Novel Site-Specific Fatty Chain-Modified GLP-1 Receptor Agonist with Potent Antidiabetic Effects

Autor: Zhu Chen, Qiong Chen, Wei Zhao, Xia Zhong, Zhi Chen
Jazyk: angličtina
Rok vydání: 2019
Předmět:
Male
antidiabetic effects
Pharmaceutical Science
Pharmacology
030226 pharmacology & pharmacy
Analytical Chemistry
Mice
0302 clinical medicine
fatty chain
Insulin-Secreting Cells
Drug Discovery
Receptor
0303 health sciences
Chemistry
Fatty Acids
digestive
oral
and skin physiology
extracellular domain
Chemistry (miscellaneous)
Molecular Medicine
Glucagon-like peptide-1 receptor
hormones
hormone substitutes
and hormone antagonists
medicine.drug
Protein Binding
Agonist
endocrine system
medicine.drug_class
Diet
High-Fat
Article
Cell Line
lcsh:QD241-441
03 medical and health sciences
Structure-Activity Relationship
lcsh:Organic chemistry
In vivo
Peptide Library
Diabetes mellitus
medicine
Extracellular
Animals
Hypoglycemic Agents
Amino Acid Sequence
Obesity
Physical and Theoretical Chemistry
Glucagon-like peptide 1 receptor
030304 developmental biology
Binding Sites
Liraglutide
Exendin-4
Organic Chemistry
Glucose Tolerance Test
medicine.disease
In vitro
Rats
Gene Expression Regulation
Hyperglycemia
Exenatide
Peptides
Glycoconjugates
Zdroj: Molecules
Volume 24
Issue 4
Molecules, Vol 24, Iss 4, p 779 (2019)
ISSN: 1420-3049
DOI: 10.3390/molecules24040779
Popis: 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&ndash
06), screened from a large phage displayed peptide library were fused to the N-terminus of Exendin-4 (29&ndash
39) to generate PEP07&ndash
12. By the use of four lysine-altered PEP07 (PEP13&ndash
16) as the starting point, a series of fatty chain conjugates (PEP17&ndash
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.
Databáze: OpenAIRE
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