摘要
淀粉样蛋白(β-amyloid peptide,Aβ)与阿尔茨海默病(Alzheimer′s disease,AD)的发展密切相关,然而靶向不可溶Aβ斑块的药物至今没能成功上市。最新的研究发现,可溶的Aβ寡聚体是更强的神经毒性物质,在疾病症状出现前10多年已经存在于大脑中,引发神经组织的损伤。Aβ寡聚体形成斑块沉积在大脑中可能是人体的一种保护机制。目前,多个针对Aβ寡聚体的小分子和单抗在临床Ⅱ期和Ⅲ期试验中显示能够显著改善患者认知,极有潜力成为AD的有效治疗药物。本文综述了基于Aβ寡聚体的AD药物研究进展,分析其结构特点、作用机制、临床前和临床数据,探讨该领域的发展前景和方向,为AD药物研究提供新的策略。
阿尔茨海默病(Alzheimer′s disease,AD)是一种多因素致死性的神经退行性疾
AD的病理机制极其复杂,淀粉样蛋白(β-amyloid peptide,Aβ)沉积为斑块以及过度磷酸化的Tau蛋白形成神经纤维缠结是患者大脑中主要的病理特
众多研究结果表明,Aβ蛋白包括Aβ单体、寡聚体和纤维在AD发生发展中发挥了关键作
AD患者的大脑中存在Aβ纤维沉积而成的斑块,早期的药物研究试图通过清除斑块来逆转疾病的发展。但是,临床试验发现,Aβ斑块的减少不能缓解患者的认知损伤,并且引发了脑血管水肿等不良反
Aβ寡聚体是由单体组成的具异质性和瞬时性的可溶性聚合物。APP在β分泌酶和γ分泌酶的解离下形成Aβ单
图1 淀粉样蛋白产生以及病理性聚集示意
本文以Aβ寡聚体为靶点,关注通过降低毒性寡聚体的水平,发展AD治疗药物的最新研究进展。主要从3个方面综述最新的研究工作,包括:(1)抑制Aβ单体聚集,减少毒性寡聚体产生;(2)促进无毒低毒聚合物形成,降低寡聚体对神经的损伤;(3)毒性Aβ寡聚体的清除。分析活性分子的结构特征、作用机制、临床前和临床数据,并对本领域的发展进行总结与展望。
离子迁移谱-质谱联用技术(ion mobility spectrometry-mass spectrometry,IMS-MS)、核磁共振光谱技术(nuclear magnetic resonance,NMR)以及分子动力学模拟证实,高牛磺酸(
图2 高牛磺酸抑制Aβ单体聚集机制示意
不同类型的Aβ蛋白具有相似的N端结构,通过靶向Aβ的N端来稳定单体,阻断寡聚体的形成是一种有效的药物设计策
图3 环状氨基酸结构以及作用模式图
A: GS-2抑制Aβ寡聚体形成和解离Aβ聚合物的模
Aβ单体和胰岛淀粉样蛋白多肽(isletamyloidpolypeptide,IAPP)一样会通过自聚集生成寡聚体,而且发生聚集的区域氨基酸序列相似。受此启发,Kumar
图4 化合物5的结构(A)及其α螺旋结构(B)示意
Aβ纤维表面作为催化中心能够促进Aβ单体聚集形成可溶性的寡聚体,阻止单体与纤维表面的相互作用可以减少Aβ寡聚体的形
图5 HASI-1,cHASI-1结构(A)以及HASI-1与Aβ纤维作用示意图(B
寡聚噻吩类化合物p-FTAA(
图6 p-FTAA的结构以及p-FTAA对Aβ聚集的影响
A: p-FTAA的结构;B: Aβ单独孵育以及与p-FTAA共孵育的蛋白组分Dot blot分析,所用抗体为6E1
从茯砖茶中提取的YCF-2(
图7 YCF-2对于Aβ42聚集的影响以及两者的相互作用
A: YCF-2的结构; B: Aβ单独孵育以及与YCF-2以1∶4物质的量浓度比例孵育4 h后的TEM图
大量的证据表明,Aβ聚集过程中形成的可溶性Aβ寡聚体比成熟的不可溶纤维毒性更
图8 ZGM1结构以及其对Aβ聚集的影响
A: ZGM-1的结构;B: 50 μmol/L Aβ在37 ℃单独孵育7 d以及在ZGM-1存在的条件下孵育形成的聚合物的TEM图
D3多肽(D型多肽序列:RPRTRLHTHRNR)具备多种抗Aβ活
图9 DB3以及DB3DB3对于Aβ42聚集的影响
A: 10 μmol/L Aβ42单独孵育24 h的TEM图
EC是具有血脑屏障透过性的钳型骨架小分子(
图10 EC对于Aβ聚集的影响以及两者的相互作用
A: EC的结构;B: Aβ40与EC在不同的浓度共孵育形成的TEM图
Trodusquemine由稠合的固醇环与聚胺精胺共价连接而成,可以取代细胞膜上的异常蛋白质从而保持膜的完整性(
图11 Trodusquemine的结构
多糖被发现具有阻止淀粉样蛋白聚集的作
BAN2401是小鼠单克隆抗体mAb158的人源化IgG1,mAb158可以特异性地结合可溶性的,相对分子质量较大的寡聚体如Aβ原纤维,对Aβ原纤维的选择性至少为单体的1 000倍,是纤维的10~15
Crenezumab是人源化IgG4单克隆抗体,与合成的可溶性的Aβ以及PS2APP转基因小鼠大脑内源性的Aβ寡聚体结合,对寡聚体的亲和力至少是单体的10倍(0.4 ~ 0.6 vs 3.0 ~ 5.0 nmol/L
Wiesehan
利福平是一种半合成抗生素,具有良好血脑屏障透过性,可以抑制Aβ聚集并缓解Aβ寡聚体诱导的细胞毒
Nec-1可以调节RIPK1/RIPK3异二聚纤维复合物达到神经保护作
图12 Nec-1与其去甲基化后的结构
针对毒性Aβ寡聚体,开发新型AD治疗药物已经成为新药研究的热点之一。本文总结了本领域内近年有代表性的3个发展方向,包括:(1)抑制Aβ肽聚集形成有毒的Aβ寡聚体。通过与Aβ单体相互作用稳定蛋白的α螺旋结构,避免向β折叠转换,或竞争性作用于Aβ纤维表面的单体结合位点从而抑制寡聚体生成。需要明确的是,尽管有大量减少Aβ纤维化的研究,但是不可溶的Aβ纤维减少,可能会引起寡聚体浓度的上升,导致不良反应增加。(2)促进Aβ蛋白转化成无毒或毒性较低的聚合物或共聚物,从而减少寡聚体的形成,减少神经毒性。(3)促进有毒的Aβ寡聚体解离或清除。Aβ寡聚体诱导特异性抗体是有效的Aβ寡聚体清除方法,但是有过度激活小胶质细胞的风险,引发促炎应答导致血管性水肿和脑微出血不良反应的发生。相对于IgG1骨架,IgG4会减弱对于Fcγ受体的激活,降低副反应的发生。研究表明,减少对血管淀粉样蛋白斑块的选择性可进一步减轻血管性水肿等不良反应。
目前,在临床Ⅱ期试验中,针对Aβ寡聚体的抗体和小分子化合物显示出积极的治疗结果,结合最新的Aβ寡聚体病理机制研究进展,可以预期基于Aβ寡聚体的AD治疗新药开发具有良好的发展前景和极大的潜力。
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