Development of an orally delivered GLP-1 receptor agonist through peptide engineering and drug delivery to treat chronic disease
Abstract Peptide therapeutics are increasingly used in the treatment of disease, but their administration by injection reduces patient compliance and convenience, especially for chronic diseases. Thus, oral administration of a peptide therapeutic represents a significant advance in medicine, but is...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2021-11-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-021-01750-0 |
| _version_ | 1818394569433153536 |
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| author | Sergei Pechenov Jefferson Revell Sarah Will Jacqueline Naylor Puneet Tyagi Chandresh Patel Lihuan Liang Leo Tseng Yue Huang Anton I. Rosenbaum Kemal Balic Anish Konkar Joseph Grimsby J. Anand Subramony |
| author_facet | Sergei Pechenov Jefferson Revell Sarah Will Jacqueline Naylor Puneet Tyagi Chandresh Patel Lihuan Liang Leo Tseng Yue Huang Anton I. Rosenbaum Kemal Balic Anish Konkar Joseph Grimsby J. Anand Subramony |
| author_sort | Sergei Pechenov |
| collection | DOAJ |
| description | Abstract Peptide therapeutics are increasingly used in the treatment of disease, but their administration by injection reduces patient compliance and convenience, especially for chronic diseases. Thus, oral administration of a peptide therapeutic represents a significant advance in medicine, but is challenged by gastrointestinal instability and ineffective uptake into the circulation. Here, we have used glucagon-like peptide-1 (GLP-1) as a model peptide therapeutic for treating obesity-linked type 2 diabetes, a common chronic disease. We describe a comprehensive multidisciplinary approach leading to the development of MEDI7219, a GLP-1 receptor agonist (GLP-1RA) specifically engineered for oral delivery. Sites of protease/peptidase vulnerabilities in GLP-1 were removed by amino acid substitution and the peptide backbone was bis-lipidated to promote MEDI7219 reversible plasma protein binding without affecting potency. A combination of sodium chenodeoxycholate and propyl gallate was used to enhance bioavailability of MEDI7219 at the site of maximal gastrointestinal absorption, targeted by enteric-coated tablets. This synergistic approach resulted in MEDI7219 bioavailability of ~ 6% in dogs receiving oral tablets. In a dog model of obesity and insulin resistance, MEDI7219 oral tablets significantly decreased food intake, body weight and glucose excursions, validating the approach. This novel approach to the development of MEDI7219 provides a template for the development of other oral peptide therapeutics. |
| first_indexed | 2024-12-14T06:03:17Z |
| format | Article |
| id | doaj.art-3ba0d823dad649b18d617f5537b9b8f7 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-12-14T06:03:17Z |
| publishDate | 2021-11-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-3ba0d823dad649b18d617f5537b9b8f72022-12-21T23:14:22ZengNature PortfolioScientific Reports2045-23222021-11-0111111510.1038/s41598-021-01750-0Development of an orally delivered GLP-1 receptor agonist through peptide engineering and drug delivery to treat chronic diseaseSergei Pechenov0Jefferson Revell1Sarah Will2Jacqueline Naylor3Puneet Tyagi4Chandresh Patel5Lihuan Liang6Leo Tseng7Yue Huang8Anton I. Rosenbaum9Kemal Balic10Anish Konkar11Joseph Grimsby12J. Anand Subramony13Drug Delivery, Dosage Form Design and Development, AstraZenecaDiscovery SciencesBioscience Metabolism, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), Biopharmaceuticals R&D, AstraZenecaBioscience Metabolism, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZenecaDrug Delivery, Dosage Form Design and Development, AstraZenecaDrug Delivery, Dosage Form Design and Development, AstraZenecaBioscience Renal, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZenecaBioscience Renal, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZenecaBioscience Renal, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZenecaIntegrated Bioanalysis, Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology & Safety Sciences, R&D, AstraZenecaIntegrated Bioanalysis, Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology & Safety Sciences, R&D, AstraZenecaBioscience Metabolism, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), Biopharmaceuticals R&D, AstraZenecaBioscience Metabolism, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), Biopharmaceuticals R&D, AstraZenecaBiologics Engineering, R&D, AstraZenecaAbstract Peptide therapeutics are increasingly used in the treatment of disease, but their administration by injection reduces patient compliance and convenience, especially for chronic diseases. Thus, oral administration of a peptide therapeutic represents a significant advance in medicine, but is challenged by gastrointestinal instability and ineffective uptake into the circulation. Here, we have used glucagon-like peptide-1 (GLP-1) as a model peptide therapeutic for treating obesity-linked type 2 diabetes, a common chronic disease. We describe a comprehensive multidisciplinary approach leading to the development of MEDI7219, a GLP-1 receptor agonist (GLP-1RA) specifically engineered for oral delivery. Sites of protease/peptidase vulnerabilities in GLP-1 were removed by amino acid substitution and the peptide backbone was bis-lipidated to promote MEDI7219 reversible plasma protein binding without affecting potency. A combination of sodium chenodeoxycholate and propyl gallate was used to enhance bioavailability of MEDI7219 at the site of maximal gastrointestinal absorption, targeted by enteric-coated tablets. This synergistic approach resulted in MEDI7219 bioavailability of ~ 6% in dogs receiving oral tablets. In a dog model of obesity and insulin resistance, MEDI7219 oral tablets significantly decreased food intake, body weight and glucose excursions, validating the approach. This novel approach to the development of MEDI7219 provides a template for the development of other oral peptide therapeutics.https://doi.org/10.1038/s41598-021-01750-0 |
| spellingShingle | Sergei Pechenov Jefferson Revell Sarah Will Jacqueline Naylor Puneet Tyagi Chandresh Patel Lihuan Liang Leo Tseng Yue Huang Anton I. Rosenbaum Kemal Balic Anish Konkar Joseph Grimsby J. Anand Subramony Development of an orally delivered GLP-1 receptor agonist through peptide engineering and drug delivery to treat chronic disease Scientific Reports |
| title | Development of an orally delivered GLP-1 receptor agonist through peptide engineering and drug delivery to treat chronic disease |
| title_full | Development of an orally delivered GLP-1 receptor agonist through peptide engineering and drug delivery to treat chronic disease |
| title_fullStr | Development of an orally delivered GLP-1 receptor agonist through peptide engineering and drug delivery to treat chronic disease |
| title_full_unstemmed | Development of an orally delivered GLP-1 receptor agonist through peptide engineering and drug delivery to treat chronic disease |
| title_short | Development of an orally delivered GLP-1 receptor agonist through peptide engineering and drug delivery to treat chronic disease |
| title_sort | development of an orally delivered glp 1 receptor agonist through peptide engineering and drug delivery to treat chronic disease |
| url | https://doi.org/10.1038/s41598-021-01750-0 |
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