Identification of a New alpha-Synuclein Aggregation Inhibitor via Mass Spectrometry Based Screening

doi:10.1021/acschemneuro.9b00092

	Identification of a New alpha-Synuclein Aggregation Inhibitor via Mass Spectrometry Based Screening
	Xu, Mingming 1; Loa-Kum-Cheung, Wendy 1; Zhang, Haiyan 2; Quinn, Ronald J.1; Mellick, George D.1
刊名	ACS CHEMICAL NEUROSCIENCE
	2019-06-01
卷号	10 期号:6 页码:2683-2691
关键词	Parkinson's disease alpha-synuclein aggregation mass spectrometry screening inhibitor
ISSN号	1948-7193
DOI	10.1021/acschemneuro.9b00092
通讯作者	Quinn, Ronald J.(r.quinn@griffith.edu.au) ; Mellick, George D.(g.mellick@griffith.edu.au)
英文摘要	The aggregation of disordered alpha-synuclein protein is pathogenically connected with Parkinson's disease. Therefore, discovering molecules that can inhibit the misfolding and aggregation of alpha-synuclein is an active research area in PD drug development. A key property of such required therapeutic agents is specific binding to the target protein. Mass spectrometry allows rapid detection of direct interactions between molecules and proteins and is an ideal technique for discovering specific alpha-synuclein binders. Here, by setting up an automated mass spectrometry-based screening system, we were able to screen over 2500 compounds and identify a new alpha-synuclein inhibitor, 3-[(3-methoxyphenyl)carbamoyl]-7-[(E)-2-phenylethenyl]-4,7-dihydropyrazolo [1,5-a]pyrimidine-5-carboxylic acid (compound 2). This compound not only significantly inhibits the misfolding and aggregation of a-synuclein and protects neuroblastoma cells from alpha-synuclein toxicity, but also has a more specific binding site compared with positive controls. Our work for the first time reports the inhibition of compound 2 on alpha-synuclein aggregation and also consolidates the capability of mass spectrometry to discover alpha-synuclein aggregation inhibitors.
资助项目	Griffith University International Postgraduate Research Scholarship (GUIPRS) ; Griffith University Postgraduate Research Scholarship (GUPRS) ; Australian Research Council[LE 120100170] ; Griffith University
WOS关键词	PARKINSONS-DISEASE ; BINDING ; OLIGOMERS
WOS研究方向	Biochemistry & Molecular Biology ; Pharmacology & Pharmacy ; Neurosciences & Neurology
语种	英语
出版者	AMER CHEMICAL SOC
WOS记录号	WOS:000472678800008
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/289241]
专题	中国科学院上海药物研究所
通讯作者	Quinn, Ronald J.; Mellick, George D.
作者单位	1.Griffith Univ, Griffith Inst Drug Discovery, Don Young Rd, Nathan, Qld 4111, Australia 2.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, 555 Zu Chong Zhi Rd, Shanghai 201203, Peoples R China
推荐引用方式 GB/T 7714	Xu, Mingming,Loa-Kum-Cheung, Wendy,Zhang, Haiyan,et al. Identification of a New alpha-Synuclein Aggregation Inhibitor via Mass Spectrometry Based Screening[J]. ACS CHEMICAL NEUROSCIENCE,2019,10(6):2683-2691.
APA	Xu, Mingming,Loa-Kum-Cheung, Wendy,Zhang, Haiyan,Quinn, Ronald J.,&Mellick, George D..(2019).Identification of a New alpha-Synuclein Aggregation Inhibitor via Mass Spectrometry Based Screening.ACS CHEMICAL NEUROSCIENCE,10(6),2683-2691.
MLA	Xu, Mingming,et al."Identification of a New alpha-Synuclein Aggregation Inhibitor via Mass Spectrometry Based Screening".ACS CHEMICAL NEUROSCIENCE 10.6(2019):2683-2691.