Self-assembled GLP-1/glucagon peptide nanofibrils prolong inhibition of food intake

Frontiers in Endocrinology

Endocrinology

Ana L. Gomes Dos Santos¹  Dominic J. Corkill²  David Baker³  Lihuan Liang³  David C. Hornigold³  Jacqueline Naylor⁴  Myriam M. Ouberai⁵  Sonja Kinna⁵  Mark E. Welland⁵ 

[1] Advanced Drug Delivery, Pharmaceutical Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, United Kingdom;Bioscience In Vivo, Research and Early Development, Respiratory & Immunology, BioPharmaceuticals, R&D, AstraZeneca, Cambridge, United Kingdom;Cardiovascular, Renal and Metabolic Diseases, BioPharmaceuticals R&D, AstraZeneca, Cambridge, United Kingdom;Cardiovascular, Renal and Metabolic Diseases, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden;Nanoscience Centre, Department of Engineering, University of Cambridge, Cambridge, United Kingdom;

关键词: nanofibrils;    GLP-1/glucagon;    peptides;    depot formulations;    self-assembly;    metabolic diseases;   

DOI  :  10.3389/fendo.2023.1217021

 received in 2023-05-04, accepted in 2023-06-27,  发布年份 2023

来源: Frontiers

【 摘 要 】

IntroductionOxyntomodulin (Oxm) hormone peptide has a number of beneficial effects on nutrition and metabolism including increased energy expenditure and reduced body weight gain. Despite its many advantages as a potential therapeutic agent, Oxm is subjected to rapid renal clearance and protease degradation limiting its clinical application. Previously, we have shown that subcutaneous administration of a fibrillar Oxm formulation can significantly prolong its bioactivity in vivo from a few hours to a few days.MethodsWe used a protease resistant analogue of Oxm, Aib2-Oxm, to form nanfibrils depot and improve serum stability of released peptide. The nanofibrils and monomeric peptide in solution were characterized by spectroscopic, microscopic techniques, potency assay, QCM-D and in vivo studies.ResultsWe show that in comparison to Oxm, Aib2-Oxm fibrils display a slower elongation rate requiring higher ionic strength solutions, and a higher propensity to dissociate. Upon subcutaneous administration of fibrillar Aib2-Oxm in rodents, a 5-fold increase in bioactivity relative to fibrillar Oxm and a significantly longer bioactivity than free Aib2-Oxm were characterized. Importantly, a decrease in food intake was observed up to 72-hour post-administration, which was not seen for free Aib2-Oxm.ConclusionOur findingsprovides compelling evidence for the development of long-lasting peptide fibrillar formulations that yield extended plasma exposure and enhanced in vivo pharmacological response.

【 授权许可】

Unknown   
Copyright © 2023 Ouberai, Gomes Dos Santos, Kinna, Hornigold, Baker, Naylor, Liang, Corkill and Welland