Novel coumarin modified GLP-1 derivatives with enhanced plasma stability and prolonged in vivo glucose-lowering ability
文献类型：期刊论文
| 作者 | Han, Jing2; Sun, Lidan2; Huang, Xun1 ; Li, Zheng2; Zhang, Chenyu2; Qian, Hai2; Huang, Wenlong2
|
| 刊名 | BRITISH JOURNAL OF PHARMACOLOGY
 |
| 出版日期 | 2014-12 |
| 卷号 | 171期号:23页码:5252-5264 |
| ISSN号 | 0007-1188 |
| DOI | 10.1111/bph.12843 |
| 文献子类 | Article |
| 英文摘要 | Background and PurposeThe short biological half-life limits the therapeutic use of glucagon-like peptide-1 (GLP-1) and chemical modification to improve the interaction of peptides with serum albumin represents an effective strategy to develop long-acting peptide analogues. Coumarin, a natural product, is known to bind tightly to plasma proteins and possesses many biological activities. Therefore, we designed and synthesized a series of coumarin-modified GLP-1 derivatives, hypothesizing that conjugation with coumarin would retain the therapeutic effects and prolong the biological half-life of the conjugates. Experimental ApproachFour cysteine-modified GLP-1 analogues (1-4) were prepared using Gly(8)-GLP-1(7-36)-NH2 peptide as a starting point. These analogues were conjugated with two coumarin maleimides to yield eight compounds (conjugates 6-13) for testing. Activation of human GLP-1 receptors, stability to enzymic inactivation in plasma and binding to human albumin were assessed in vitro. In vivo, effects on oral glucose tolerance tests (OGTT) in rats and on blood glucose levels in db/db mice were studied. Key ResultsMost conjugates showed well preserved receptor activation efficacy, enhanced albumin-binding properties and improved in vitro plasma stability and conjugate 7 was selected to undergo further assessment. In rats, conjugate 7 had a longer circulating t(1/2) than exendin-4 or liraglutide. A prolonged antidiabetic effect of conjugate 7 was observed after OGTT in rats and a prolonged hypoglycaemic effect in db/db mice. Conclusions and ImplicationsCysteine-specific coumarin conjugation with GLP-1 offers a useful approach to the development of long-acting incretin-based antidiabetic agents. Conjugate 7 is a promising long-lasting GLP-1 derivative deserving further investigation. |
| WOS关键词 | TYPE-2 DIABETES-MELLITUS ; SOLID-PHASE SYNTHESIS ; RECEPTOR AGONISTS ; PEPTIDE-1 DERIVATIVES ; INSULIN-RESISTANCE ; ARRIVE GUIDELINES ; CONCISE GUIDE ; HALF-LIFE ; ANALOGS ; EXENATIDE |
| 资助项目 | National Natural Science Foundation of China[81172932] ; National Natural Science Foundation of China[81273376] ; Natural Science Foundation of Jiangsu Province[BK2012356] ; Project Program of State Key Laboratory of Natural Medicines, China Pharmaceutical University[JKGZ201103] |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:000345560300007 |
| 出版者 | WILEY |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/276818]  |
| 专题 | 药理学第一研究室 |
| 通讯作者 | Qian, Hai |
| 作者单位 | 1.Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, Shanghai 200031, Peoples R China 2.China Pharmaceut Univ, Ctr Drug Discovery, State Key Lab Nat Med, Nanjing 210009, Jiangsu, Peoples R China; |
| 推荐引用方式 GB/T 7714 | Han, Jing,Sun, Lidan,Huang, Xun,et al. Novel coumarin modified GLP-1 derivatives with enhanced plasma stability and prolonged in vivo glucose-lowering ability[J]. BRITISH JOURNAL OF PHARMACOLOGY,2014,171(23):5252-5264. |
| APA | Han, Jing.,Sun, Lidan.,Huang, Xun.,Li, Zheng.,Zhang, Chenyu.,...&Huang, Wenlong.(2014).Novel coumarin modified GLP-1 derivatives with enhanced plasma stability and prolonged in vivo glucose-lowering ability.BRITISH JOURNAL OF PHARMACOLOGY,171(23),5252-5264. |
| MLA | Han, Jing,et al."Novel coumarin modified GLP-1 derivatives with enhanced plasma stability and prolonged in vivo glucose-lowering ability".BRITISH JOURNAL OF PHARMACOLOGY 171.23(2014):5252-5264. |
入库方式： OAI收割
来源：上海药物研究所
浏览0
下载0
收藏0
其他版本
除非特别说明，本系统中所有内容都受版权保护，并保留所有权利。