基于多重弱相互作用的A<italic style="font-style: italic">β</italic>聚集抑制剂研究

张倩; 袁直

doi:10.11777/j.issn1000-3304.2018.18025

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基于多重弱相互作用的Aβ聚集抑制剂研究

专论 | 更新时间：2021-01-26

- 基于多重弱相互作用的Aβ聚集抑制剂研究
- Study of Aβ Aggregation Inhibitors Based on Multiple Weak Interactions
- 高分子学报 2018年0卷第7期页码：776-785
- 作者机构：
  
  1.功能高分子材料教育部重点实验室南开大学化学学院　天津 300071
  2.天津化学化工协同创新中心　天津 300071
- 作者简介：
  
  [ "袁直，女，1961年出生. 教育部跨世纪优秀人才，天津市“131工程”第一层次人才，南开大学化学系攻读学士、硕士、博士学位，导师是何炳林教授. 现任南开大学高分子化学研究所教授、博士生导师，中国生物材料学会理事，南开大学学位评定委员会高分子分委会主席. 研究方向为智能靶向药物递送系统，吸附分离功能材料以及基于多重弱相互作用的分子识别研究. 先后主持十余项国家自然科学基金(含两项重点基金)，首批973课题，及10余项省部级项目. 在Biomaterials, Acta Biomaterialia, Biomacromolecules等国际权威刊物发表论文150余篇，获中国发明专利14项，美国发明专利2项. 获国家科技进步二等奖，天津市科技进步二等奖、教育部科技进步三等奖、杜邦科技创新奖、天津市青年科技奖、中国化学会青年化学奖、天津青年科技奖等以及全国先进女职工称号" ]
- 基金信息：
  
  国家自然科学基金(基金号 51273094，51433004)资助项目()
- DOI：10.11777/j.issn1000-3304.2018.18025
  中图分类号：
- 纸质出版日期：2018-7，
  
  收稿日期：2018-1-21，
  
  修回日期：2018-4-17，
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张倩, 袁直. 基于多重弱相互作用的Aβ聚集抑制剂研究[J]. 高分子学报, 2018,0(7):776-785.

Qian Zhang, Zhi Yuan. Study of Aβ Aggregation Inhibitors Based on Multiple Weak Interactions[J]. Acta Polymerica Sinica, 2018,0(7):776-785.
张倩, 袁直. 基于多重弱相互作用的Aβ聚集抑制剂研究[J]. 高分子学报, 2018,0(7):776-785. DOI： 10.11777/j.issn1000-3304.2018.18025.

Qian Zhang, Zhi Yuan. Study of Aβ Aggregation Inhibitors Based on Multiple Weak Interactions[J]. Acta Polymerica Sinica, 2018,0(7):776-785. DOI： 10.11777/j.issn1000-3304.2018.18025.

摘要

阿尔茨海默症(Alzheimer’s disease

AD)是一种神经退行性疾病，是老年痴呆最常见的一种形式，它具有不可治愈性、进行性以及致命性. 目前对AD发病机制尚无定论，但普遍认为AD的发生与脑中

淀粉样肽(amyloid

，A

)的聚集累积以及由金属离子富集导致的氧化应激效应有关. 在我们的工作中，首先通过拓展A

识别片段，利用多重弱相互作用，采用计算机模拟设计并筛选出新型A

聚集抑制肽(RR)，该抑制肽具有高效、低毒以及无自聚等优点；之后，在RR中引入具有Cu离子螯合能力的GGH寡肽片段，使之同时具有抑制A

聚集以及活氧物质(ROS)生成的能力. 通过解聚A

或A

-Cu复合物成熟纤维，可促进脑内A

聚集体的细胞胞吞清除，有可能达到治疗AD的效果，并在体内外实验中进行了验证. 综上我们认为，计算机模拟法是一种更高效准确地筛选药物分子的方式，而利用多重弱相互作用设计A

聚集抑制剂是行之有效的，该方法不仅适用于AD相关疾病的研究，也可为其他蛋白质及多肽相关疾病提供一种新的研究思路.

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disorder associated with the loss of memory

cognitive decline

and behavioral disability

leading to dementia and death ultimately. The pathogenesis of AD is still unclear

but it is generally accepted that the occurrence of AD is related to the accumulation of amyloid

) in the brain and the oxidative stress effect caused by the enrichment of metal ions. In our previous work

we expanded the targeting site from A

16-22 to A

11-23 (EVHHQKLVFFAED)

which could offer multiple weak interaction sites

such as the electrostatic

hydrophobic interactions and hydrogen bonding. We designed and screened a novel A

aggregation inhibitory peptide (RR) by computer simulation. The tripeptide chelator GGH

selected by ITC experiment with selectively Cu ion chelating ability

was introduced into RR to get the bifunctional peptide inhibitor GR

which have the ability to inhibit A

aggregation and produce the oxygen species (ROS) production at the same time. The results of ThT fluorescence

turbidity analysis

MTT methods showed that GR can inhibit the aggregation of A

and A

-Cu complex (A

:Cu = 1:0.25) to form amorphous aggregates

and the cell survival of GR group can reach 88%

significantly higher than chelator GGH (49%) and single functional inhibitor RR (68%). Moreover

it is proposed for the first time that the endocytosis of A

aggregates in the brain could be promoted by the disaggregation of A

or A

-Cu complex fibrils to achieve the effect of treating AD. The results showed that RR and GR can disaggregate A

and A

-Cu complex fibrils to nanorod-like structure with a length of 200 − 250 nm (rA

)

and

-sheet structure content in the system was reduced by 45%. rA

more easily to PC12 cell endocytosis

and it can enter the cells and further into the cell lysosomes. The

in vitro

lysosomal cathepsin B (CatB) degradation experimental results showed that

compared to fA

is more susceptible to CatB degradation

and its degradation products have no longer full hydrophobic core region

thereby greatly reducing their chances of re-aggregation. Finally the feasibility of GR and RR has been verified in Morris water maze test.

关键词

阿尔茨海默症β淀粉样肽抑制剂

Keywords

Alzheimer’s diseaseAmyloid βPeptide inhibitor

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基于多重弱相互作用的Aβ聚集抑制剂研究

Study of Aβ Aggregation Inhibitors Based on Multiple Weak Interactions

DOI：10.11777/j.issn1000-3304.2018.18025

摘要

Abstract

关键词

Keywords

references