Centre for Healthcare Science and Technology, IIEST, Shibpur, P.O. Botanic Garden, Howrah, West Bengal, 711103, India.
Structural Biology & Bioinformatics Division, CSIR-IICB, Kolkata, 4, S.C. Mallick Road, Jadavpur, Kolkata, West Bengal, 700032, India.
Mol Neurobiol. 2019 Sep;56(9):6551-6565. doi: 10.1007/s12035-019-1542-1. Epub 2019 Mar 12.
The amyloid cascade hypothesis dealing with the senile plaques is until date thought to be one of the causative pathways leading to the pathophysiology of Alzheimer's disease (AD). Though many aggregation inhibitors of misfolded amyloid beta (Aβ) peptide have failed in clinical trials, there are some positive aspects of the designed therapeutic peptides for diseases involving proteinaceous aggregation. Here, we evaluated a smart design of side chain tripeptide (Leu-Val-Phe)-based polymeric inhibitor addressing the fundamental hydrophobic amino acid stretch "Lys-Leu-Val-Phe-Phe-Ala" (KLVFFA) of the Aβ peptide. The in vitro analyses performed through the thioflavin T (ThT) fluorescence assay, infrared spectroscopy, isothermal calorimetry, cytotoxicity experiments, and so on evinced a promising path towards the development of new age AD therapeutics targeting the inhibition of misfolded Aβ peptide fibrillization. The in silico simulations done contoured the mechanism of drug action of the present block copolymer as the competitive inhibition of aggregate-prone hydrophobic stretch of Aβ. Graphical abstract The production of misfolded Aβ peptide from amyloid precursor protein initiates amyloidosis pathway which ends with the deposition of fibrils via the oligomerization and aggregation of Aβ monomers. The side chain tripeptide-based PEGylated polymer targets these Aβ monomers and oligomers inhibiting their aggregation. This block copolymer also binds and helps degrading the preformed fibrils of Aβ.
淀粉样蛋白级联假说涉及老年斑，直到目前为止，它被认为是导致阿尔茨海默病（AD）病理生理学的致病途径之一。虽然许多错误折叠淀粉样β（Aβ）肽的聚集抑制剂在临床试验中失败了，但针对涉及蛋白质聚集的疾病的设计治疗性肽具有一些积极方面。在这里，我们评估了一种基于侧链三肽（亮氨酸-缬氨酸-苯丙氨酸）的智能设计的聚合物抑制剂，该抑制剂针对 Aβ 肽的基本疏水性氨基酸片段“赖氨酸-亮氨酸-缬氨酸-苯丙氨酸-苯丙氨酸-丙氨酸”（KLVFFA）。通过硫黄素 T（ThT）荧光测定、红外光谱、等温量热法、细胞毒性实验等进行的体外分析表明，针对错误折叠 Aβ 肽纤维化抑制的新型 AD 治疗药物的开发具有广阔的前景。所做的计算机模拟描绘了本嵌段共聚物的作用机制，即作为 Aβ 聚集倾向疏水性片段的竞争性抑制。
