CN103910781B - 一种Aβ聚集抑制剂 - Google Patents
一种Aβ聚集抑制剂 Download PDFInfo
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- CN103910781B CN103910781B CN201410100093.5A CN201410100093A CN103910781B CN 103910781 B CN103910781 B CN 103910781B CN 201410100093 A CN201410100093 A CN 201410100093A CN 103910781 B CN103910781 B CN 103910781B
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- aggregation inhibitor
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Abstract
本发明公开了一种Aβ聚集抑制剂,其特征在于它的氨基酸序列为:氨基端-CTIWYG-羧基端。本肽序列经原子力显微镜扫描技术检测,进一步用细胞毒性实验评价得到。它对导致阿尔茨海默病的主要毒性体-Aβ的聚集具有良好的抑制作用,可尝试开发为阿尔茨海默病治疗药物。
Description
技术领域
本发明涉及一种Aβ聚集抑制剂,特别是一种抗阿尔茨海默病的毒性体Aβ抑制剂。
背景技术
目前,全球至少有3500万人患有阿尔茨海默病,且每年的致死率正在上升。每年全球的总花费估计达到2000亿美元,研究表明,Aβ(Amyloidβ-peptide)寡聚体是老年痴呆症病人体内的显著毒性体,因此抑制Aβ寡聚体的生成是阻止老年痴呆症发生最有效的策略。然而,目前无有效方法用于Aβ抑制剂设计,主要面对三方面的严重挑战:1、缺少有效的高通量筛选方法:实验筛选方法需要合成和纯化Aβ,这对于大量化合物的筛选无疑是费时、昂贵且不现实。2、缺少Aβ寡聚体的高分辨率结构:Aβ寡聚体呈亚稳态,因此利用X-射线衍射和NMR技术很难得到其结构,使基于结构的合理药物设计难以实现。3、缺少对Aβ自组装机制的理解:包括肽的哪一部分构成在淀粉样纤维生成过程中起着关键作用;种子和纤维生成相关的路径与中间体是什么;Aβ是否亲和到特定的受体;Aβ如何生成毒性体以及毒性的机制是什么。因此,设计新型Aβ抑制剂对老年痴呆症诊断和治疗具有重要的实践意义。
发明内容
有鉴于此,为了解决上述问题,本发明提供了一种Aβ聚集抑制剂,它的氨基酸序列为:氨基端-CTIWYG-羧基端,可尝试开发为抗阿尔茨海默病治疗药物。
附图说明
为了使本发明的目的、技术方案和优点更加清楚,下面将结合附图对本发明作进一步的详细描述,其中:
图1是新设计肽CTIWYG对Aβ抑制作用的原子力显微镜扫描结果。
具体实施方式
1)肽对Aβ抑制作用的原子力显微镜扫描实验;
用单光束硅悬臂探测器,在轻敲模式(TappingMode)模式下测定,至少扫描4个区域以确保结构正确采样。图1为新设计肽CTIWYG对Aβ抑制作用的原子力显微镜扫描结果,可看出,经过2天,CTIWYG对Aβ具有明显的抑制作用。此肽可作为Aβ聚集抑制剂,其序列为:氨基端-CTIWYG-羧基端。
图1新设计肽CTIWYG对Aβ抑制作用的原子力显微镜扫描结果(Tapping模式,A为对照实验(无抑制剂),Aβ的浓度为1μm,B中Aβ的浓度为20μM,六肽的浓度为50μM,存放2天,37℃)。
e)细胞毒性试验;
用Polyanionicdyecalcein对活细胞进行绿色荧光标记,并测定其活性,ethidium-1染色对死细胞进行红色荧光标记。相对于由Aβ导致的细胞失活,加入CTIWYG和新制备的Aβ与细胞共同培养后,对应的死亡与成活细胞率为0.412,相对于没有加入肽的对照实验可明显地减少细胞凋亡。当肽与存放24小时的Aβ溶液与细胞进行混合后,经检测得到死与活细胞比率为0.780。
以上所述仅为本发明的优选实施例,并不用于限制本发明,显然,本领域的技术人员可以对本发明进行各种改动和变型而不脱离本发明的精神和范围。这样,倘若本发明的这些修改和变型属于本发明权利要求及其等同技术的范围之内,则本发明也意图包含这些改动和变型在内。
<110>重庆大学
<120>一种Aβ聚集抑制剂
<140>
<141>
<160>1
<210>1
<211>6
<212>PRT
<213>人工序列
<220>
<223>
<400>1
CysThrIlePheTyrGly
15
Claims (1)
1.一种Aβ聚集抑制剂,其特征在于它的氨基酸序列为:氨基端-CTIWYG-羧基端。
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CN108676065A (zh) * | 2018-05-24 | 2018-10-19 | 华南理工大学 | 一种抗Aβ蛋白聚集的四肽及其应用与编码该四肽的基因 |
Citations (7)
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WO2009131975A1 (en) * | 2008-04-22 | 2009-10-29 | Schering Corporation | Phenyl-substituted 2-imino-3-methyl pyrrolo pyrimidinone compounds as bace-1 inhibitors, compositions, and their use |
WO2010098487A1 (en) * | 2009-02-26 | 2010-09-02 | Eisai R&D Management Co., Ltd. | Nitrogen-containing fused heterocyclic compounds and their use as beta amyloid production inhibitors |
WO2011044181A1 (en) * | 2009-10-08 | 2011-04-14 | Schering Corporation | Iminothiadiazine dioxide compounds as bace inhibitors, compositions, and their use |
CN102180947A (zh) * | 2011-02-25 | 2011-09-14 | 重庆大学 | 一种Aβ聚集抑制剂 |
CN102218055A (zh) * | 2010-08-31 | 2011-10-19 | 南京大学医学院附属鼓楼医院 | 一种治疗阿尔茨海默病的药物 |
CN102516359A (zh) * | 2011-12-08 | 2012-06-27 | 重庆大学 | 一种新型抗老年痴呆症先导化合物 |
CN102675419A (zh) * | 2011-03-16 | 2012-09-19 | 上海博智生物科技有限公司 | 一种Aβ短肽聚合抑制剂及其制备与应用 |
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Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2009131975A1 (en) * | 2008-04-22 | 2009-10-29 | Schering Corporation | Phenyl-substituted 2-imino-3-methyl pyrrolo pyrimidinone compounds as bace-1 inhibitors, compositions, and their use |
WO2010098487A1 (en) * | 2009-02-26 | 2010-09-02 | Eisai R&D Management Co., Ltd. | Nitrogen-containing fused heterocyclic compounds and their use as beta amyloid production inhibitors |
WO2011044181A1 (en) * | 2009-10-08 | 2011-04-14 | Schering Corporation | Iminothiadiazine dioxide compounds as bace inhibitors, compositions, and their use |
CN102218055A (zh) * | 2010-08-31 | 2011-10-19 | 南京大学医学院附属鼓楼医院 | 一种治疗阿尔茨海默病的药物 |
CN102180947A (zh) * | 2011-02-25 | 2011-09-14 | 重庆大学 | 一种Aβ聚集抑制剂 |
CN102675419A (zh) * | 2011-03-16 | 2012-09-19 | 上海博智生物科技有限公司 | 一种Aβ短肽聚合抑制剂及其制备与应用 |
CN102516359A (zh) * | 2011-12-08 | 2012-06-27 | 重庆大学 | 一种新型抗老年痴呆症先导化合物 |
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