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Rational Design by Structural Biology of Industrializable, Long-Acting Antihyperglycemic GLP-1 Receptor Agonists

Glucagon-like peptide-1 (GLP-1) is easily degraded by dipeptidyl peptidase-4 (DPP-4) in the human body, limiting its therapeutic effect on type II diabetes. Therefore, improving GLP-1 receptor agonist (GLP-1RA) stability is a major obstacle for drug development. We analyzed human GLP-1, DPP-4, and G...

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Detalles Bibliográficos
Autores principales: Sun, Lei, Zheng, Zhi-Ming, Shao, Chang-Sheng, Zhang, Zhi-Yong, Li, Ming-Wei, Wang, Li, Wang, Han, Zhao, Gen-Hai, Wang, Peng
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9230455/
https://www.ncbi.nlm.nih.gov/pubmed/35745659
http://dx.doi.org/10.3390/ph15060740
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author Sun, Lei
Zheng, Zhi-Ming
Shao, Chang-Sheng
Zhang, Zhi-Yong
Li, Ming-Wei
Wang, Li
Wang, Han
Zhao, Gen-Hai
Wang, Peng
author_facet Sun, Lei
Zheng, Zhi-Ming
Shao, Chang-Sheng
Zhang, Zhi-Yong
Li, Ming-Wei
Wang, Li
Wang, Han
Zhao, Gen-Hai
Wang, Peng
author_sort Sun, Lei
collection PubMed
description Glucagon-like peptide-1 (GLP-1) is easily degraded by dipeptidyl peptidase-4 (DPP-4) in the human body, limiting its therapeutic effect on type II diabetes. Therefore, improving GLP-1 receptor agonist (GLP-1RA) stability is a major obstacle for drug development. We analyzed human GLP-1, DPP-4, and GLP-1 receptor structures and designed three GLP-1RAs, which were introduced into fusion protein fragments and changed in the overall conformation. This modification effectively prevented GLP-1RAs from entering the DPP-4 active center without affecting GLP-1RAs’ ability to bind to GLP-1R, the new GLP-1RA hypoglycemic effect lasting for >24 h. Through molecular modeling, molecular dynamics calculation, and simulation, possible tertiary structure models of GLP-1RAs were obtained; molecular docking with DPP-4 and GLP-1R showed access to the fusion protein. The overall conformational change of GLP-1RAs prevented DPP-4 binding, without affecting GLP-1RAs’ affinity to GLP-1R. This study provides important drug design ideas for GLP-1RA development and a new example for application of structural biology-based protein design in drug development.
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spelling pubmed-92304552022-06-25 Rational Design by Structural Biology of Industrializable, Long-Acting Antihyperglycemic GLP-1 Receptor Agonists Sun, Lei Zheng, Zhi-Ming Shao, Chang-Sheng Zhang, Zhi-Yong Li, Ming-Wei Wang, Li Wang, Han Zhao, Gen-Hai Wang, Peng Pharmaceuticals (Basel) Article Glucagon-like peptide-1 (GLP-1) is easily degraded by dipeptidyl peptidase-4 (DPP-4) in the human body, limiting its therapeutic effect on type II diabetes. Therefore, improving GLP-1 receptor agonist (GLP-1RA) stability is a major obstacle for drug development. We analyzed human GLP-1, DPP-4, and GLP-1 receptor structures and designed three GLP-1RAs, which were introduced into fusion protein fragments and changed in the overall conformation. This modification effectively prevented GLP-1RAs from entering the DPP-4 active center without affecting GLP-1RAs’ ability to bind to GLP-1R, the new GLP-1RA hypoglycemic effect lasting for >24 h. Through molecular modeling, molecular dynamics calculation, and simulation, possible tertiary structure models of GLP-1RAs were obtained; molecular docking with DPP-4 and GLP-1R showed access to the fusion protein. The overall conformational change of GLP-1RAs prevented DPP-4 binding, without affecting GLP-1RAs’ affinity to GLP-1R. This study provides important drug design ideas for GLP-1RA development and a new example for application of structural biology-based protein design in drug development. MDPI 2022-06-13 /pmc/articles/PMC9230455/ /pubmed/35745659 http://dx.doi.org/10.3390/ph15060740 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/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 (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Sun, Lei
Zheng, Zhi-Ming
Shao, Chang-Sheng
Zhang, Zhi-Yong
Li, Ming-Wei
Wang, Li
Wang, Han
Zhao, Gen-Hai
Wang, Peng
Rational Design by Structural Biology of Industrializable, Long-Acting Antihyperglycemic GLP-1 Receptor Agonists
title Rational Design by Structural Biology of Industrializable, Long-Acting Antihyperglycemic GLP-1 Receptor Agonists
title_full Rational Design by Structural Biology of Industrializable, Long-Acting Antihyperglycemic GLP-1 Receptor Agonists
title_fullStr Rational Design by Structural Biology of Industrializable, Long-Acting Antihyperglycemic GLP-1 Receptor Agonists
title_full_unstemmed Rational Design by Structural Biology of Industrializable, Long-Acting Antihyperglycemic GLP-1 Receptor Agonists
title_short Rational Design by Structural Biology of Industrializable, Long-Acting Antihyperglycemic GLP-1 Receptor Agonists
title_sort rational design by structural biology of industrializable, long-acting antihyperglycemic glp-1 receptor agonists
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9230455/
https://www.ncbi.nlm.nih.gov/pubmed/35745659
http://dx.doi.org/10.3390/ph15060740
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