Lipidation and conformational constraining for prolonging the effects of peptides: Xenopus glucagon-like peptide 1 analogues with potent and long-acting hypoglycemic activity.
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| Abstract |
The main disadvantages of glucagon-like peptide 1 (GLP-1) are its rapid degradation and excretion. These bottlenecks can be overcome by lipidation or other structural modification. The aim of this study was to design a series of long-acting GLP-1 analogues based on our previously discovered Xenopus GLP-1 analogs (1-3). The structure-activity relationship around lipidated 1-3 derivatives (1a-3l) with respect to in vitro potency as well as protraction was firstly explored. Compound 3g was selected for further modification. The Gly2 of 3g was replaced with Aib2, and a lactam constraint between Glu16 and Lys20 (i to i + 4) was introduced to further improve the in vivo activity and stability, affording compound 4. The receptor activation capability and in vitro stability of 4 were better than 3g and liraglutide. In addition, the hypoglycemic and insulinotropic activity of 4 was significantly better than liraglutide in db/db mice. Moreover, the enhanced in vitro stability of 4 translated into improved in vivo pharmacokinetic profiles and a prolonged antidiabetic duration. Administration of 4 twice daily for one week in diet-induced obese mice caused a significant decrease in food intake, body fat and body weight. The five-week treatment study on db/db mice of 4 further demonstrated the therapeutic effects of 4 on body weight, HbA1c and glucose tolerance. These preclinical studies demonstrate the therapeutic potential of 4 for type 2 diabetes and obesity. The present study also suggests that combined lipidation and conformational constraint strategy has potential to be used for improving the therapeutic properties of peptides.
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| Authors | Jing Han, Yue Huang, Xinyu Chen, Feng Zhou, Yingying Fei, Junjie Fu |
| Journal | European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences (Eur J Pharm Sci) Vol. 123 Pg. 111-123 (Oct 15 2018) ISSN: 1879-0720 [Electronic] Netherlands |
| PMID | 30031858 (Publication Type: Journal Article) |
| Copyright | Copyright © 2018 Elsevier B.V. All rights reserved. |
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