Inhibition of islet amyloid polypeptide fibril formation: A potential role for heteroaromatic interactions
Inhibition of islet amyloid polypeptide fibril formation: A potential role for heteroaromatic interactions
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DOI：
10.1021/bi048582a
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发表时间：
2004-11-16
期刊：
影响因子：
2.9
通讯作者：
Gazit, E
中科院分区：
文献类型：
--
作者：
Porat, Y;Mazor, Y;Gazit, E
淀粉样蛋白原纤维的形成与主要的人类疾病有关，包括阿尔茨海默病、朊病毒病和2型糖尿病。因此，有效抑制淀粉样蛋白原纤维形成的方法在临床上是非常重要的。抑制淀粉样蛋白形成的主要方法是基于使用修饰的分子识别元件。在这里，我们证明了2型糖尿病相关的人胰岛淀粉样多肽（hIAPP）的淀粉样蛋白形成的有效抑制的修饰的芳香族肽片段和小的芳香族多酚分子。使用肽阵列分析的分子识别试验表明，hIAPP和其核心淀粉样蛋白生成模块之间的分子识别是由芳香族而不是疏水相互作用介导的。为了研究芳香族相互作用对抑制hIAPP原纤维形成的可能影响，我们使用了肽和小分子抑制剂。添加核心模块NFGAILSS的非淀粉样蛋白生成肽类似物，其中苯丙氨酸被酪氨酸取代（NYGAILSS），导致hIAPP对原纤维形成的实质性抑制。该抑制显著强于使用β-折叠断裂剂缀合的肽NFGAILPP实现的抑制。基于酪氨酸-苯丙氨酸相互作用的分子排列，我们认为这种抑制作用源于芳香杂环苯-苯酚相互作用的几何约束。根据这一观点，我们证明了小多酚分子（无毒的酚红化合物）对hIAPP原纤维形成和对胰腺β细胞的细胞毒性的显著抑制。总之，我们的研究结果提供了进一步的实验支持的潜在作用的芳香族相互作用的淀粉样蛋白的形成，并建立了一个新的方法，其抑制。
The formation of amyloid fibril is associated with major human diseases, including Alzheimer's disease, prion diseases, and type 2 diabetes. Methods for efficient inhibition of amyloid fibril formation are therefore highly clinically important. A principal approach for the inhibition of amyloid formation is based on the use of modified molecular recognition elements. Here, we demonstrate efficient inhibition of amyloid formation of the type 2 diabetes-related human islet amyloid polypeptide (hIAPP) by a modified aromatic peptide fragment and a small aromatic polyphenol molecule. A molecular recognition assay using peptide array analysis suggested that molecular recognition between hIAPP and its core amyloidogenic module is mediated by aromatic rather than hydrophobic interactions. To study the possible effect of aromatic interactions on inhibition of hIAPP fibril formation, we have used peptide and small molecule inhibitors. The addition of a nonamyloidogenic peptide analogue of the core module NFGAILSS, in which phenylalanine was substituted with tyrosine (NYGAILSS), resulted in substantial inhibition of fibril formation by hIAPP. The inhibition was significantly stronger than the one achieved using a beta-sheet breaker-conjugated peptide NFGAILPP. On the basis of the molecular arrangement of the tyrosinephenylalanine interaction, we suggest that the inhibition stems from the geometrical constrains of the heteroaromatic benzene-phenol interaction. In line with this notion, we demonstrate remarkable inhibition of hIAPP fibril formation and cytotoxicity toward pancreatic beta-cells by a small polyphenol molecule, the nontoxic phenol red compound. Taken together, our results provide further experimental support for the potential role of aromatic interactions in amyloid formation and establish a novel approach for its inhibition.