The flavanol (-)-epigallocatechin 3-gallate inhibits amyloid formation by islet amyloid polypeptide, disaggregates amyloid fibrils, and protects cultured cells against IAPP-induced toxicity.
The flavanol (-)-epigallocatechin 3-gallate inhibits amyloid formation by islet amyloid polypeptide, disaggregates amyloid fibrils, and protects cultured cells against IAPP-induced toxicity.
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DOI：
10.1021/bi100939a
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发表时间：
2010-09-21
期刊：
影响因子：
2.9
通讯作者：
Raleigh, Daniel P.
中科院分区：
文献类型：
--
作者：
Meng, Fanling;Abedini, Andisheh;Plesner, Annette;Verchere, C. Bruce;Raleigh, Daniel P.
胰岛淀粉样多肽（IAPP，amylin）是与 2 型糖尿病相关的胰岛淀粉样蛋白沉积物的主要蛋白质成分。该多肽在单体状态下缺乏明确的结构，但很容易组装形成淀粉样蛋白。由 IAPP 形成的淀粉样原纤维、IAPP 淀粉样蛋白组装过程中产生的中间体或两者对 β 细胞具有毒性，表明胰岛淀粉样蛋白的形成可能导致 2 型糖尿病的病理学。 IAPP 抑制淀粉样蛋白形成的报道相对较少。在这里，我们发现茶衍生的黄烷醇，(−)-表没食子儿茶素 3-没食子酸酯，[(2R,3R)-5,7-二羟基-2-(3,4,5-三羟基苯基)-3,4-二氢-2H-1-苯并吡喃-3-基3,4,5-三羟基苯甲酸酯]，(EGCG)，是体外 IAPP 淀粉样蛋白形成和解聚的有效抑制剂。源自 IAPP 的淀粉样原纤维。因此，该化合物是已被证明可以分解 IAPP 淀粉样原纤维的极小分子之一。荧光检测的硫黄素-T 结合测定和透射电子显微镜证实该化合物抑制未接种的淀粉样蛋白原纤维的形成以及解聚 IAPP 淀粉样蛋白。播种研究表明，IAPP 和 EGCG 形成的复合物不会为 IAPP 形成淀粉样蛋白形成种子。在这方面，IAPP 的行为类似于已报道的 Aβ 和 α-突触核蛋白与 EGCG 的相互作用。阿尔马尔蓝测定和光学显微镜表明该化合物可以保护培养的大鼠 INS-1 细胞免受 IAPP 诱导的毒性。因此，EGCG 为进一步开发 IAPP 淀粉样蛋白形成抑制剂和分解 IAPP 淀粉样蛋白的化合物提供了一个有趣的先导结构。
Islet amyloid polypeptide (IAPP, amylin) is the major protein component of islet amyloid deposits associated with type 2 diabetes. The polypeptide lacks a well–defined structure in its monomeric state, but readily assembles to form amyloid. Amyloid fibrils formed from IAPP, intermediates generated in the assembly of IAPP amyloid, or both are toxic to β-cells suggesting that islet amyloid formation may contribute to the pathology of type 2 diabetes. There are relatively few reported inhibitors of amyloid formation by IAPP. Here we show that the tea–derived flavanol, (−)-Epigallocatechin 3-Gallate, [(2R,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-2H-1-benzopyran-3-yl 3,4,5-trihydroxybenzoate], (EGCG), is an effective inhibitor of in vitro IAPP amyloid formation and disaggregates preformed amyloid fibrils derived from IAPP. The compound is thus one of a very small set of molecules which have been shown to disaggregate IAPP amyloid fibrils. Fluorescence detected thioflavin-T binding assays and transmission electron microscopy confirm that the compound inhibits unseeded amyloid fibril formation as well as disaggregates IAPP amyloid. Seeding studies show that the complex formed by IAPP and EGCG does not seed amyloid formation by IAPP. In this regard, the behavior of IAPP is similar to the reported interactions of Aβ and α–synuclein with EGCG. Alamar blue assays and light microscopy indicate that the compound protects cultured rat INS-1 cells against IAPP–induced toxicity. Thus, EGCG offers an interesting lead structure for further development of inhibitors of IAPP amyloid formation and compounds that disaggregate IAPP amyloid.
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