Bhasikuttan Achikanath C, Mohanty Jyotirmayee
Radiation & Photochemistry Division, Bhabha Atomic Research Centre, Mumbai 400085, India.
Chem Commun (Camb). 2017 Mar 2;53(19):2789-2809. doi: 10.1039/c6cc08727b.
Amyloid fibrils are formed by the aberrant aggregation of proteins into highly ordered β-sheet structures and are believed to be the root cause of several neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Prion diseases, etc. and have been the subject of extensive biochemical, biophysical and clinical studies. Developing methods for the early detection of fibril formation using optical spectroscopic techniques and inhibition/disintegration of amyloid fibrils/plaques by introducing small molecules have been a major challenge to establish a clinically facile therapeutic intervention to combat these neurodegenerative diseases. This feature article provides an account of the recent reports from different research groups, including ours, on the optical detection, and inhibition/disintegration of mature fibrils using fluorescent probes and macrocyclic hosts such as cucurbiturils, calixarenes and cyclodextrins. Site specific or spectrally distinct fluorescence emission from a large number of fluorophores in a broad spectral region has been used to detect the fibrillation of different proteins/peptides, mainly insulin, α-synuclein, transthyretin, barstar, lysozyme, Aβ40 peptide, etc. On the one hand, while macrocyclic receptors modify the inter-protein interactions through molecular recognition of amino acid residues leading to the inhibition of amyloid fibrillation, on the other hand, one of the cavitands, p-sulfonatocalixarenes, has been demonstrated to cause the disintegration of mature fibrils, effectively through surface charge interactions, which destabilize the extended fibrillar structure into soluble or fine particles. Beneficially, the presence of extrinsic p-sulfonatocalix[4/6]arenes did not introduce any additional toxicity to the cell viability, which advocates its potential utility as a therapeutic for amyloidosis.
淀粉样纤维由蛋白质异常聚集形成高度有序的β-折叠结构，被认为是阿尔茨海默病、帕金森病、朊病毒病等多种神经退行性疾病的根本原因，并且一直是广泛的生物化学、生物物理学和临床研究的主题。利用光谱技术开发早期检测纤维形成的方法，以及通过引入小分子抑制/分解淀粉样纤维/斑块，一直是建立针对这些神经退行性疾病的临床简便治疗干预措施的一项重大挑战。这篇专题文章介绍了包括我们在内的不同研究小组最近关于使用荧光探针和大环主体（如葫芦脲、杯芳烃和环糊精）对成熟纤维进行光学检测以及抑制/分解的报道。在很宽的光谱区域内，大量荧光团的位点特异性或光谱不同的荧光发射已被用于检测不同蛋白质/肽（主要是胰岛素、α-突触核蛋白、转甲状腺素蛋白、芽孢杆菌RNA酶抑制剂、溶菌酶、Aβ40肽等）的纤维化。一方面，大环受体通过对氨基酸残基的分子识别来改变蛋白质间的相互作用，从而抑制淀粉样纤维化；另一方面，已证明一种穴状配体对磺基杯芳烃可通过表面电荷相互作用有效地使成熟纤维解体，这种相互作用会使延伸的纤维状结构不稳定，形成可溶的或细小的颗粒。有利的是，外在的对磺基杯[4/6]芳烃的存在对细胞活力没有引入任何额外的毒性，这表明其作为淀粉样变性治疗剂的潜在用途。
