Journal
FRONTIERS IN ENDOCRINOLOGY
Volume 14, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fendo.2023.1217021
Keywords
nanofibrils; GLP-1; glucagon; peptides; depot formulations; self-assembly; metabolic diseases
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In this study, the researchers successfully improved the clearance and degradation issues of Oxm by using Aib2-Oxm nanofibril depot, which extended its bioactivity and pharmacological response in vivo. The results showed that compared to Oxm, Aib2-Oxm fibrils had a slower elongation rate and a higher propensity to dissociate, resulting in higher bioactivity and prolonged efficacy in rodents. This finding highlights the significance of developing long-lasting peptide fibrillar formulations for extended plasma exposure.
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 findings provides compelling evidence for the development of long-lasting peptide fibrillar formulations that yield extended plasma exposure and enhanced in vivo pharmacological response.
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