Aromaticity and amyloid formation: Effect of π-electron distribution and aryl substituent geometry on the self-assembly of peptides derived from hIAPP22-29
Aromaticity and amyloid formation: Effect of π-electron distribution and aryl substituent geometry on the self-assembly of peptides derived from hIAPP22-29
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DOI：
10.1016/j.abb.2014.12.008
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发表时间：
2015-02-01
影响因子：
3.9
通讯作者：
Desamero, Rue Z. B.
中科院分区：
文献类型：
--
作者：
Profit, Adam A.;Vedad, Jayson;Desamero, Rue Z. B.
来自人胰岛淀粉样多肽（hIAPP）的22-29区的肽（其在23位含有具有各种供电子和吸电子基团的苯丙氨酸类似物以及沿着杂芳族替代物）的全面研究已被用于询问π-电子分布如何影响淀粉样蛋白形成。使用浊度测量的动力学聚集研究表明，富电子芳环系统一致地消除hIAPP的淀粉样蛋白生成倾向（22-29）。贫电子系统调节聚集速率。拉曼和傅里叶变换红外光谱证实了衍生自含有贫电子苯丙氨酸类似物的肽的聚集体的平行β-折叠二级结构，并提供了环堆积的直接证据。透射电子显微镜证实淀粉样纤维的存在。芳基取代基的几何形状对肽自组装的影响表明，取代基的电子性质，而不是它们的空间分布是负责给电子基团肽聚集失败。发现非聚集性hIAPP（22-29）肽抑制全长hIAPP（1-37）的自组装。最有效的抑制肽含有具有对氨基和对甲酰胺基官能团的苯丙氨酸。这些新的肽可以作为未来的聚集抑制剂的发展线索。提出了富电子hIAPP（22-29）肽抑制胰淀素自组装的潜在机制。(C)2014 Elsevier Inc. All rights reserved.
A comprehensive investigation of peptides derived from the 22-29 region of human islet amyloid polypeptide (hIAPP) that contain phenylalanine analogs at position 23 with a variety of electron donating and withdrawing groups, along with heteroaromatic surrogates, has been employed to interrogate how pi-electron distribution effects amyloid formation. Kinetic aggregation studies using turbidity measurements indicate that electron rich aromatic ring systems consistently abolish the amyloidogenic propensity of hIAPP(22-29). Electron poor systems modulate the rate of aggregation. Raman and Fourier transform infrared spectroscopy confirm the parallel beta-sheet secondary structure of aggregates derived from peptides containing electron poor phenylalanine analogs and provide direct evidence of ring stacking. Transmission electron microscopy confirms the presence of amyloid fibrils. The effect of aryl substituent geometry on peptide self-assembly reveals that the electronic nature of substituents and not their steric profile is responsible for failure of the electron donating group peptides to aggregate. Non-aggregating hIAPP(22-29) peptides were found to inhibit the self-assembly of full-length hIAPP(1-37). The most potent inhibitory peptides contain phenylalanine with the p-amino and p-formamido functionalities. These novel peptides may serve as leads for the development of future aggregation inhibitors. A potential mechanism for inhibition of amylin self-assembly by electron rich hIAPP(22-29) peptides is proposed. (C) 2014 Elsevier Inc. All rights reserved.