A spectroscopic and molecular dynamics study on the aggregation process of a long-acting lipidated therapeutic peptide: the case of semaglutide

The aggregation properties of Semaglutide, a lipidated peptide drug agonist of the Glucagon-like peptide 1 receptor recently
approved for treatment of diabetes type 2, have been investigated by spectroscopic techniques (UV-Vis absorption, steadystate
and time-resolved fluorescence, electronic circular dichroism) and Molecular Dynamics simulations. We show that in
the micromolar concentration region, in aqueous solution, Semaglutide is present as monomeric and dimeric species, with
a characteristic monomer-to-dimer transition occurring at around 20 μM. The lipid chain stabilizes a globular morphology
of the monomer and dimer species, giving rise to a locally well-defined polar outer surface where the lipid and peptide
portions are packed to each other. At very long times, these peptide clusters nucleate the growth of larger aggregates
characterized by a blue luminescence and a β-sheet arrangement of the peptide chains. The understanding of the
oligomerization and aggregation potential of peptide candidates is key for the development of long acting and stable drugs