基于Aβ寡聚体的阿尔茨海默病治疗药物研究进展  

Research progress of anti-Alzheimer′s disease drugs targeting Aβoligomers

作　　者：李小芳 任陇飞 王丹丹[1] 李玉艳[1] LI Xiaofang;REN Longfei;WANG Dandan;LI Yuyan(Department of Medicinal Chemistry,China Pharmaceutical University,Nanjing 211198,China)

机构地区：[1]中国药科大学药物化学系,南京211198

出　　处：《中国药科大学学报》2021年第4期398-409,共12页Journal of China Pharmaceutical University

基　　金：江苏省自然科学基金资助项目(No.BK20191320)。

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。Alzheimer's disease(AD)is the most common cause of senile dementia,accounting for an estimated 60%to 80%of cases,but there are no approved drugs to slow or stop the progressive clinical decline in the past years.Amyloid cascade hypothesis is recognized as the major etiologic basis for AD,however,the failures of several amyloid plaque-targeted programs have led many to dismiss the amyloid beta(Aβ)hypothesis of AD.Several reports show that soluble oligomers of Aβ(AβOs),which appear in brains more than 10 years before the clinical syndrome,are more toxic than Aβplaque,causing synaptic dysfunction and neuronal apoptosis.Some agents that can effectively inhibit Aβoligomer formation or block their toxicity made significant efficacy in clinical 2 and 3 trials,with the potential to be approved for the treatment of AD.This article reviews the recent development of AD drugs targeting Aβoligomers,analyzes their structural characteristics,mechanism of action,preclinical and clinical data,and discusses the future direction of AD treatment,thus providing new strategies for AD drug research.

关 键 词：阿尔茨海默病 淀粉样蛋白 寡聚体 治疗药物 进展 

分 类 号：R749[医药卫生—神经病学与精神病学]