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Novel Site-Specific Fatty Chain-Modified GLP-1 Receptor Agonist with Potent Antidiabetic Effects.
Molecules. 2019 Feb 21; 24(4)M

Abstract

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.

Authors+Show Affiliations

College of Life Science and Technology, Jinan University, Guangzhou 510000, China. x_zhong@outlook.com. Reyoung Biopharmaceuticals Co., Ltd, Suzhou 215000, China. x_zhong@outlook.com.Reyoung Biopharmaceuticals Co., Ltd, Suzhou 215000, China. Zchen@163.com. East China University of Science and Technology, Shanghai 200000, China. Zchen@163.com.Reyoung Biopharmaceuticals Co., Ltd, Suzhou 215000, China. qchen0862@yeah.net.Reyoung Biopharmaceuticals Co., Ltd, Suzhou 215000, China. zwei1008@163.com.East China University of Science and Technology, Shanghai 200000, China. Paulchan121@outlook.com.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

30795583

Citation

Zhong, Xia, et al. "Novel Site-Specific Fatty Chain-Modified GLP-1 Receptor Agonist With Potent Antidiabetic Effects." Molecules (Basel, Switzerland), vol. 24, no. 4, 2019.
Zhong X, Chen Z, Chen Q, et al. Novel Site-Specific Fatty Chain-Modified GLP-1 Receptor Agonist with Potent Antidiabetic Effects. Molecules. 2019;24(4).
Zhong, X., Chen, Z., Chen, Q., Zhao, W., & Chen, Z. (2019). Novel Site-Specific Fatty Chain-Modified GLP-1 Receptor Agonist with Potent Antidiabetic Effects. Molecules (Basel, Switzerland), 24(4). https://doi.org/10.3390/molecules24040779
Zhong X, et al. Novel Site-Specific Fatty Chain-Modified GLP-1 Receptor Agonist With Potent Antidiabetic Effects. Molecules. 2019 Feb 21;24(4) PubMed PMID: 30795583.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Novel Site-Specific Fatty Chain-Modified GLP-1 Receptor Agonist with Potent Antidiabetic Effects. AU - Zhong,Xia, AU - Chen,Zhu, AU - Chen,Qiong, AU - Zhao,Wei, AU - Chen,Zhi, Y1 - 2019/02/21/ PY - 2019/01/16/received PY - 2019/02/15/revised PY - 2019/02/15/accepted PY - 2019/2/24/entrez PY - 2019/2/24/pubmed PY - 2019/6/14/medline KW - Exendin-4 KW - Glucagon-like peptide-1 receptor KW - antidiabetic effects KW - extracellular domain KW - fatty chain JF - Molecules (Basel, Switzerland) JO - Molecules VL - 24 IS - 4 N2 - 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. SN - 1420-3049 UR - https://www.unboundmedicine.com/medline/citation/30795583/Novel_Site_Specific_Fatty_Chain_Modified_GLP_1_Receptor_Agonist_with_Potent_Antidiabetic_Effects_ L2 - http://www.mdpi.com/resolver?pii=molecules24040779 DB - PRIME DP - Unbound Medicine ER -