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...

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Autores principales:	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
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/3ba0d823dad649b18d617f5537b9b8f7
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spelling	oai:doaj.org-article:3ba0d823dad649b18d617f5537b9b8f72021-11-21T12:24:57ZDevelopment of an orally delivered GLP-1 receptor agonist through peptide engineering and drug delivery to treat chronic disease10.1038/s41598-021-01750-02045-2322https://doaj.org/article/3ba0d823dad649b18d617f5537b9b8f72021-11-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-01750-0https://doaj.org/toc/2045-2322Abstract 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.Sergei PechenovJefferson RevellSarah WillJacqueline NaylorPuneet TyagiChandresh PatelLihuan LiangLeo TsengYue HuangAnton I. RosenbaumKemal BalicAnish KonkarJoseph GrimsbyJ. Anand SubramonyNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-15 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q 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
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.
format	article
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
title	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_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_sort	development of an orally delivered glp-1 receptor agonist through peptide engineering and drug delivery to treat chronic disease
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/3ba0d823dad649b18d617f5537b9b8f7
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Development of an orally delivered GLP-1 receptor agonist through peptide engineering and drug delivery to treat chronic disease

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