Oligo(ethylene glycol) derivatives of thioflavin T as inhibitors of protein-amyloid interactions
Oligo(ethylene glycol) derivatives of thioflavin T as inhibitors of protein-amyloid interactions
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DOI：
10.1002/cbic.200600119
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发表时间：
2006-10-01
期刊：
影响因子：
3.2
通讯作者：
Yang, Jerry
中科院分区：
文献类型：
--
作者：
Inbar, Petra;Li, Cui Q.;Yang, Jerry
抑制蛋白质与聚集形式的β-淀粉样蛋白（Aβ）肽相互作用的小分子可能有助于减轻Aβ在阿尔茨海默病（AD）中的潜在毒性。[1，2]例如，细胞蛋白与聚集的Aβ肽的相互作用被认为是Aβ的潜在致病机制，可能导致其在AD中的神经毒性。[1，3-6]我们最近报道了淀粉样斑块的组织学染色剂，如硫磺素T（ThT），能够部分抑制抗A β IgG与合成Aβ肽（残基1-42）形成的原纤维的相互作用。[2]我们提出，小分子以足够高的密度和均匀性结合，从而在Aβ原纤维表面产生蛋白质抗性涂层（图1A）。在此，我们描述了两种新的ThT衍生物的开发，其设计为1）与ThT相比，Aβ纤维上的结合位点密度增加，2）比ThT更好的生物相容性，用于细胞或体内测定中蛋白质-淀粉样蛋白抑制的潜在研究（例如，增强的透过细胞膜和血脑屏障的可能性[7]），和3）在水溶液中的良好溶解性。我们检测了ThT的这两种寡聚（乙二醇）衍生物（BTA-EG 4和BTA-EG 6，图1B）抑制Aβ原纤维与三种蛋白质（抗A β IgG、过氧化氢酶（EC 1.11. 1.6，来自人红细胞）和人淀粉样蛋白结合醇脱氢酶（ABAD，EC 1.1. 1.35）。我们的研究结果表明，用ThT的这些衍生物在Aβ原纤维上产生分子涂层通常比ThT更有效地抑制蛋白质-淀粉样蛋白相互作用。我们以前报道过，ThT可以抑制最多约65%的单克隆Aβ结合IgG与Aβ肽（残基1-42）形成的原纤维的结合。[2]观察到的par-ACHTUNGTRENNUNGtial抑制可能是由于小分子不能完全包被表面并阻断蛋白质沿原纤维轴沿着的所有潜在结合位点。有了这些结果，我们假设与Aβ纤维结合的分子比ThT密度更高，
Small molecules that inhibit the interaction of proteins with aggregated forms of β-amyloid (Aβ) peptides could be useful for attenuating the potential toxicity of Aβ in Alzheimer’s disease (AD).[1, 2] The interaction of cellular proteins with aggregated Aβ peptides has been suggested, for instance, as a potential pathogenic mechanism for Aβ that could contribute to its neurotoxicity in AD.[1, 3–6] We recently reported that histological staining agents for amyloid plaques, such as thioflavin T (ThT), were capable of partially inhibiting the interaction of anti-Aβ IgGs with fibrils formed from synthetic Aβ peptides (residues 1–42).[2] We proposed that the small molecules bound with high enough density and uniformity that they generated protein-resistive coatings on the surface of Aβ fibrils (Figure 1A). Herein, we describe the development of two new derivatives of ThT that are designed to have 1) increased density of binding sites on Aβ fibrils compared to ThT, 2) better biocompatibility than ThT for the potential study of protein–amyloid inhibition in cellular or in vivo assays (eg, enhanced likeliness for permeability through cell membranes and the blood–brain barrier [7]), and 3) good solubility in aqueous solutions. We examined the ability of these two oligo (ethylene glycol) derivatives of ThT (BTA-EG4 and BTA-EG6, Figure 1B) to inhibit the binding interaction between Aβ fibrils and three proteins—an anti-Aβ IgG, catalase (EC 1.11. 1.6, from human erythrocytes), and human amyloid-binding alcohol dehydrogenase (ABAD, EC 1.1. 1.35). Our results suggest that generating molecular coatings on Aβ fibrils with these derivatives of ThT is generally more effective at inhibiting protein–amyloid interactions than ThT.We previously reported that ThT can inhibit a maximum of∼ 65% of the binding of monoclonal Aβ-binding IgGs to fibrils formed from Aβ peptides (residues 1–42).[2] The observed par-ACHTUNGTRENNUNGtial inhibition might be due to the inability of the small molecule to completely coat the surface and block all potential binding sites for the protein along the fibril axis. With these results in hand, we hypothesized that molecules that bind to Aβ fibrils with a higher density than ThT might generate more