期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 212, 期 -, 页码 -出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2020.113118
关键词
Glucagon-like peptide-1; Glucagon; Diabetes; Obesity; Metabolic disorders
资金
- Special Funds for Science and Technology Development under the Guidance of the Central Government [ZY20198020]
- National Natural Science Foundation of China [31970371, 81973533, 21762009]
- Guangxi Medical University Training Program for Distinguished Young Scholars
- Guangxi Science and Technology Base and Special Talents Program [AD18281032]
- Natural Science Foundation of Guangxi Zhuang Autonomous Region of China [2017GXNSFAA198077, 2018GXNSFAA281219]
- Guangxi First-class Discipline Project for Pharmaceutical Sciences [GXFCDPPS-2018]
- Guangxi Key RD Project [AB17195009]
- Natural Science Foundation of Xuzhou [KC19154]
Dual activation of the glucagon receptor (GCGR) and glucagon-like peptide 1 receptor (GLP-1R) can potentially lead to effective therapy for diabetes and obesity. Novel peptides with dual activity on GLP-1R and GCGR were discovered through rational design, with xGLP/GCG-15 showing promising anti-obesity and anti-diabetic effects in preclinical studies.
Dual activation of the glucagon receptor (GCGR) and glucagon-like peptide 1 receptor (GLP-1R) has the potential to lead to an effective therapy for the treatment of diabetes and obesity. Here, we report the discovery of a series of peptides with dual activity on GLP-1R and GCGR that were discovered by rational design. Structural elements of oxyntomodulin (OXM), glucagon or exendin-4 were engineered into the selective GLP-1R agonist Xenopus GLP-1 (xGLP-1) on the basis of sequence analysis, resulting in hybrid peptides with potent dual activity at GLP-1R and GCGR. Further modifications with fatty acid resulted in a novel metabolically stable peptide (xGLP/GCG-15) with enhanced and balanced GLP-1R and GCGR activations. This lead peptide was further explored pharmacologically in both db/db and diet-induced obesity (DIO) rodent models. Chronic administration of xGLP/GCG-15 significantly induced hypoglycemic effects and body weight loss, improved glucose tolerance, and normalized lipid metabolism, adiposity, and liver steatosis in relevant rodent models. These preclinical studies suggest that xGLP/GCG-15 has potential for development as a novel anti-obesity and/or anti-diabetic candidate. Considering the equal effects of xGLP/GCG-15 and the clinical candidate MEDI0382 on reverse hepatic steatosis, it may also be explored as a new therapy for nonalcoholic steatohepatitis (NASH) in the future. (C) 2020 Elsevier Masson SAS. All rights reserved.
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