Molecular Science Lab, National Institute of Immunology, New Delhi 110067, India.
Molecular Science Lab, National Institute of Immunology, New Delhi 110067, India.
Eur J Med Chem. 2018 Jan 1;143:1174-1184. doi: 10.1016/j.ejmech.2017.10.002. Epub 2017 Oct 12.
Inhibition of amyloid formation along with modulation of toxicity employing small molecules is emerging as a potential therapeutic approach for protein misfolding disorders which includes Parkinson's disease, Alzheimer's disease and Multiple System Atrophy etc. Countless current interventional strategies for treating α-synucleinopathies consider using peptidic and non-peptidic inhibitors for arresting fibrillisation, disrupting existing fibrils and reducing associated toxicity. One group of molecules less exploited in this regard are triphenylmethane dyes. Herein we tested the inhibitory effect of two routinely used protein staining dyes viz Coomassie Brilliant blue G (CBBG) and Coomassie Brilliant blue R (CBBR) employing several biophysical and cell based methods. Our results showed that both the dyes not only efficiently inhibit fibrillisation but also disrupt existing fibrils. Nonetheless, only CBBR prevented the appearance of A11 epitopes which are marker of toxicity. Moreover, CBBR was also able to stall fibrillisation of A53T mutant α-synuclein and reduce associated neurotoxicity. This study thus reports the potential of CBBR as a therapeutic molecule.
采用小分子抑制淀粉样蛋白形成并调节毒性，这正在成为一种治疗蛋白质错误折叠疾病（包括帕金森病、阿尔茨海默病和多系统萎缩等）的潜在治疗方法。目前有无数针对α-突触核蛋白病的干预策略，考虑使用肽类和非肽类抑制剂来阻止纤维化、破坏现有的纤维和降低相关毒性。在这方面，三苯甲烷染料一类的分子尚未得到充分利用。本文中，我们使用多种生物物理和基于细胞的方法，测试了两种常规使用的蛋白质染色染料考马斯亮蓝 G（CBBG）和考马斯亮蓝 R（CBBR）的抑制效果。结果表明，这两种染料不仅能有效抑制纤维化，还能破坏现有的纤维。然而，只有 CBBR 能阻止毒性标志物 A11 表位的出现。此外，CBBR 还能阻止 A53T 突变型α-突触核蛋白的纤维化，并降低相关神经毒性。因此，本研究报告了 CBBR 作为一种治疗分子的潜力。
