Semaglutide aggregates into oligomeric micelles and short fibrils in aqueous solution

Hamley, I. W. ORCID: https://orcid.org/0000-0002-4549-0926, de Mello, L. R. ORCID: https://orcid.org/0000-0001-7630-5087, Castelletto, V. ORCID: https://orcid.org/0000-0002-3705-0162, Zinn, T. ORCID: https://orcid.org/0000-0001-8502-544X, Cowieson, N., Seitsonen, J. and Bizien, T. ORCID: https://orcid.org/0000-0002-8779-7897 (2025) Semaglutide aggregates into oligomeric micelles and short fibrils in aqueous solution. Biomacromolecules, 26 (6). pp. 3786-3794. ISSN 1526-4602 doi: 10.1021/acs.biomac.5c00342

Abstract/Summary

Semaglutide is a lipopeptide with important applications in the treatment of diabetes, obesity, and other conditions. This class of drug (glucagon-like peptide-1 agonists and other lipidated peptides) may be susceptible to aggregation due to the tendency of lipopeptides to self-assemble into various nanostructures. Here, we show using cryogenic-TEM, small-angle X-ray scattering, and molecular dynamics simulations that semaglutide in aqueous solution undergoes slow aggregation into spherical micelles in water at sufficiently high concentration. A small population of needle-shaped fibril aggregates is also observed. At a lower concentration, dimer and trimer structures are formed. The micelles, once formed, are stable toward further aging. The aggregation influences the effect of semaglutide on the permeability of an epithelial gut model membrane of Caco-2 cells. These findings are expected to be important in understanding the long-term stability of semaglutide solutions and the potential effects of aggregation on therapeutic efficacy.

Item Type	Article
URI	https://centaur.reading.ac.uk/id/eprint/122729
Identification Number/DOI	10.1021/acs.biomac.5c00342
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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