d-Enantiomeric RTHLVFFARK-NH2: A Potent Multifunctional Decapeptide Inhibiting Cu2+-Mediated Amyloid β-Protein Aggregation and Remodeling Cu2+-Mediated Amyloid β Aggregates.
d-Enantiomeric RTHLVFFARK-NH2: A Potent Multifunctional Decapeptide Inhibiting Cu2+-Mediated Amyloid β-Protein Aggregation and Remodeling Cu2+-Mediated Amyloid β Aggregates.
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DOI：
10.1021/acschemneuro.8b00440
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发表时间：
2019-01
影响因子：
5
通讯作者：
Wei Liu;Xiaoyan Dong;Yan Sun
中科院分区：
文献类型：
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作者：
Wei Liu;Xiaoyan Dong;Yan Sun
淀粉样β蛋白（Aβ）聚集成富含β-片层的斑块是阿尔茨海默病（AD）的一般特征。Cu 2+的稳态失调介导Aβ形成高细胞毒性聚集体，其通过产生活性氧（ROS）引起细胞损伤。为了提高抑制效力并探索我们先前设计的十肽RTHLVFFARK-NH 2（RK 10）的多方面功能，我们在此将十肽重新配制为其d-对映体rk 10，并研究手性对Aβ聚集、Cu 2+介导的Aβ聚集和聚集重塑效应的影响。结果表明：（1）与RK 10相比，d-对映体对Aβ纤维形成的抑制作用增强;在与Aβ等摩尔浓度下，rk 10和RK 10分别使细胞活力从60%提高到91%和71%。(2)对映体的化学等价于Cu 2+螯合，ROS抑制和氧化损伤救援。(3)与RK 10相比，D-对映体对Cu 2+介导的Aβ聚集的抑制作用更强，对Aβ42-Cu 2+复合物引起的细胞毒性的抑制作用更显著。通过与50 μM rk 10和RK 10共孵育，细胞活力分别从51%恢复至89%和74%。rk 10处理后，Aβ42和Aβ42-Cu 2+物质产生的细胞内ROS水平也显著降低。(4)对映体可通过Cu 2+螯合作用重塑成熟Aβ42-Cu 2+聚集体，rk 10表现出比RK 10更高的性能，如RK 10将细胞活力从57%提高到86%和rk 10提高到96%所证明的。d-对映体也显示出比RK 10更高的保护被破坏的物种免于再聚集的能力。综上所述，十肽的D-手性衍生化产生了抑制Cu 2+介导的Aβ聚集和重塑成熟Aβ-Cu 2+种类的有效多功能剂。据我们所知，这是首次研究多功能肽抑制剂对Cu 2+介导的Aβ聚集的手性效应以及对成熟Aβ-Cu 2+聚集体的重塑效应。这项工作为手性在肽抑制剂对淀粉样蛋白形成及其毒性的多方面功能中的关键作用提供了新的见解。
Aggregation of amyloid β-protein (Aβ) into β-sheet-rich plaques is a general feature of Alzheimer's disease (AD). Homeostasis dysregulation of Cu2+ mediates Aβ to form high cytotoxic aggregates, which causes cell damage by generation of reactive oxygen species (ROS). To improve the inhibitory potency and explore the multifaceted functions of our previously designed decapeptide, RTHLVFFARK-NH2 (RK10), we have herein reformulated the decapeptide into its d-enantiomer, rk10, and the effects of chirality on Aβ aggregation, Cu2+-mediated Aβ aggregations, and aggregate-remodeling effects were investigated. The results revealed the following: (1) The d-enantiomer presented enhanced inhibitory potency on Aβ fibrillogenesis in comparison to RK10; rk10 and RK10 increased the cell viability from 60% to 91% and 71%, respectively, at an equimolar concentration to Aβ. (2) The enantiomers were chemically equivalent to Cu2+ chelation, ROS suppression and oxidative damage rescue. (3) The d-enantiomer exhibited higher performance to inhibit Cu2+-mediated Aβ aggregation, and more significantly attenuated the cytotoxicity caused by Aβ42-Cu2+ complex than RK10. Cell viability was rescued from 51% to 89% and 74% by coincubating with rk10 and RK10 at 50 μM, respectively. Intracellular ROS levels generated by Aβ42 and Aβ42-Cu2+ species were also remarkably decreased by treating with rk10. (4) The enantiomers could remodel mature Aβ42-Cu2+ aggregates by Cu2+ chelation, and rk10 showed higher performance than RK10, as evidenced by the enhanced cell viability from 57% to 86% by RK10 and to 96% by rk10. The d-enantiomer also showed higher ability than RK10 on protecting the disrupted species from reaggregation. Taken together, D-chiral derivatization of the decapeptide resulted in a potent multifunctional agent in inhibiting Cu2+-mediated Aβ aggregation and remodeling mature Aβ-Cu2+ species. To the best of our knowledge, this is the first investigation on the chirality effect of a multifunctional peptide inhibitor on Cu2+-mediated Aβ aggregation and on the remodeling effect of mature Aβ-Cu2+ aggregates. The work provides new insights into the critical role of chirality in the multifaceted functions of peptide inhibitors against amyloid formation and its toxicity.