Peptide aggregation poses a significant challenge in biopharmaceutical development and neurodegenerative diseases. This study combines computational simulations and experimental validation to uncover the underlying mechanisms and countermeasures for the aggregation of glucagon, a peptide with a high tendency to aggregate. In silico simulations demonstrate that lactose and 2-hydroxypropyl-beta-cyclodextrin (2-HP beta CD) influence glucagon aggregation differently: lactose stabilizes glucagon by increasing the alpha-helical content, while 2-HP beta CD disrupts protein-protein interactions. According to the simulations, 2-HP beta CD is particularly effective at preserving the monomeric form of glucagon. Experimental validation with microfluidic modulation spectroscopy (MMS) confirms these findings, showing that glucagon in the presence of 2-HP beta CD remains structurally stable, supporting the antiaggregation effect of this excipient. This research provides essential insights into glucagon aggregation obtained through a new powerful tool for monitoring the critical properties of peptide aggregation, suggesting new strategies for addressing this challenge in therapeutic peptide development.
Understanding glucagon aggregation: in silico insights and experimental validation / Pisano, Roberto; Arsiccio, Andrea; Collins, Valerie; King, Patrick; Macis, Marco; Cabri, Walter; Ricci, Antonio. - In: MOLECULAR PHARMACEUTICS. - ISSN 1543-8384. - 21:8(2024), pp. 3815-3823. [10.1021/acs.molpharmaceut.4c00038]
Understanding glucagon aggregation: in silico insights and experimental validation
Pisano, Roberto;Arsiccio, Andrea;
2024
Abstract
Peptide aggregation poses a significant challenge in biopharmaceutical development and neurodegenerative diseases. This study combines computational simulations and experimental validation to uncover the underlying mechanisms and countermeasures for the aggregation of glucagon, a peptide with a high tendency to aggregate. In silico simulations demonstrate that lactose and 2-hydroxypropyl-beta-cyclodextrin (2-HP beta CD) influence glucagon aggregation differently: lactose stabilizes glucagon by increasing the alpha-helical content, while 2-HP beta CD disrupts protein-protein interactions. According to the simulations, 2-HP beta CD is particularly effective at preserving the monomeric form of glucagon. Experimental validation with microfluidic modulation spectroscopy (MMS) confirms these findings, showing that glucagon in the presence of 2-HP beta CD remains structurally stable, supporting the antiaggregation effect of this excipient. This research provides essential insights into glucagon aggregation obtained through a new powerful tool for monitoring the critical properties of peptide aggregation, suggesting new strategies for addressing this challenge in therapeutic peptide development.File | Dimensione | Formato | |
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https://hdl.handle.net/11583/2992046