: 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-β-cyclodextrin (2-HPβCD) influence glucagon aggregation differently: lactose stabilizes glucagon by increasing the α-helical content, while 2-HPβCD disrupts protein-protein interactions. According to the simulations, 2-HPβCD 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-HPβCD 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.

Pisano, R., Arsiccio, A., Collins, V., King, P., Macis, M., Cabri, W., et al. (2024). Understanding Glucagon Aggregation: In Silico Insights and Experimental Validation. MOLECULAR PHARMACEUTICS, 21(8), 3815-3823 [10.1021/acs.molpharmaceut.4c00038].

Understanding Glucagon Aggregation: In Silico Insights and Experimental Validation

Cabri W.;
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-β-cyclodextrin (2-HPβCD) influence glucagon aggregation differently: lactose stabilizes glucagon by increasing the α-helical content, while 2-HPβCD disrupts protein-protein interactions. According to the simulations, 2-HPβCD 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-HPβCD 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.
2024
Pisano, R., Arsiccio, A., Collins, V., King, P., Macis, M., Cabri, W., et al. (2024). Understanding Glucagon Aggregation: In Silico Insights and Experimental Validation. MOLECULAR PHARMACEUTICS, 21(8), 3815-3823 [10.1021/acs.molpharmaceut.4c00038].
Pisano, R.; Arsiccio, A.; Collins, V.; King, P.; Macis, M.; Cabri, W.; Ricci, A.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11585/980837
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