Hydrophobic Modification of Carboxyl-Terminated Polyamidoamine Dendrimer Surface Creates a Potent Inhibitor of Amyloid-β Fibrillation.
Hydrophobic Modification of Carboxyl-Terminated Polyamidoamine Dendrimer Surface Creates a Potent Inhibitor of Amyloid-β Fibrillation.
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DOI：
10.1021/acs.langmuir.8b02890
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发表时间：
2018-11
期刊：
影响因子：
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通讯作者：
Ziyuan Wang;Xiaoyan Dong;Y. Sun
中科院分区：
文献类型：
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作者：
Ziyuan Wang;Xiaoyan Dong;Y. Sun
淀粉样β-肽（a β）纤维形成是阿尔茨海默病（AD）的主要标志；因此，抑制a β颤动被认为是一种很有前途的AD预防和治疗策略。本课组此前提出了疏水结合-静电斥力（HyBER）假说，为设计新的淀粉样蛋白抑制剂提供了指导。受HyBER假设的启发，我们在此提出了合成疏水修饰的第5代端羧基聚氨基胺树状大分子，记为PAMP，以创造一种具有负电荷疏水表面的有效抑制剂。结果表明，适当苯基取代（30-42%）的PAMP通过其表面的疏水结合和静电斥力改变了a β42的构象。通过这些平衡的相互作用，抑制剂甚至可以完全抑制肽β-片结构的形成，并伴有原纤维结构水平的变化。此外，结果还表明，受PAMP影响的Aβ42聚集途径的变化发生在早期，因此PAMP可以显著避免Aβ42聚集的毒性中间体的形成。
Amyloid β-peptide (Aβ) fibrillogenesis is a major hallmark of Alzheimer's disease (AD); inhibition of Aβ fibrillation is thus considered as a promising strategy for AD prevention and treatment. Our group has previously proposed the hydrophobic binding-electrostatic repulsion (HyBER) hypothesis, which provides guidance for the design of new amyloid inhibitors. Inspired by the HyBER hypothesis, we have herein proposed to synthesize hydrophobic-modified generation 5 carboxyl-terminated polyamidoamine dendrimer, denoted as PAMP, to create a potent inhibitor with a negatively charged hydrophobic surface. Results indicate that the PAMP with a proper degree of phenyl substitution (30-42%) alters the conformation of Aβ42 through both hydrophobic binding and electrostatic repulsive forces on its surface. With these well-balanced interactions, the inhibitor can even completely inhibit the formation of β-sheet structure of the peptide, accompanied by changes at the level of the fibrillary architecture. Moreover, the results also indicate that changes of Aβ42 aggregation pathway influenced by the PAMP occur at the very early stage, so the PAMP can significantly avoid the formation of toxic intermediates of Aβ42 aggregation.