The chronic administration of two novel long‐acting Xenopus glucagon‐like peptide‐1 analogs xGLP159 and XGLP296 potently improved systemic metabolism and glycemic control in rodent models

Abstract

We here reported 2 novel Xenopus glucagon‐like peptide‐1 (xGLP‐1) analogs, xGLP159 and xGLP296, whose therapeutic effects on metabolic efficacy and glycemie control were evaluated in rodents. The in vitro potency of xGLP159 and xGLP296 were investigated on human embryonic kidney 293 cells. The acute glucose‐lowering and insulinotropic effects of xGLP159 and xGLP296 were assessed in the Institute of Cancer Research, Kunming, and diabetic (db/db) mice. The pharmacokinetic profiles of xGLP159 and xGLP296 were confirmed on Sprague‐Dawley (SD) rats and their long‐acting hypoglycemic and anorectic effects were evaluated in db/db mice. Chronic treatment effects of xGLP159 and xGLP296 were evaluated in diet‐induced obese (DIO) mice and db/db mice. The results showed that xGLP159 and xGLP296 exhibited comparable receptor activation potency, hypoglycemic effect, and insulinotropic activity to liraglutide. The enhanced half‐lives of xGLP159 and xGLP296 in SD rats (5.1 and 5.8 h, respectively) resulted in prolonged anti‐db/db durations in db/db mice. Three weeks' administration of xGLP159 and xGLP296 normalized glucose tolerance and adiposity in DIO mice. Furthermore, 11‐wk treatment of xGLP159 and xGLP296 corrected hyperglycemia and improved pancreatic function in db/db mice. These preclinical studies supported xGLP159 and xGLP296 as promising candidates for the treatment of metabolic diseases.—Han, J., Meng, T., Chen, X., Han, Y., Fu, J., Zhou, F., Fei, Y., Li, C. The chronic administration of two novel long‐acting Xenopus glucagon‐like peptide‐1 analogs xGLP159 and xGLP296 potently improved systemic metabolism and glycemie control in rodent models. FASEB J. 33, 7113–7125 (2019). http://www.fasebj.org

Stapled and Xenopus Glucagon-Like Peptide 1 (GLP-1)-Based Dual GLP-1/Gastrin Receptor Agonists with Improved Metabolic Benefits in Rodent Models of Obesity and Diabetes

“…Using previously described methods, activation of human GLP-1R was determined by cAMP formation, and activation of human CCK-1R and CCK-2R was determined by pERK induction. , For each assay, HEK293 cells expressing receptors were grown in DMEM (Dulbecco’s modified Eagle’s medium) supplemented with 10% v/v FBS, 100 units·mL –1 penicillin, 100 μg·mL –1 streptomycin, 2 mM l -glutamine, and 100 μg·mL –1 G418. HEK293 cells expressing GLP-1R were washed, resuspended in assay buffer (20 mM HEPES, 1× HBSS, 2 mM IBMX, 0.1% BSA), and plated into 96-well plates coated with 0.01% poly- l -lysine before testing.…”

“…Our previous research identified Xenopus GLP-1, a GLP-1 analogue from amphibians, as an alternative GLP-1R agonist . In addition, some Xenopus GLP-1 derivatives were found to be long-acting GLP-1R agonists with better effects on glycemic control and body weight reduction than those of liraglutide and lixisenatide (a C-terminal modified exendin-4 analogue). , …”

Discovery of lixisenatide analogues as long-acting hypoglycemic agents using novel peptide half-life extension technology based on mycophenolic acid

“…IPGTT were carried out in normal male Kunming mice (n ¼ 6) using a previously described method with small modication. 35 Mice were fasted overnight (12 h) prior to a 2 g kg À1 i.p. injected of glucose.…”

Stapled, Long-Acting Xenopus GLP-1-Based Dual GLP-1/Glucagon Receptor Agonists with Potent Therapeutic Efficacy for Metabolic Disease

“…Moreover, our previous studies conducted on xGLP-1 revealed that long-acting xGLP-1 derivatives have many beneficial antidiabetic effects, including slowing of gastric emptying, weight loss due to reduced food intake, glucose-dependent promotion of insulin secretion, and increase in β-cell mass/area and pancreas function. 15,16 Many of the dual GLP-1R/GCGR agonists described previously are based on the structures of OXM, glucagon, or exendin-4, leading to a big challenge to tune and optimize the physicochemical properties. 17 Due to its favorable physicochemical properties, xGLP-1 was an attractive scaffold for the development of novel dual GLP-1R and GCGR agonists.…”

“…We previously identified a novel GLP-1 analogue (xGLP-1, Figure ) based on Xenopus GLP-1, through rational peptide design and structure–activity relationship (SAR) studies. Moreover, our previous studies conducted on xGLP-1 revealed that long-acting xGLP-1 derivatives have many beneficial antidiabetic effects, including slowing of gastric emptying, weight loss due to reduced food intake, glucose-dependent promotion of insulin secretion, and increase in β-cell mass/area and pancreas function. , …”