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

• DOI: 10.1016/j.bpj.2023.04.027
• Publication Date: 2023-05-02T18:49:31Z
• Authors: Eva Přáda Brichtová; Monika Krupová; Petr Bouř; Viv Lindo; Ana Gomes dos Santos; Sophie E. Jackson
• Keywords: Oligomer; Amyloid (mycology)

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