期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 132, 期 -, 页码 81-89出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2017.03.032
关键词
Glucagon-like peptide-1; Type 2 diabetes; PEGylation
资金
- National Natural Science Foundation of China [81602964, 81602960]
- Natural Science Foundation of Jiangsu Province [BK20150243, BK20161028]
- Natural Science Foundation of the Higher Education Institutions of Jiangsu Province [14KJB350003, 15KJB150005, 16KJB350002]
- PAPD of Jiangsu Higher Education Institutions
- Startup Funding for Introduced Talents of Nanjing Medical University [KY109-RC1602]
In order to develop novel long-acting GLP-1 derivatives, a peptide hybrid (1a) from human GLP-1 and Xenopus GLP-1 discovered in our previous research was selected as the lead compound. Exendin-4 inspired modification resulted in peptide 1b with enhanced glucose-lowering activity. Cysteine mutated 1b derivatives with reserved bioactivity were further site-specifically connected with mPEG(2000)-MAL to provide conjugates 3a-h, among which 3d and 3e were found to have significantly improved hypoglycemic activity and insulinotropic ability than GLP-1. The hypoglycemic durations of 3d and 3e were remarkably prolonged to similar to 20 h in type 2 diabetic db/db mice, compared with the 5.3 h of exendin-4 in the same test. Finally, chronic in vivo studies revealed that a once-daily treatment of 3d or 3e for five weeks resulted in recovered glucose-controlling ability of type 2 diabetic db/db mice, along with other benefits, such as reduced body weight gains, food intake amounts and HbA1c values. Collectively, our results suggest 3d and 3e as potential long-acting glucose-lowering agents for treating type 2 diabetes. (C) 2017 Elsevier Masson SAS. All rights reserved.
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