Fibrillar and micellar aggregation of semaglutide and formation of a chiral-imprinted glass

Castelletto, V. ORCID: https://orcid.org/0000-0002-3705-0162, De Mello, L. D. ORCID: https://orcid.org/0000-0001-7630-5087, Seitsonen, J. and Hamley, I. W. ORCID: https://orcid.org/0000-0002-4549-0926 (2026) Fibrillar and micellar aggregation of semaglutide and formation of a chiral-imprinted glass. Biomacromolecules. ISSN 1525-7797 doi: 10.1021/acs.biomac.5c02669 (In Press)

Abstract/Summary

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).

Item Type	Article
URI	https://centaur.reading.ac.uk/id/eprint/129199
Identification Number/DOI	10.1021/acs.biomac.5c02669
Refereed	Yes
Divisions	Interdisciplinary centres and themes > Chemical Analysis Facility (CAF) Life Sciences > School of Chemistry, Food and Pharmacy > Department of Chemistry
Publisher	American Chemical Society
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