Insulin fibrillation: Strategies for inhibition

Insulin and its homologous are the most utilized protein drugs due to their role in diabetic patients' treatment. Insulin forms amyloid-like fibrils in vivo at the injection site. Therefore, the study of its fibrillation mechanism and designing efficient inhibitors have high importance in the pharmaceutical industry. Insulin fibrils are formed at both acidic and neutral pH in vitro. Overall, this process involves the dissociation of hexameric form to monomeric, partially dissociating the native monomeric form, nuclei formation, and finally converting oligomers to large ordered aggregates. Intermediate and terminal species are different pathologically. This review is focused on the research works dedicated to the inhibition of insulin fibril formation. The inhibitors include various polyphenols, natural compounds, nanoparticles, and synthetic chemicals/peptides, as well as the classification of inhibitors targets concerning protein fibrillation. Although most inhibitors stabilize the native structure of the protein and prevent the formation of partially folded species, there are other inhibitors that hinder other steps in the course of fibrillation. Also, several inhibitors were able to dissociate the pre-existing fibrils. Finding inhibition strategies could be beneficial for developing new inhibitors that are more efficient and can block the amyloid pathway in a specific desired stage.