High-Throughput Screening for GPR119 Modulators Identifies a Novel Compound with Anti-Diabetic Efficacy in db/db Mice

doi:10.1371/journal.pone.0063861

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	High-Throughput Screening for GPR119 Modulators Identifies a Novel Compound with Anti-Diabetic Efficacy in db/db Mice
	Zhang, Meng 2; Feng, Yang 2; Wang, Jia1 ; Zhao, Jianwei 1; Li, Ting 2; He, Min 1; Yang, Dehua2 ; Nosjean, Olivier 3; Boutin, Jean 3; Renard, Pierre 3
刊名	PLOS ONE
	2013-05-21
卷号	8 期号:5
ISSN号	1932-6203
DOI	10.1371/journal.pone.0063861
文献子类	Article
英文摘要	G protein-coupled receptor 119 (GPR119) is highly expressed in pancreatic beta cells and enteroendocrine cells. It is involved in glucose-stimulated insulin secretion and glucagon-like peptide-1 (GLP-1) release, thereby representing a promising target for the treatment of type 2 diabetes. Although a number of GPR119 agonists were developed, no positive allosteric modulator (PAM) to this receptor has been reported. Here we describe a high-throughput assay for screening GPR119 PAMs and agonists simultaneously. Following screening of a small molecule compound library containing 312,000 synthetic and natural product-derived samples, one potent GPR119 agonist with novel chemical structure, MW1219, was identified. Exposure of MIN6 and GLUTag cells to MW1219 enhanced glucose-stimulated insulin secretion and GLP-1 release; once-daily oral dosing of MW1219 for 6 weeks in diabetic db/db mice reduced hemoglobin A1c (HbA1c) and improved plasma glucose, insulin and GLP-1 levels; it also increased glucose tolerance. The results demonstrate that MW1219 is capable of effectively controlling blood glucose level and may have the potential to be developed as a new class of anti-diabetic agents.
资助项目	Ministry of Health of China[2012ZX09304011] ; Ministry of Health of China[2013ZX09507002] ; Shanghai Science and Technology Development Fund[11DZ2292200] ; Les Laboratories Servier (France)[00000000]
WOS关键词	GLUCAGON-LIKE PEPTIDE-1 ; GLYCEMIC CONTROL ; RECEPTOR ; AGONISTS ; G-PROTEIN-COUPLED-RECEPTOR-119 ; PATHOGENESIS ; SECRETION ; DISCOVERY ; RELEASE ; NIDDM
WOS研究方向	Science & Technology - Other Topics
语种	英语
出版者	PUBLIC LIBRARY SCIENCE
WOS记录号	WOS:000319330200077
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/277614]
专题	国家新药筛选中心中科院受体结构与功能重点实验室新药研究国家重点实验室药物制剂研究中心
通讯作者	Wang, Ming-Wei
作者单位	1.Chinese Natl Cpd Lib, Shanghai, Peoples R China; 2.Chinese Acad Sci, Shanghai Inst Mat Med, Natl Ctr Drug Screening, State Key Lab Drug Res, Shanghai 200031, Peoples R China; 3.Les Labs Servier, Neuilly Sur Seine, France
推荐引用方式 GB/T 7714	Zhang, Meng,Feng, Yang,Wang, Jia,et al. High-Throughput Screening for GPR119 Modulators Identifies a Novel Compound with Anti-Diabetic Efficacy in db/db Mice[J]. PLOS ONE,2013,8(5).
APA	Zhang, Meng.,Feng, Yang.,Wang, Jia.,Zhao, Jianwei.,Li, Ting.,...&Wang, Ming-Wei.(2013).High-Throughput Screening for GPR119 Modulators Identifies a Novel Compound with Anti-Diabetic Efficacy in db/db Mice.PLOS ONE,8(5).
MLA	Zhang, Meng,et al."High-Throughput Screening for GPR119 Modulators Identifies a Novel Compound with Anti-Diabetic Efficacy in db/db Mice".PLOS ONE 8.5(2013).