Design, synthesis and biological evaluation of PEGylated Xenopus glucagon-like peptide-1 derivatives as long-acting hypoglycemic agents.
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 mPEG2000-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 ∼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.
School of Chemistry and Chemical Engineering, Jiangsu Key Laboratory of Green Synthetic Chemistry for Functional Materials, Jiangsu Normal University, Xuzhou 221116, PR China. Electronic address: hj1986424@jsnu.edu.cn.
Jing
J
Han
Wanbang Biopharmaceuticals Co. Ltd., Xuzhou 221004, PR China.
Yiyun
Y
Wang
School of Chemistry and Chemical Engineering, Jiangsu Key Laboratory of Green Synthetic Chemistry for Functional Materials, Jiangsu Normal University, Xuzhou 221116, PR China.
Qinghua
Q
Meng
School of Chemistry and Chemical Engineering, Jiangsu Key Laboratory of Green Synthetic Chemistry for Functional Materials, Jiangsu Normal University, Xuzhou 221116, PR China.
Guangchao
G
Li
School of Chemistry and Chemical Engineering, Jiangsu Key Laboratory of Green Synthetic Chemistry for Functional Materials, Jiangsu Normal University, Xuzhou 221116, PR China.
Fangmin
F
Huang
Jiangsu Chia-Tai Tianqing Pharmaceutical Co. Ltd, Lianyungang 222006, PR China.
Su
S
Wu
School of Chemistry and Chemical Engineering, Jiangsu Key Laboratory of Green Synthetic Chemistry for Functional Materials, Jiangsu Normal University, Xuzhou 221116, PR China.
Yingying
Y
Fei
School of Chemistry and Chemical Engineering, Jiangsu Key Laboratory of Green Synthetic Chemistry for Functional Materials, Jiangsu Normal University, Xuzhou 221116, PR China.
Feng
F
Zhou
Department of Medicinal Chemistry, School of Pharmacy, Nanjing Medical University, Nanjing 211166, PR China. Electronic address: jfu@njmu.edu.cn.
Junjie
J
Fu
D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D003545:Cysteine / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D015195:Drug Design; D052216:Glucagon-Like Peptide 1 / Q000737:chemistry* / Q000494:pharmacology; D006207:Half-Life; D006801:Humans; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics* / Q000494:pharmacology; D007328:Insulin / Q000097:blood; D008815:Mice, Inbred Strains; D016297:Mutagenesis, Site-Directed; D050506:Mutant Chimeric Proteins / Q000494:pharmacology; D011092:Polyethylene Glycols / Q000737:chemistry* / Q000494:pharmacology; D014981:Xenopus
D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D050506:Mutant Chimeric Proteins; D011092:Polyethylene Glycols; D052216:Glucagon-Like Peptide 1; D003545:Cysteine
Glucagon-like peptide-1; PEGylation; Type 2 diabetes