M. Venanzi, M. Savioli, R. Cimino, E. Gatto, A. Palleschi, G. Ripani, D. Cicero, E. Placidi, F. Orvieto and E. Bianchi, Soft Matter, 2020, 16, 10122 DOI: 10.1039/D0SM01011A

The aggregation properties of semaglutide, a lipidated peptide drug and agonist of the glucagon-like peptide 1 receptor (GLP-1R) recently approved for the treatment of type 2 diabetes, were studied using a combination of spectroscopic techniques—including UV-Vis absorption, steady-state and time-resolved fluorescence, and electronic circular dichroism—and molecular dynamics simulations.

Our findings reveal that in aqueous solutions at micromolar concentrations, semaglutide exists as both monomeric and dimeric species, with a monomer-to-dimer transition occurring at approximately 20 μM. The lipid chain of semaglutide stabilizes a globular morphology in both the monomer and dimer forms, creating a well-defined polar outer surface where the lipid and peptide regions are closely packed. Over extended periods, these peptide clusters act as nuclei for the formation of larger aggregates characterized by blue luminescence and a β-sheet arrangement of peptide chains.

Understanding the oligomerization and aggregation potential of peptide drug candidates is critical for the design of long-acting and stable therapeutics. This study provides valuable insights into the molecular behavior of semaglutide, aiding in the development of next-generation peptide-based treatments.