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

Jing HanFeng ZhouYingying FeiXinyu ChenJunjie FuHai Qian
Published in: Bioconjugate chemistry (2018)
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 once daily administration of 9 or 11 in db/db mice achieved more beneficial effects on HbA1c reduction and glucose tolerance normalization than liraglutide. Our research demonstrated lipidization and dimerization as useful tools for the development of novel GLP-1 receptor agonists. The preclinical studies suggested the potential of 9 and 11 to be developed as novel anti-diabetic agents.
Keyphrases
  • type diabetes
  • case control
  • wound healing
  • high fat diet induced
  • cancer therapy
  • physical activity
  • drug delivery
  • metabolic syndrome
  • mass spectrometry
  • bone marrow
  • adipose tissue
  • molecular docking
  • risk assessment