A Spectroscopic and Molecular Dynamics Study on the Aggregation Properties of a Lipopeptide Analogue of Liraglutide, a Therapeutic Peptide against Diabetes Type 2

The pharmacokinetics of peptide drugs are strongly affected by their aggregation properties and the morphology of the nanostructures they form in their native state as well as in their therapeutic formulation. In this contribution, we analyze the aggregation properties of a Liraglutide analogue (LG18), a leading drug against diabetes type 2. LG18 is a lipopeptide characterized by the functionalization of a lysine residue (K26) with an 18C lipid chain. To this end, spectroscopic experiments, dynamic light scattering measurements, and molecular dynamics simulations were carried out, following the evolution of the aggregation process from the small LG18 clusters formed at sub-micromolar concentrations to the mesoscopic aggregates formed by aged micromolar solutions. The critical aggregation concentration of LG18 in water (pH = 8) was found to amount to 4.3 μM, as assessed by the pyrene fluorescence assay. MD simulations showed that the LG18 nanostructures are formed by tetramer building blocks that, at longer times, self-assemble to form micrometric supramolecular architectures.