Discovery of nitazoxanide-based derivatives as autophagy activators for the treatment of Alzheimer's disease

doi:10.1016/j.apsb.2019.07.006

	Discovery of nitazoxanide-based derivatives as autophagy activators for the treatment of Alzheimer's disease
	Li, Xiaokang 1; Lu, Jian 2; Xu, Yixiang 1; Wang, Jiaying 2; Qiu, Xiaoxia 1; Fan, Lei 3; Li, Baoli 1; Liu, Wenwen 1; Mao, Fei 1; Zhu, Jin 1
刊名	ACTA PHARMACEUTICA SINICA B
	2020-04-01
卷号	10 期号:4 页码:646-666
关键词	Alzheimer's disease Autophagy Nitazoxanide beta-amyloid Tau protein
ISSN号	2211-3835
DOI	10.1016/j.apsb.2019.07.006
通讯作者	Shen, Xu(xshen@njucm.edu.cn) ; Li, Jian(jianli@ecust.edu.cn)
英文摘要	Drug repurposing is an efficient strategy for new drug discovery. Our latest study found that nitazoxanide (NTZ), an approved anti-parasite drug, was an autophagy activator and could alleviate the symptom of Alzheimer's disease (AD). In order to further improve the efficacy and discover new chemical entities, a series of NTZ-based derivatives were designed, synthesized, and evaluated as autophagy activator against AD. All compounds were screened by the inhibition of phosphorylation of p70S6K, which was the direct substrate of mammalian target of rapamycin (mTOR) and its phosphorylation level could reflect the mTOR-dependent autophagy level. Among these analogs, compound 22 exhibited excellent potency in promoting beta-amyloid (A beta) clearance, inhibiting tau phosphorylation, as well as stimulating autophagy both in vitro and in vivo. What's more, 22 could effectively improve the memory and cognitive impairments in APP/PS1 transgenic AD model mice. These results demonstrated that 22 was a potential candidate for the treatment of AD. (C) 2020 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.
资助项目	National Sciences and Technology Major Project of China[2018ZX09711002-003-010] ; National Natural Science Foundation of China[81872747] ; National Natural Science Foundation of China[21672064] ; 111 Project (China)[B07023] ; Chinese Postdoctoral Science Foundation[2018M641946] ; Shanghai Sailing Program (China)[19YF1412600] ; Shanghai Morning Light Program (China)[18CG33] ; National Special Fund for State Key Laboratory of Bioreactor Engineering (China)[2060204] ; Postgraduate Research & Practice Innovation Program of Jiangsu Province (China)[KYCX18_1600]
WOS关键词	AMYLOID-BETA-PROTEIN ; TAU ; SEMAGACESTAT ; SOLANEZUMAB ; HYPOTHESIS ; INHIBITOR ; TANGLES ; DESIGN ; SYSTEM ; TRIALS
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	INST MATERIA MEDICA, CHINESE ACAD MEDICAL SCIENCES
WOS记录号	WOS:000526087100006
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/280991]
专题	中国科学院上海药物研究所
通讯作者	Shen, Xu; Li, Jian
作者单位	1.East China Univ Sci & Technol, Sch Pharm, State Key Lab Bioreactor Engn, Shanghai Key Lab New Drug Design, Shanghai 200237, Peoples R China 2.Nanjing Univ Chinese Med, Sch Med & Life Sci, Nanjing 210023, Peoples R China 3.Chinese Acad Sci, Ctr Drug Safety Evaluat & Res, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
推荐引用方式 GB/T 7714	Li, Xiaokang,Lu, Jian,Xu, Yixiang,et al. Discovery of nitazoxanide-based derivatives as autophagy activators for the treatment of Alzheimer's disease[J]. ACTA PHARMACEUTICA SINICA B,2020,10(4):646-666.
APA	Li, Xiaokang.,Lu, Jian.,Xu, Yixiang.,Wang, Jiaying.,Qiu, Xiaoxia.,...&Li, Jian.(2020).Discovery of nitazoxanide-based derivatives as autophagy activators for the treatment of Alzheimer's disease.ACTA PHARMACEUTICA SINICA B,10(4),646-666.
MLA	Li, Xiaokang,et al."Discovery of nitazoxanide-based derivatives as autophagy activators for the treatment of Alzheimer's disease".ACTA PHARMACEUTICA SINICA B 10.4(2020):646-666.