Structural and mechanistic insights into the inhibition of amyloid-β aggregation by Aβ39-42 fragment derived synthetic peptides
Structural and mechanistic insights into the inhibition of amyloid-β aggregation by Aβ39-42 fragment derived synthetic peptides
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DOI：
10.1016/j.ejmech.2020.113126
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发表时间：
2021-01-01
影响因子：
6.7
通讯作者：
Jain, Rahul
中科院分区：
文献类型：
--
作者：
Kapadia, Akshay;Sharma, Krishna K.;Jain, Rahul
抑制淀粉样蛋白- β (A β)聚集是治疗阿尔茨海默病（AD）的一种很有前途的方法。以亲本A β肽的A β (39-42) c端片段为基础合成了38个四肽。采用非天然氨基酸的顺序替换/修饰赋予支架多样性，增强活性，增强血脑屏障通透性，并为合成肽提供蛋白水解稳定性。在10 μ M到0.1 μ M的剂量范围内，一些肽对PC-12细胞的A β聚集介导的神经毒性有很好的保护作用，进一步由硫黄素- t荧光试验证实。CD研究表明，这些肽限制了β片的形成，并且在电子显微镜下没有出现A β(42)纤维结构证实了A β(42)聚集的抑制作用。HRMS和ANS荧光光谱分析提供了额外的机制见解。两种选择的导联肽5和16描述了对血清和蛋白水解酶增强的血脑渗透和稳定性。在A β的单体和原纤维单位上对配体-A β相互作用的结构见解进行了计算研究。前导肽具有良好的抑制潜力和较短的序列，为肽源性阿尔茨海默病的治疗提供了新的途径。(C) 2020 Elsevier Masson SAS。版权所有。
The inhibition of amyloid-beta (A beta) aggregation is a promising approach towards therapeutic intervention for Alzheimer's disease (AD). Thirty eight tetrapeptides based upon A beta(39-42) C-terminus fragment of the parent A beta peptide were synthesized. The sequential replacement/modification employing unnatural amino acids imparted scaffold diversity, augmented activity, enhanced blood brain barrier permeability and offered proteolytic stability to the synthetic peptides. Several peptides exhibited promising protection against A beta aggregation-mediated-neurotoxicity in PC-12 cells at doses ranged between 10 mu M and 0.1 mu M, further confirmed by the thioflavin-T fluorescence assay. CD study illustrate that these peptides restrict the beta-sheet formation, and the non-appearance of A beta(42) fibrillar structures in the electron microscopy confirm the inhibition of A beta(42) aggregation. HRMS and ANS fluorescence spectroscopic analysis provided additional mechanistic insights. Two selected lead peptides 5 and 16 depicted enhanced blood-brain penetration and stability against serum and proteolytic enzyme. Structural insights into ligand-A beta interactions on the monomeric and proto-fibrillar units of A beta were computationally studied. Promising inhibitory potential and short sequence of the lead peptides offers new avenues for the advancement of peptide-derived therapeutics for AD. (C) 2020 Elsevier Masson SAS. All rights reserved.