Peptide aggregation (revision 3)

Peptide aggregation is the association of peptide molecules with one another. It ranges from reversible self-association into defined oligomers, which may be a stabilising feature of a formulation, to irreversible formation of amyloid-like fibrils or amorphous particles, which is a degradation route.^[1]

The distinction between the two is central and is frequently lost. Liraglutide self-associates into heptamers in its formulation, and that association contributes to its duration of action; human amylin forms fibrils, which is why it could not be developed as a medicine without engineering. Both are "aggregation" in a loose sense and they are not the same phenomenon.^[2]

Aggregation proceeds through partially unfolded or conformationally exposed states rather than from the native state directly. Anything that increases the population of such states — heat, interfaces, shear, extremes of pH — increases the rate.^[1]

Nucleation-dependent aggregation, characteristic of amyloid formation, shows a lag phase during which nuclei form, followed by rapid growth. The lag is why a solution can appear stable for a period and then change quickly, and why seeding with pre-formed aggregate abolishes the lag entirely — a relevant consideration when material is drawn repeatedly from one container.