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Sustained release of a GLP-1 and FGF21 dual agonist from an injectable depot protects mice from obesity and hyperglycemia

There is great interest in identifying a glucagon-like peptide-1 (GLP-1)–based combination therapy that will more effectively promote weight loss in patients with type 2 diabetes. Fibroblast growth factor 21 (FGF21) is a compelling yet previously unexplored drug candidate to combine with GLP-1 due t...

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Autores principales: Gilroy, C. A., Capozzi, M. E., Varanko, A. K., Tong, J., D'Alessio, D. A., Campbell, J. E., Chilkoti, A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Association for the Advancement of Science 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7449677/
https://www.ncbi.nlm.nih.gov/pubmed/32923621
http://dx.doi.org/10.1126/sciadv.aaz9890
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author Gilroy, C. A.
Capozzi, M. E.
Varanko, A. K.
Tong, J.
D'Alessio, D. A.
Campbell, J. E.
Chilkoti, A.
author_facet Gilroy, C. A.
Capozzi, M. E.
Varanko, A. K.
Tong, J.
D'Alessio, D. A.
Campbell, J. E.
Chilkoti, A.
author_sort Gilroy, C. A.
collection PubMed
description There is great interest in identifying a glucagon-like peptide-1 (GLP-1)–based combination therapy that will more effectively promote weight loss in patients with type 2 diabetes. Fibroblast growth factor 21 (FGF21) is a compelling yet previously unexplored drug candidate to combine with GLP-1 due to its thermogenic and insulin-sensitizing effects. Here, we describe the development of a biologic that fuses GLP-1 to FGF21 with an elastin-like polypeptide linker that acts as a sustained release module with zero-order drug release. We show that once-weekly dual-agonist treatment of diabetic mice results in potent weight-reducing effects and enhanced glycemic control that are not observed with either agonist alone. Furthermore, the dual-agonist formulation has superior efficacy compared to a GLP-1/FGF21 mixture, demonstrating the utility of combining two structurally distinct peptides into one multifunctional molecule. We anticipate that these results will spur further investigation into GLP-1/FGF21 multiagonism for the treatment of metabolic disease.
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spelling pubmed-74496772020-09-11 Sustained release of a GLP-1 and FGF21 dual agonist from an injectable depot protects mice from obesity and hyperglycemia Gilroy, C. A. Capozzi, M. E. Varanko, A. K. Tong, J. D'Alessio, D. A. Campbell, J. E. Chilkoti, A. Sci Adv Research Articles There is great interest in identifying a glucagon-like peptide-1 (GLP-1)–based combination therapy that will more effectively promote weight loss in patients with type 2 diabetes. Fibroblast growth factor 21 (FGF21) is a compelling yet previously unexplored drug candidate to combine with GLP-1 due to its thermogenic and insulin-sensitizing effects. Here, we describe the development of a biologic that fuses GLP-1 to FGF21 with an elastin-like polypeptide linker that acts as a sustained release module with zero-order drug release. We show that once-weekly dual-agonist treatment of diabetic mice results in potent weight-reducing effects and enhanced glycemic control that are not observed with either agonist alone. Furthermore, the dual-agonist formulation has superior efficacy compared to a GLP-1/FGF21 mixture, demonstrating the utility of combining two structurally distinct peptides into one multifunctional molecule. We anticipate that these results will spur further investigation into GLP-1/FGF21 multiagonism for the treatment of metabolic disease. American Association for the Advancement of Science 2020-08-26 /pmc/articles/PMC7449677/ /pubmed/32923621 http://dx.doi.org/10.1126/sciadv.aaz9890 Text en Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY). https://creativecommons.org/licenses/by/4.0/ https://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution license (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Articles
Gilroy, C. A.
Capozzi, M. E.
Varanko, A. K.
Tong, J.
D'Alessio, D. A.
Campbell, J. E.
Chilkoti, A.
Sustained release of a GLP-1 and FGF21 dual agonist from an injectable depot protects mice from obesity and hyperglycemia
title Sustained release of a GLP-1 and FGF21 dual agonist from an injectable depot protects mice from obesity and hyperglycemia
title_full Sustained release of a GLP-1 and FGF21 dual agonist from an injectable depot protects mice from obesity and hyperglycemia
title_fullStr Sustained release of a GLP-1 and FGF21 dual agonist from an injectable depot protects mice from obesity and hyperglycemia
title_full_unstemmed Sustained release of a GLP-1 and FGF21 dual agonist from an injectable depot protects mice from obesity and hyperglycemia
title_short Sustained release of a GLP-1 and FGF21 dual agonist from an injectable depot protects mice from obesity and hyperglycemia
title_sort sustained release of a glp-1 and fgf21 dual agonist from an injectable depot protects mice from obesity and hyperglycemia
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7449677/
https://www.ncbi.nlm.nih.gov/pubmed/32923621
http://dx.doi.org/10.1126/sciadv.aaz9890
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