新型抗阿尔茨海默病药物甘露寡糖二酸

发布时间：2018-11-23 20:29

【摘要】：目的阿尔茨海默病(AD),是一种由多因素引起的神经系统退行性疾病,严重危害人类健康。目前临床治疗药物主要为胆碱酯酶抑制剂等疾病症状改善药物,存在疗效不确切、毒副作用大等缺点,无法有效防止AD的进展。因此开发能够改变疾病进程的抗AD药物是目前医药界共同关注的焦点。方法采用基于SPR的芯片筛选方法,针对糖库进行筛选;采用一系列的生物化学和物理方法,观察对amyloidβ(Aβ)聚集以及神经毒性的影响;采用转基因动物模型,观察对转基因动物行为学的影响。结果我们通过筛选获得国际首个靶向Aβ的寡糖分子——971。核磁共振技术直接证明971能够与Aβ多位点结合;通过其独特的结合方式,971能够抑制Aβ聚集,并且能够促进已经聚集的Aβ解聚,同时抑制Aβ的神经毒性。体内研究表明971能够明显改善转基因小鼠的学习记忆能力以及日常生活能力。Ⅱ期临床研究表明,971安全性好、能明显改善轻中度AD患者认知功能障碍。临床Ⅲ期正在进行中。结论 971有望成为近十几年来首个靶向Aβ的抗AD新药。
[Abstract]:Objective Alzheimer's disease (AD),) is a neurodegenerative disease caused by many factors, which seriously endangers human health. At present, the main clinical treatment drugs are cholinesterase inhibitors and other disease symptoms to improve the drug, there are some shortcomings, such as inaccurate efficacy, toxic side effects, can not effectively prevent the progress of AD. Therefore, the development of anti-AD drugs that can change the course of disease is the common focus of the medical industry. Methods A series of biochemical and physical methods were used to study the effects of microarray screening based on SPR on the aggregation and neurotoxicity of amyloid 尾 (A 尾). The effects of transgenic animal models on the behavior of transgenic animals were observed. Results through screening, we obtained the first oligosaccharide molecule targeting A 尾-971. Nuclear magnetic resonance (NMR) technique directly demonstrated that 971 could bind to A 尾 multiloci, and 971 could inhibit A 尾 aggregation, promote the aggregation of A 尾 and inhibit the neurotoxicity of A 尾 through its unique binding mode. In vivo studies showed that 971 could significantly improve the ability of learning and memory as well as the ability of daily living in transgenic mice. Stage II clinical studies showed that 971 was safe and could significantly improve cognitive dysfunction in patients with mild and moderate AD. Stage III is in progress. Conclusion 971 is expected to be the first anti-AD drug targeting A-尾 in recent ten years.
【作者单位】：中国科学院上海药物研究所;
【分类号】：R971

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