GPR52 Antagonist Reduces Huntingtin Levels and Ameliorates Huntington's Disease-Related Phenotypes

doi:10.1021/acs.jmedchem.0c01133

	GPR52 Antagonist Reduces Huntingtin Levels and Ameliorates Huntington's Disease-Related Phenotypes
	Wang, Congcong 4,5; Zhang, Yu-Fang 6; Guo, Shimeng 2,7; Zhao, Quan 4,5; Zeng, Yanping 6; Xie, Zhicheng 6; Xie, Xin 1,2,3,7; Lu, Boxun 4,5; Hu, Youhong 1,6
刊名	JOURNAL OF MEDICINAL CHEMISTRY
	2021-01-28
卷号	64 期号:2 页码:941-957
ISSN号	0022-2623
DOI	10.1021/acs.jmedchem.0c01133
通讯作者	Xie, Xin(xxie@simm.ac.cn) ; Lu, Boxun(luboxun@fudan.edu.cn) ; Hu, Youhong(yhhu@simm.ac.cn)
英文摘要	GPR52 is an orphan G protein-coupled receptor (GPCR) that has been recently implicated as a potential drug target of Huntington's disease (HD), an incurable monogenic neurodegenerative disorder. In this research, we found that striatal knockdown of GPR52 reduces mHTT levels in adult HdhQ140 mice, validating GPR52 as an HD target. In addition, we discovered a highly potent and specific GPR52 antagonist Comp43 with an IC50 value of 0.63 mu M by a structure-activity relationship (SAR) study. Further studies showed that Comp-43 reduces mHTT levels by targeting GPR52 and promotes survival of mouse primary striatal neurons. Moreover, in vivo study showed that Comp-43 not only reduces inHTT levels but also rescues HDrelated phenotypes in HdhQ140 mice. Taken together, our study confirms that inhibition of GPR52 is a promising strategy for HD therapy, and the GPR52 antagonist Comp-43 might serve as a lead compound for further investigation.
资助项目	National Natural Science Foundation of China[81925012] ; National Natural Science Foundation of China[81870990] ; National Natural Science Foundation of China[31961130379] ; Fudan-SIMM Joint Research Fund[FU-SIMM 20174013] ; China Postdoctoral Science Foundation[2018M632010]
WOS关键词	MUTANT-HUNTINGTIN ; MOUSE MODEL ; PROTEIN ; NEUROPATHOLOGY ; REVERSAL ; NEURONS ; MOTOR ; IDENTIFICATION ; TOXICITY ; SCREEN
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	AMER CHEMICAL SOC
WOS记录号	WOS:000614306000004
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/295702]
专题	中国科学院上海药物研究所
通讯作者	Xie, Xin; Lu, Boxun; Hu, Youhong
作者单位	1.UCAS, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China 2.Chinese Acad Sci, Natl Ctr Drug Screening, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China 3.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China 4.Fudan Univ, Neurol Dept, State Key Lab Med Neurobiol, Huashan Hosp, Shanghai 200438, Peoples R China 5.Fudan Univ, MOE Frontiers Ctr Brain Sci, Sch Life Sci, Shanghai 200438, Peoples R China 6.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China 7.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210046, Peoples R China
推荐引用方式 GB/T 7714	Wang, Congcong,Zhang, Yu-Fang,Guo, Shimeng,et al. GPR52 Antagonist Reduces Huntingtin Levels and Ameliorates Huntington's Disease-Related Phenotypes[J]. JOURNAL OF MEDICINAL CHEMISTRY,2021,64(2):941-957.
APA	Wang, Congcong.,Zhang, Yu-Fang.,Guo, Shimeng.,Zhao, Quan.,Zeng, Yanping.,...&Hu, Youhong.(2021).GPR52 Antagonist Reduces Huntingtin Levels and Ameliorates Huntington's Disease-Related Phenotypes.JOURNAL OF MEDICINAL CHEMISTRY,64(2),941-957.
MLA	Wang, Congcong,et al."GPR52 Antagonist Reduces Huntingtin Levels and Ameliorates Huntington's Disease-Related Phenotypes".JOURNAL OF MEDICINAL CHEMISTRY 64.2(2021):941-957.