intermediate species. The compound is less effective against the Aβ peptide, indicating specificity in its ability to inhibit amyloid formation by IAPP. The work reported here provides a new structural class of IAPP amyloid inhibitors and demonstrates the power of two-dimensional IR for characterizing amyloid inhibitor interactions.
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DOI：
10.1021/jp810261x
发表时间：
2009-02-26
期刊：
The journal of physical chemistry. B
影响因子：
--
作者：
Ling YL;Strasfeld DB;Shim SH;Raleigh DP;Zanni MT
通讯作者：
Zanni MT
影响因子：
2.9
作者：
Abedini, A;Singh, G;Raleigh, DP
通讯作者：
Raleigh, DP
影响因子：
82.9
作者：
KISILEVSKY, R;LEMIEUX, LJ;SZAREK, WA
通讯作者：
SZAREK, WA
DOI：
10.1073/pnas.84.23.8628
发表时间：
1987-12-01
影响因子：
11.1
作者：
COOPER, GJS;WILLIS, AC;REID, KBM
通讯作者：
REID, KBM
影响因子：
8.2
作者：
HUTTON, JC
通讯作者：
HUTTON, JC