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

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.

Automated summary

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.