A novel glucagon-like peptide-1/glucagon receptor dual agonist exhibits weight-lowering and diabetes-protective effects

doi:10.1016/j.ejmech.2017.07.046

CORC > 上海药物研究所 > 中国科学院上海药物研究所 > 药理学第一研究室

	A novel glucagon-like peptide-1/glucagon receptor dual agonist exhibits weight-lowering and diabetes-protective effects
	Zhou, Jie 1,2; Cai, Xingguang 2; Huang, Xun5 ; Dai, Yuxuan 2; Sun, Lidan 2; Zhang, Bo 2; Yang, Bo 2; Lin, Haiyan 4; Huang, Wenlong 2,3; Qian, Hai 2,3
刊名	EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
	2017-09-29
卷号	138 页码:1158-1169
关键词	Glucagon GLP-1/GCGR agonist Weight-lowering Diabetes-protective
ISSN号	0223-5234
DOI	10.1016/j.ejmech.2017.07.046
文献子类	Article
英文摘要	Glucagon has plenty of effects via a specific glucagon receptor(GCGR) like elevating the blood glucose, improving fatty acids metabolism, energy expenditure and increasing lipolysis in adipose tissue. The most important role of glucagon is to regulate the blood glucose, but the emergent possibilities of hyperglycaemia is exist. Glucagon could also slightly activate glucagon-like peptide-1 receptor(GLP-1R), which lead to blood glucose lowering effect. This study aims to erase the likelihood of hyperglycaemia and to remain the inherent catabolic effects through improving GLP-1R activation and deteriorating GCGR activation so as to lower the bodyweight and show diabetes-protective effects. Firstly, twelve cysteine modified GLP-1/GCGR dual agonists were synthesized (1-12). Then, the GLP-1R/GCGR mediated activation and biological activity in normal ICR mice were comprehensively performed. Compounds substituted by cysteine at positions 22, 23 and 25 in glucagon were observed to be better regulators of the body weight and blood glucose. To prolong the half-lives of derivatives, various fatty side chain maleimides were modified to optimal glucagon analogues. Laurate maleimide conjugate 4d was the most potent. Administration of 1000 nmol/kg 4d once every two days for a month normalized adiposity and glucose tolerance in diet-induced obese (DIO) mice. Improvements in plasma metabolic parameters including insulin, leptin, and adiponectin were observed. These studies suggest that compound 4d behaves well in lowering body weight and maintaining energy expenditure without a chance of hyperglycaemia, 4d has strong clinical potential as an efficient GLP-1/GCGR agonist in the prevention and treatment of obesity and dyslipidemia. (C) 2017 Elsevier Masson SAS. All rights reserved.
资助项目	National Natural Science Foundation of China[81673299] ; National Natural Science Foundation of China[81370878] ; Innovation Project Program of Hua Hai Pharmaceutical[HH13B003]
WOS关键词	IN-VIVO ACTIVITY ; ADIPOSE-TISSUE ; DISTAL GUT ; PEPTIDE-I ; OXYNTOMODULIN ; GLP-1 ; SECRETION ; HORMONE ; ANALOGS ; STIMULATION
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
WOS记录号	WOS:000411297000090
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/272477]
专题	药理学第一研究室
通讯作者	Lin, Haiyan; Huang, Wenlong; Qian, Hai
作者单位	1.Wenzhou Med Univ, Struct Biol Ctr, Wenzhou 325027, Peoples R China; 2.China Pharmaceut Univ, Ctr Drug Discovery, State Key Lab Nat Med, Nanjing 210009, Jiangsu, Peoples R China; 3.China Pharmaceut Univ, Jiangsu Key Lab Drug Discovery Metab Dis, 24 Tongjiaxiang, Nanjing 210009, Jiangsu, Peoples R China 4.Nanjing Med Univ, Dept Biochem & Mol Biol, 140 Hanzhong Rd, Nanjing 210029, Jiangsu, Peoples R China; 5.Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, Shanghai, Peoples R China;
推荐引用方式 GB/T 7714	Zhou, Jie,Cai, Xingguang,Huang, Xun,et al. A novel glucagon-like peptide-1/glucagon receptor dual agonist exhibits weight-lowering and diabetes-protective effects[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2017,138:1158-1169.
APA	Zhou, Jie.,Cai, Xingguang.,Huang, Xun.,Dai, Yuxuan.,Sun, Lidan.,...&Qian, Hai.(2017).A novel glucagon-like peptide-1/glucagon receptor dual agonist exhibits weight-lowering and diabetes-protective effects.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,138,1158-1169.
MLA	Zhou, Jie,et al."A novel glucagon-like peptide-1/glucagon receptor dual agonist exhibits weight-lowering and diabetes-protective effects".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 138(2017):1158-1169.