Semaglutide Forms Fibrils at Low pH and a Novel Chiral-Imprinted Glass
Background
Semaglutide is a crucial lipopeptide drug, known for its GLP-1 (glucagon-like peptide-1) sequence, which makes it highly effective in treating conditions like type 2 diabetes and obesity. However, like many peptides, it is prone to aggregation, which can impact its stability and therapeutic efficacy. This study investigates how semaglutide aggregates under varying pH conditions and explores the potential to form novel material structures, specifically a chiral-imprinted glass.
Results
The study revealed distinct aggregation behaviors of semaglutide depending on the pH of the solution. At a low pH of 2.4, semaglutide was found to form well-defined β-sheet fibrils, a structure often associated with protein aggregation. In contrast, at higher pH values, the peptide primarily formed oligomeric and micellar structures, indicating a pH-dependent conformational switch. Cryo-TEM images clearly showed these fibrils were twisted, and modeling of SAXS data, supported by fiber XRD and molecular dynamics simulations, proposed a detailed β-sheet structure comprising curved β-strands arranged in an antiparallel fashion around a core containing the lipidated lysine residue. Remarkably, the researchers successfully formed a novel chiral-imprinted glass from the base form of semaglutide when combined with crotonic acid, an organic salt capable of hydrogen bonding. This glass formation represents a significant new material property for semaglutide.
Why It Matters
This research provides crucial insights into the structural stability and aggregation mechanisms of semaglutide, which is vital for optimizing its formulation and storage. Understanding the pH-dependent formation of β-sheet fibrils versus micellar structures can help prevent unwanted aggregation, thereby enhancing drug efficacy and shelf-life. The groundbreaking discovery of forming a semaglutide glass with crotonic acid opens up exciting possibilities for novel therapeutic applications. Such semaglutide glasses could potentially serve as slow-release depots, offering sustained drug delivery and potentially reducing dosing frequency for patients with type 2 diabetes or obesity. Future work will likely involve in-depth characterization of the glass properties and preclinical studies to evaluate its in vivo drug release profile and therapeutic potential.