Glucagon-like peptide 1 aggregates into low-molecular-weight oligomers off-pathway to fibrillation

0572653 - ÚOCHB 2024 RIV US eng J - Článek v odborném periodiku
Přáda Brichtová, E. - Krupová, Monika - Bouř, Petr - Lindo, V. - Gomes dos Santos, A. - Jackson, S. E.
Glucagon-like peptide 1 aggregates into low-molecular-weight oligomers off-pathway to fibrillation.
Biophysical Journal. Roč. 122, č. 12 (2023), s. 2475-2488. ISSN 0006-3495. E-ISSN 1542-0086
Grant CEP: GA ČR(CZ) GA22-33060S
Institucionální podpora: RVO:61388963
Klíčová slova: aggregation * amyloid * oligomers * glucagon-like peptide 1 * self-assembly
Obor OECD: Physical chemistry
Impakt faktor: 3.4, rok: 2022
Způsob publikování: Open access
https://doi.org/10.1016/j.bpj.2023.04.027

The physical stability of peptide-based drugs is of great interest to the pharmaceutical industry. Glucagon-like peptide 1 (GLP-1) is a 31-amino acid peptide hormone, the analogs of which are frequently used in the treatment of type 2 diabetes. We investigated the physical stability of GLP-1 and its C-terminal amide derivative, GLP-1-Am, both of which aggregate into amyloid fibrils. While off-pathway oligomers have been proposed to explain the unusual aggregation kinetics observed previously for GLP-1 under specific conditions, these oligomers have not been studied in any detail. Such states are important as they may represent potential sources of cytotoxicity and immunogenicity. Here, we identified and isolated stable, low-molecular-weight oligomers of GLP-1 and GLP-1-Am, using size-exclusion chromatography. Under the conditions studied, isolated oligomers were shown to be resistant to fibrillation or dissociation. These oligomers contain between two and five polypeptide chains and they have a highly disordered structure as indicated by a variety of spectroscopic techniques. They are highly stable with respect to time, temperature, or agitation despite their noncovalent character, which was established using liquid chromatography-mass spectrometry and sodium dodecyl sulfate-polyacrylamide gel electrophoresis. These results provide evidence of stable, low-molecular-weight oligomers that are formed by an off-pathway mechanism which competes with amyloid fibril formation.
Trvalý link: https://hdl.handle.net/11104/0343256