Novel Site-Specific Fatty Chain-Modified GLP-1 Receptor Agonist with Potent Antidiabetic Effects.
Glucagon-like peptide-1 receptor (GLP-1R) agonists have emerged as treatment options for type 2 diabetes mellitus (T2DM). Here, we designed a high-throughput GLP-1R extracellular domain (ECD)-based system that enabled the screening of high-potency receptor-biased GLP-1R agonists demonstrating new pharmacological virtues. Firstly, six 12-mer peptides (termed PEP01⁻06), screened from a large phage displayed peptide library were fused to the N-terminus of Exendin-4 (29⁻39) to generate PEP07⁻12. By the use of four lysine-altered PEP07 (PEP13⁻16) as the starting point, a series of fatty chain conjugates (PEP17⁻20) were synthesized and evaluated by in vitro GLP-1R-based cell assays. In addition, the acute and long-term in vivo effects on diet-induced obesity (DIO) mice were further evaluated. All four conjugates showed good receptor activation efficacy, and PEP20 was selected to undergo further assessment. Preclinical experiments in DIO mice demonstrated that PEP20 had significant insulinotropic activities and glucose-lowering abilities. Moreover, a prolonged antidiabetic effect of PEP20 was also observed by the hypoglycemic test in DIO mice. Furthermore, long-term treatment with PEP20 achieved beneficial effects on the food intake, weight gain, hemoglobin A1C (HbA1C) lowering activity, and glucose tolerance compared with the control and was similar to the Liraglutide. In conclusion, PEP20, a GLP-1R ECD-biased agonist, may provide a novel therapeutic approach to T2DM.
['Zhong|Xia|X|', 'Chen|Zhu|Z|', 'Chen|Qiong|Q|', 'Zhao|Wei|W|', 'Chen|Zhi|Z|']
D000595:Amino Acid Sequence D000818:Animals D001665:Binding Sites D002460:Cell Line D059305:Diet, High-Fat D000077270:Exenatide D005227:Fatty Acids D005786:Gene Expression Regulation D000067757:Glucagon-Like Peptide-1 Receptor D005951:Glucose Tolerance Test D006001:Glycoconjugates D006943:Hyperglycemia D007004:Hypoglycemic Agents D050417:Insulin-Secreting Cells D008297:Male D051379:Mice D009765:Obesity D019151:Peptide Library D010455:Peptides D011485:Protein Binding D051381:Rats D013329:Structure-Activity Relationship
antidiabetic effects Glucagon-like peptide-1 receptor extracellular domain Exendin-4 fatty chain