Xenopus GLP-1-inspired discovery of novel GLP-1 receptor agonists as long-acting hypoglycemic and insulinotropic agents with significant therapeutic potential

Han, Jing; Chen, Xinyu; Wang, Yiyun; Fei, Yingying; Zhou, Feng; Zhang, Ying; Liu, Lin; Si, Pengbin; Fu, Junjie

doi:10.1016/j.bcp.2017.06.132

Cited by 20 publications

(16 citation statements)

References 29 publications

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“…In addition, the pancreata in mice were isolated and preserved in 4% paraformaldehyde. The same experimental procedure was used to conduct the H&E and insulin immunohistochemistry staining. , In H&E sections, the islet area and islet number were quantified using Olympus DP2-BSW (Center Valley, PA). In immunohistochemistry sections, the insulin integrated optical density (IOD) levels were quantified using a fluorescence microscope (Nikon DS-Ri2) and Image-pro plus software.…”

Section: Materials and Methodsmentioning

confidence: 99%

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

et al. 2021

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Novel peptidic glucagon receptor (GCGR) and glucagon-like peptide 1 receptor (GLP-1R) dual agonists are reported to have increased efficacy over GLP-1R monoagonists for the treatment of diabetes and obesity. We identified a novel Xenopus GLP-1-based dual GLP-1R/GCGR agonist (xGLP/GCG-13) designed with a proper activity ratio favoring the GLP-1R versus the GCGR. However, the clinical utility of xGLP/GCG-13 is limited by its short in vivo half-life. Starting from xGLP/GCG-13, dual Cys mutation was performed, followed by covalent side-chain stapling and serum albumin binder incorporation, resulting in a stabilized secondary structure, enhanced agonist potency at GLP-1R and GCGR, and improved stability. The lead peptide 2c (stapled xGLP/GCG-13 analogue with a palmitic acid albumin binder) exhibits balanced GLP-1R and GCGR activations and potent, long-lasting effects on in vivo glucose control. 2c was further explored pharmacologically in diet-induced obesity and db/db rodent models. Chronic administration of 2c potently induced body weight loss and hypoglycemic effects, improved glucose tolerance, increased energy expenditure, and normalized lipid metabolism and adiposity in relevant animal models. These results indicated that 2c has potential for development as a novel antidiabetic and/or antiobesity drug. Furthermore, we propose that the incorporation of a proper serum protein-binding motif into a di-Cys staple is an effective method for improving the stabilities and bioactivities of peptides. This approach is likely applicable to other therapeutic peptides, such as glucose-dependent insulin-tropic peptide receptor (GIPR) and GLP-1R dual agonists or GLP-1R/GCGR/GIPR triagonists.

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Section: Materials and Methodsmentioning

confidence: 99%

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

et al. 2021

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“…The agonism of peptides for the GLP-1 receptor was measured by functional assays using a stable HEK-293 cell line expressing a human GLP-1 receptor. 18 Intracellular cAMP content was determined by using Cisbio cAMP dynamic kit based on HTRF (homogeneous time-resolved fluorescence technology) using a multilabel reader (Envision 2,104, PerkinElmer). For preparation, cells were grown in DMEM medium supplemented with 0.5% FBS, 20 mM HEPES, 50 units•mL −1 of penicillin, 2 mM glutamine, and 50 μg•mL −1 of streptomycin.…”

Section: ■ Materials and Methodsmentioning

confidence: 99%

“…The agonism of peptides for the GLP-1 receptor was measured by functional assays using a stable HEK-293 cell line expressing a human GLP-1 receptor . Intracellular cAMP content was determined by using Cisbio cAMP dynamic kit based on HTRF (homogeneous time-resolved fluorescence technology) using a multilabel reader (Envision 2,104, PerkinElmer).…”

Section: Materials and Methodsmentioning

confidence: 99%

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Lithocholic Acid-Based Peptide Delivery System for an Enhanced Pharmacological and Pharmacokinetic Profile of Xenopus GLP-1 Analogs

et al. 2018

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GLP-1 analogs suffer from the main disadvantage of a short in vivo half-life. Lithocholic acid (LCA), one of the four main bile acids in the human body, possesses a high albumin binding rate. We therefore envisioned that a LCA-based peptide delivery system could extend the half-life of GLP-1 analogs by facilitating the noncovalent binding of peptides to human serum albumin. On the basis of our previously identified Xenopus GLP-1 analogs (1-3), a series of LCA-modified Xenopus GLP-1 conjugates were designed (4a-4r), and the bioactivity studies of these conjugates were performed to identify compounds with balanced in vitro receptor activation potency and plasma stability. 4c, 4i, and 4r were selected, and their LCA side chains were optimized to further increase their stability, affording 5a-5c. Compound 5b showed a more increased albumin affinity and prolonged in vitro stability than that of 4i and liraglutide. In db/ db mice, 5b exhibited comparable hypoglycemic and insulinotropic activity to liraglutide and semaglutide. Importantly, the enhanced albumin affinity of 5b resulted in a prolonged in vivo antidiabetic duration. Finally, chronic treatment investigations of 5b demonstrated the therapeutic effects of 5b on HbA1c, body weight, blood glucose, and pancreatic endocrine deficiencies on db/ db mice. Our studies revealed 5b as a promising antidiabetic candidate. Furthermore, our study suggests the derivatization of Xenopus GLP-1 analogs with LCA represents an effective strategy to develop potent long-acting GLP-1 receptor agonists for the treatment of type 2 diabetes.

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“…Effects of xGLP159 and xGLP296 on cAMP production were tested in human embryonic kidney 293 cells stably expressing human GLP-1 receptor, using a previously described method (20,21). In brief, cells were grown in DMEM with supplement.…”

Section: Glp-1 Receptor Agonist Potencymentioning

confidence: 99%

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

et al. 2019

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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

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Xenopus GLP-1-inspired discovery of novel GLP-1 receptor agonists as long-acting hypoglycemic and insulinotropic agents with significant therapeutic potential

Cited by 20 publications

References 29 publications

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

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

Lithocholic Acid-Based Peptide Delivery System for an Enhanced Pharmacological and Pharmacokinetic Profile of Xenopus GLP-1 Analogs

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

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