Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
Tumor Marker Research Center, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
Curr Neuropharmacol. 2018;16(6):758-768. doi: 10.2174/1570159X15666171030142108.
Alzheimer's disease (AD) as the most common cause of dementia among older people has aroused the universal concern of the whole world. However, until now there is still none effective treatments. Consequently, the development of new drugs targeting this complicated brain disorder is urgent and needs more efforts. In this review, we detailed the current state of knowledge about new candidate drugs targeting the pathological proteins especially the drugs which are employed using the combined methods of in vitro and in silico.
We looked up and reviewed online papers related to the pathogenesis and new drugs development of AD. Then, articles up to the requirements were respectively analyzed and summaried to provide the latest knowledge about the pathogenic effect and the new candidate drugs targeting Aβ and Tau proteins.
New candidate drugs targeting the Aβ include decreasing the production, promoting the clearence and preventing aggregation. However these drugs have mostly failed in Phase III clinical trial stage due to the unsuccessful of reversing cognition symptoms. As to tau protein, the prevention of tau aggregation and propagation is a promising strategy to synthesize/design mechanismbased drugs against tauopathies. Some candidate drugs are under research. Moreover, because of the complex pathogenesis of AD, multi-target drugs have also shed light on the treatment of AD.
Given to the consecutive failure of Aβ-directed drugs and the feasibilities of tautargeted therapy, more and more researchers suggested that the AD treatment should be moved from Aβ to tau or focused on considering the soluble form of Aβ and tau as a whole. Moreover, the novel in silico methods also have great potential in drug discovery, drug repositioning, virtual screening of chemical libraries. No matter how many difficulties and challenges in prevention and treatment of AD, we firmly believe that the effective and safe drugs will be found using the combined methods in the immediate future with the global effort.
阿尔茨海默病（AD）作为老年人中最常见的痴呆症病因，引起了全世界的普遍关注。然而，到目前为止，仍然没有有效的治疗方法。因此，针对这种复杂的大脑疾病开发新的药物迫在眉睫，需要付出更多的努力。在这篇综述中，我们详细介绍了针对病理蛋白的新型候选药物的最新研究进展，特别是采用体外和计算相结合方法的药物。
我们查阅并在线检索了与 AD 的发病机制和新药开发相关的论文。然后，分别分析和总结符合要求的文章，以提供有关 Aβ和 Tau 蛋白的致病作用和新型候选药物的最新知识。
针对 Aβ的新型候选药物包括减少其产生、促进清除和防止聚集。然而，由于在认知症状改善方面的失败，这些药物在 III 期临床试验阶段大多失败。对于 Tau 蛋白，预防 Tau 聚集和传播是合成/设计针对 Tau 病的基于机制药物的有前途的策略。一些候选药物正在研究中。此外，由于 AD 的发病机制复杂，多靶点药物也为 AD 的治疗带来了曙光。
鉴于 Aβ 靶向药物的连续失败和 Tau 靶向治疗的可行性，越来越多的研究人员建议将 AD 的治疗方法从 Aβ 转移到 Tau 或集中考虑作为一个整体的可溶性 Aβ和 Tau 形式。此外，新型计算方法在药物发现、药物重定位、化学文库的虚拟筛选中也具有巨大的潜力。无论 AD 的防治存在多少困难和挑战，我们坚信，通过全球合作，在不久的将来，将采用联合方法找到有效且安全的药物。
