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Preparation and Pharmaceutical Characterizations of Lipidated Dimeric Xenopus Glucagon-Like Peptide-1 Conjugates

A pair of glucagon-like peptide-1 (GLP-1) analogs (1 and 2) were synthesized by hybridizing the key sequences of GLP-1, exendin-4, lixisenatide, and xenGLP-1B (Xenopus GLP-1 analog). To achieve long-acting hypoglycemic effects and to further improve their anti-diabetic potencies, lipidization and dimerization strategies were used to afford two lipidated dimeric conjugates (9 and 11). Conjugates 9 and 11 showed stronger receptor activation potency than GLP-1 and exendin-4 in vitro. Moreover, 9 and 11 exhibited superior hypoglycemic and insulinotropic activities to liraglutide in type 2 diabetic C57BL/6J-m+/+ Leprdb (db/db) mice. Pharmacokinetic studies revealed that the circulating half-lives (t1/2) of 9 and 11 were 2.3- and 1.7-fold longer than that of liraglutide. The improved pharmacokinetic profiles led to significantly protracted in vivo anti-diabetic effects as confirmed by multiple oral glucose tolerance tests and hypoglycemic duration tests. Most importantly, chronic treatment studies found that on...

Authors:   Jing Han; Feng Zhou; Yingying Fei; Xinyu Chen; Junjie Fu; Hai Qian
Journal:   Bioconjugate Chemistry
Year:   2018
DOI:   10.1021/acs.bioconjchem.7b00712
Publication date:   09-Jan-2018
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