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

文献类型：期刊论文

作者Wang, Congcong2,3; Zhang, Yu-Fang4; Guo, Shimeng5,6; Zhao, Quan2,3; Zeng, Yanping4; Xie, Zhicheng4; Xie, Xin1,5,6,7; Lu, Boxun2,3; Hu, Youhong4,7
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2021-01-28
卷号64期号:2页码:941-957
ISSN号0022-2623
DOI10.1021/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.
WOS关键词MUTANT-HUNTINGTIN ; MOUSE MODEL ; PROTEIN ; NEUROPATHOLOGY ; REVERSAL ; NEURONS ; MOTOR ; IDENTIFICATION ; TOXICITY ; SCREEN
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研究方向Pharmacology & Pharmacy
语种英语
出版者AMER CHEMICAL SOC
WOS记录号WOS:000614306000004
源URL[http://119.78.100.183/handle/2S10ELR8/295702]  
专题新药研究国家重点实验室
通讯作者Xie, Xin; Lu, Boxun; Hu, Youhong
作者单位1.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China
2.Fudan Univ, Neurol Dept, State Key Lab Med Neurobiol, Huashan Hosp, Shanghai 200438, Peoples R China
3.Fudan Univ, MOE Frontiers Ctr Brain Sci, Sch Life Sci, Shanghai 200438, Peoples R China
4.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
5.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210046, Peoples R China
6.Chinese Acad Sci, Natl Ctr Drug Screening, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China
7.UCAS, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, 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.

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来源：上海药物研究所

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