Recognition sequence design for peptidyl modulators of β-amyloid aggregation and toxicity
Recognition sequence design for peptidyl modulators of β-amyloid aggregation and toxicity
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DOI：
10.1021/bi982119e
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发表时间：
1999-03-23
期刊：
影响因子：
2.9
通讯作者：
Murphy, RM
中科院分区：
文献类型：
--
作者：
Pallitto, MM;Ghanta, J;Murphy, RM
β-淀粉样蛋白（Aβ）是阿尔茨海默病斑块的主要蛋白质成分，当聚集成原纤维时具有神经毒性。我们设计了一种模块化策略，用于生成抑制 A β 毒性的化合物，其基础是将 A β 的识别元件与旨在干扰 A β 聚集的破坏元件连接起来。一种这样的化合物，以 A β 的 15-25 序列作为识别元件，以赖氨酸六聚体作为破坏元件，改变了 A β 聚集动力学并保护细胞免受 A β 毒性[Ghanta 等，2017]。 (1996) J.Biol。化学。 271, 29525]。为了优化识别元件，合成了由 15-25 结构域内的重叠序列组成的 4-8 个残基的肽，以及含有与赖氨酸六聚体偶联的这些识别序列的杂合化合物。没有一个识别肽改变 Aβ 聚集动力学，并且只有 KLVFF 和 KLVF 两种对 Aβ 毒性具有任何保护作用。与单独的识别肽相比，杂合肽 KLVFF-KKKKKK 显着改变了 A β 聚集动力学和聚集体形态，并提供了显着改善的针对 A β 毒性的保护。相比之下，FAEDVG-KKKKKK 仅具有适度的抑制活性，并且对 Aβ 聚集没有显着影响。乱序序列 VLFKF 几乎与 KLVFF 一样有效，这表明识别序列的疏水特性至关重要。没有一种细胞保护肽能够阻止 Aβ 聚集；相反，它们增加了聚集体尺寸并改变了聚集体形态。这些结果表明，将识别与破坏元件耦合是创建 Aβ 抑制剂的有效的通用策略。值得注意的是，预防 Aβ 聚集可能不需要预防毒性。
beta-Amyloid (A beta), the primary protein component of Alzheimer's plaques, is neurotoxic when aggregated into fibrils. We have devised a modular strategy for generating compounds that inhibit A beta toxicity, based on linking a recognition element for A beta to a disrupting element designed to interfere with A beta aggregation. One such compound, with the 15-25 sequence of A beta as the recognition element and a lysine hexamer as the disrupting element, altered A beta aggregation kinetics and protected cells from A beta toxicity [Ghanta et al. (1996) J. Biol. Chem. 271, 29525]. To optimize the recognition element, peptides of 4-8 residues composed of overlapping sequences within the 15-25 domain were synthesized, along with hybrid compounds containing those recognition sequences coupled to a lysine hexamer, None of the recognition peptides altered A beta aggregation kinetics and only two, KLVFF and KLVF, had any protective effect against A beta toxicity. The hybrid peptide KLVFF-KKKKKK dramatically altered A beta aggregation kinetics and aggregate morphology and provided significantly improved protection against A beta toxicity compared to the recognition peptide alone. In contrast, FAEDVG-KKKKKK possessed only modest inhibitory activity and had no marked effect on A beta aggregation. The scrambled sequence VLFKF was nearly as effective a recognition domain as KLVFF, suggesting the hydrophobic characteristics of the recognition sequence are critical. None of the cytoprotective peptides prevented A beta aggregation; rather, they increased aggregate size and altered aggregate morphology. These results suggest that coupling recognition with disrupting elements is an effective generalizable strategy for the creation of A beta inhibitors. Significantly, prevention of A beta aggregation may not be required fur prevention of toxicity.