Self-Assembly of a Therapeutic Peptide Surfactant: A Small-Angle X-ray Scattering Study.

Amphiphilic compounds are important in many fields including pharmaceutical processes and development. Synthetic surfactants are often toxic to biological systems and frequently display poor biodegradability. Biosurfactants, such as lipopeptides and bile salts, on the other hand, can offer superior properties with regard to toxicity, biodegradability, and efficiency. Lipidated peptides are also gaining interest as therapeutic agents, as they can offer enhanced pharmacokinetic properties, compared with native peptides. The amphiphilic nature of lipidated peptides suggests that they may self-assemble into micellar structures, which can influence formulation stability and biological performance. Understanding the aggregation behavior of lipidated peptides is thus important for identifying and avoiding stability issues that could affect drug efficacy and safety. Structural characterization of self-assembled aggregates provides insight into aggregation mechanisms, which is valuable for identifying potential challenges during the production, storage, and administration of pharmaceutical peptides. By using small-angle X-ray scattering (SAXS), we have investigated the size and morphology of aggregates formed by MEDI7219, a bis-lipidated glucagon-like peptide-1 (GLP-1) analogue, in various aqueous solutions. We demonstrate that the lipopeptide MEDI7219 behaves as a surfactant with high spontaneous curvature that forms small micelles with a clear core-and-shell structure in aqueous solvents. The aggregation numbers of the micelles vary in the range of 5-8 and are found to be surprisingly insensitive to environmental conditions such as type of electrolyte and tonicity modifier, different buffers, and temperature, while exhibiting very low critical micelle concentrations (cmc).