Mapping ApoE/Aβ binding regions to guide inhibitor discovery.-猫眼课题宝

绘制 ApoE/Aβ 结合区域图以指导抑制剂的发现。

DOI：

发表时间：

2011

期刊：

Molecular Biosystems

影响因子：

通讯作者：

中科院分区：

生物3区

文献类型：

作者：

Qian;Wei‐hui Wu;C. Fang;Ren;Peng Liu;P. Lei;Jia Hu;Xun Sun;Yi;Yu;Yan‐Mei Li

阻断载脂蛋白E（ApoE）E4亚型与淀粉样β肽（Aβ）之间的相互作用可能是药物干预阿尔茨海默病（AD）的一种途径。这两种蛋白相互作用的主要区域分别是ApoE 244 -272和Aβ12-28。这些蛋白质片段太大而不利于小分子抑制剂的设计。我们将ApoE/Aβ相互作用的主要组分定位到较小的肽段。在主要负责ApoE/Aβ相互作用的三个基序中，我们鉴定了四个基本上阻断ApoE/Aβ相互作用的肽，并通过合理的疏水氨基酸取代进一步提高了它们的抑制活性。此外，定位结果提供了与ApoE相互作用的Aβ残基似乎位于Aβ自身相互作用的同一区域的线索。根据这一信息，我们发现刚果红和X-34可以强烈抑制ApoE/Aβ相互作用。我们的发现扩展了我们对ApoE/Aβ相互作用的理解，并可能指导通过拮抗ApoE/Aβ相互作用来治疗AD的抑制剂的发现。

Blocking the interaction between the E4 isoform of apolipoprotein E (ApoE) and amyloid beta-peptide (Aβ) may be an avenue for pharmacological intervention in Alzheimer's disease (AD). The main regions of interaction of the two proteins are, respectively, ApoE244-272 and Aβ12-28. These protein segments are too large to facilitate the design of small molecule inhibitors. We mapped the primary components of ApoE/Aβ interaction to smaller peptide segments. Within the three motifs that are primarily responsible for ApoE/Aβ interaction, we identified four peptides that substantially block ApoE/Aβ interaction and further improved their inhibitory activity by rational hydrophobic amino acid substitution. Moreover, the mapping results provide the clue that the Aβ residues which interact with ApoE appear to be in the same region where Aβ self-interacts. According to this information, we found that Congo Red and X-34 could strongly inhibit ApoE/Aβ interaction. Our findings extend our understanding of ApoE/Aβ interaction and may guide the discovery of inhibitors that treat AD by antagonizing ApoE/Aβ interaction.