Center for Insoluble Protein Structures (inSPIN), Aarhus University, Denmark.
J Phys Chem B. 2010 Dec 9;114(48):16003-10. doi: 10.1021/jp108035y. Epub 2010 Nov 15.
Aggregation of the Amyloid β peptide into amyloid fibrils is closely related to development of Alzheimer's disease. Many small aromatic compounds have been found to act as inhibitors of fibril formation, and have inspired the search for new drug candidates. However, the detailed mechanisms of inhibition are largely unknown. In this study, we have examined in detail the binding of the fibril-formation inhibitor Congo Red (CR) to monomeric Aβ(1-40) using a combination of 1D, 2D, saturation transfer difference, and diffusion NMR, as well as dynamic light scattering experiments. Our results show that CR binds to the fibril forming stretches of Aβ(1-40) monomers, and that complex formation occurs in two steps: An initial 1:1 CR:Aβ(1-40) complex is formed by a relatively strong interaction (K(d) ≈ 5 μM), and a 2:1 complex is formed by binding another CR molecule in a subsequent weaker binding step (K(d) ≈ 300 μM). The size of these complexes is comparable to that of Aβ(1-40) alone. The existence of two different complexes might explain the contradictory reports regarding the inhibitory effects of CR on the fibril-formation process.
β淀粉样蛋白肽的聚集与阿尔茨海默病的发展密切相关。已经发现许多小分子芳香化合物可以作为纤维形成抑制剂，并激发了对新候选药物的研究。然而，抑制的详细机制在很大程度上尚不清楚。在这项研究中，我们使用 1D、2D、饱和转移差异和扩散 NMR 以及动态光散射实验，详细研究了纤维形成抑制剂刚果红（CR）与单体 Aβ（1-40）的结合。我们的结果表明，CR 结合到 Aβ（1-40）单体的纤维形成伸展部位，并且复合物的形成分两步进行：通过相对较强的相互作用（K（d）≈5μM）形成初始 1:1 CR:Aβ（1-40）复合物，并且在随后较弱的结合步骤中通过结合另一个 CR 分子形成 2:1 复合物（K（d）≈300μM）。这些复合物的大小与 Aβ（1-40）本身的大小相当。两种不同复合物的存在可能解释了 CR 对纤维形成过程的抑制作用的相互矛盾的报告。
