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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 ph...

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Detalles Bibliográficos
Autores principales: Zhong, Xia, Chen, Zhu, Chen, Qiong, Zhao, Wei, Chen, Zhi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6412877/
https://www.ncbi.nlm.nih.gov/pubmed/30795583
http://dx.doi.org/10.3390/molecules24040779
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author Zhong, Xia
Chen, Zhu
Chen, Qiong
Zhao, Wei
Chen, Zhi
author_facet Zhong, Xia
Chen, Zhu
Chen, Qiong
Zhao, Wei
Chen, Zhi
author_sort Zhong, Xia
collection PubMed
description 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.
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spelling pubmed-64128772019-04-09 Novel Site-Specific Fatty Chain-Modified GLP-1 Receptor Agonist with Potent Antidiabetic Effects Zhong, Xia Chen, Zhu Chen, Qiong Zhao, Wei Chen, Zhi Molecules Article 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. MDPI 2019-02-21 /pmc/articles/PMC6412877/ /pubmed/30795583 http://dx.doi.org/10.3390/molecules24040779 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Zhong, Xia
Chen, Zhu
Chen, Qiong
Zhao, Wei
Chen, Zhi
Novel Site-Specific Fatty Chain-Modified GLP-1 Receptor Agonist with Potent Antidiabetic Effects
title Novel Site-Specific Fatty Chain-Modified GLP-1 Receptor Agonist with Potent Antidiabetic Effects
title_full Novel Site-Specific Fatty Chain-Modified GLP-1 Receptor Agonist with Potent Antidiabetic Effects
title_fullStr Novel Site-Specific Fatty Chain-Modified GLP-1 Receptor Agonist with Potent Antidiabetic Effects
title_full_unstemmed Novel Site-Specific Fatty Chain-Modified GLP-1 Receptor Agonist with Potent Antidiabetic Effects
title_short Novel Site-Specific Fatty Chain-Modified GLP-1 Receptor Agonist with Potent Antidiabetic Effects
title_sort novel site-specific fatty chain-modified glp-1 receptor agonist with potent antidiabetic effects
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6412877/
https://www.ncbi.nlm.nih.gov/pubmed/30795583
http://dx.doi.org/10.3390/molecules24040779
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