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首页> 美国卫生研究院文献>PLoS Clinical Trials >The triphenylmethane dye brilliant blue G is only moderately effective at inhibiting amyloid formation by human amylin or at disaggregating amylin amyloid fibrils, but interferes with amyloid assays; Implications for inhibitor design
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The triphenylmethane dye brilliant blue G is only moderately effective at inhibiting amyloid formation by human amylin or at disaggregating amylin amyloid fibrils, but interferes with amyloid assays; Implications for inhibitor design

机译：三苯基甲烷染料亮蓝G仅在抑制人淀粉样蛋白形成淀粉样蛋白或分解淀粉样蛋白淀粉样蛋白原纤维方面具有中等效力，但会干扰淀粉样蛋白的测定。对抑制剂设计的影响

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The development of inhibitors of islet amyloid formation is important as pancreatic amyloid deposition contributes to type-2 diabetes and islet transplant failure. The Alzheimer’s Aβ peptide and human amylin (h-amylin), the polypeptide responsible for amyloid formation in type-2 diabetes, share common physio-chemical features and some inhibitors of Aβ also inhibit amyloid formation by h-amylin and vice versa. Thus, a popular and potentially useful strategy to find lead compounds for anti-amylin amyloid agents is to examine compounds that have effects on Aβ amyloid formation. The triphenylmethane dye, brilliant blue G (BBG, Sodium;3-[[4-[(E)-[4-(4-ethoxyanilino)phenyl]-[4-[ethyl-[(3-sulfonatophenyl)methyl]azaniumylidene]-2-methylcyclohexa-2,5-dien-1-ylidene]methyl]-N-ethyl-3-methylanilino]methyl]benzenesulfonate) has been shown to modulate Aβ amyloid formation and inhibit Aβ induced toxicity. However, the effects of BBG on h-amylin have not been examined, although other triphenylmethane derivatives inhibit h-amylin amyloid formation. The compound has only a modest impact on h-amylin amyloid formation unless it is added in significant excess. BBG also remodels preformed h-amylin amyloid fibrils if added in excess, however BBG has no significant effect on h-amylin induced toxicity towards cultured β-cells or cultured CHO-T cells except at high concentrations. BBG is shown to interfere with standard thioflavin-T assays of h-amylin amyloid formation and disaggregation, highlighting the difficulty of interpreting such experiments in the absence of other measurements. BBG also interferes with ANS based assays of h-amylin amyloid formation. The work highlights the differences between inhibition of Aβ and h-amylin amyloid formation, illustrates the limitation of using Aβ inhibitors as leads for h-amylin amyloid inhibitors, and reinforces the difficulties in interpreting dye binding assays of amyloid formation.
机译：胰岛淀粉样蛋白形成抑制剂的开发非常重要，因为胰腺淀粉样蛋白沉积会导致2型糖尿病和胰岛移植失败。阿尔茨海默氏症的Aβ肽和人类淀粉样蛋白（h-淀粉样蛋白）（负责2型糖尿病淀粉样蛋白形成的多肽）具有共同的生理化学特征，某些Aβ抑制剂也抑制h-淀粉样蛋白形成淀粉样蛋白，反之亦然。因此，寻找抗淀粉样蛋白淀粉状蛋白剂的先导化合物的一种流行且潜在有用的策略是研究对Aβ淀粉样蛋白形成有影响的化合物。三苯基甲烷染料，亮蓝色G（BBG，钠； 3-[[4-[（E）-[4-（4-乙氧基苯胺基）苯基]-[4- [乙基-[（3-磺酰基苯基）甲基]氮杂亚基]] -2-甲基环六-2,5-二烯基-1，亚基]甲基] -N-乙基-3-甲基苯胺基]甲基]苯磺酸盐已被证明可调节Aβ淀粉样蛋白的形成并抑制Aβ诱导的毒性。然而，尽管其他三苯基甲烷衍生物抑制了β-淀粉样蛋白的淀粉样蛋白形成，但是BBG对β-淀粉样蛋白的作用尚未得到检验。除非添加明显过量，否则该化合物对h-淀粉样蛋白淀粉样蛋白的形成仅具有中等程度的影响。如果过量加入，BBG也会重塑预先形成的h-淀粉样蛋白淀粉样原纤维，但是，BBG对h-淀粉样蛋白诱导的对培养的β细胞或CHO-T细胞的毒性没有显着影响，除非高浓度。已证明BBG会干扰h-淀粉状蛋白淀粉样蛋白形成和分解的标准硫代黄素-T分析，突显了在没有其他测量值的情况下难以解释此类实验的困难。 BBG还干扰了基于h-淀粉样蛋白淀粉样蛋白形成的ANS分析。这项工作突出了抑制Aβ和h-淀粉样蛋白淀粉样蛋白形成之间的差异，说明了使用Aβ抑制剂作为h-淀粉样蛋白淀粉样蛋白抑制剂的限制，并增加了解释淀粉样蛋白形成的染料结合测定法的难度。

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