Fibrillar and Micellar Aggregation of Semaglutide and Formation of a Chiral-Imprinted Glass

Semaglutide is a therapeutically important lipopeptide that comprises a lipidated peptide with a glucagon-like peptide-1 (GLP-1) sequence, and may be prone to aggregation. We show that semaglutide in low pH 2.4 solutions forms β-sheet fibrils, in contrast to the oligomeric and micellar structures formed at higher pH. Based on cryo-TEM images showing twisted fibrils and the modeling of SAXS data (and with knowledge from fiber XRD) and molecular dynamics simulations, a model for the β-sheet structure is proposed, which comprises curved β-strands arranged in an antiparallel fashion around a core that comprises the lipidated lysine residue. This structure results from the patterning of the charged, polar, hydrophobic, and lipidated residues. Remarkably, it is possible to form a glass from the base form of semaglutide with crotonic acid, an organic salt capable of hydrogen bonding. Semaglutide glasses may have applications in biomedicine or therapeutics (for example, as slow-release depots).