Peptide Inhibitors of Insulin Fibrillation: Current and Future Challenges

Abstract

Amyloidoses include a large variety of local and systemic diseases that share the common feature of protein unfolding or refolding into amyloid fibrils. The most studied amyloids are those directly involved in neurodegenerative diseases, while others, such as those formed by insulin, are surprisingly far less studied. Insulin is a very important polypeptide that plays a variety of biological roles and, first and foremost, is at the basis of the therapy of diabetic patients. It is well-known that it can form fibrils at the site of injection, leading to inflammation and immune response, in addition to other side effects. In this concise review, we analyze the current knowledge on insulin fibrillation, with a focus on the development of peptide-based inhibitors, which are promising candidates for their biocompatibility but still pose challenges to their effective use in therapy.

Keywords: D-amino acids; amyloid; chirality; diabetes; fibrillation; inhibitors; insulin; peptides; phenylalanine; β-sheets.

Figure 1

The three-dimensional structure of insulin shows three helical portions, two of chain A (green) and one of chain B (cyan), and three disulfide bridges (yellow).

Figure 2

Scheme of insulin fibrillization. Reprinted from [21] with permission from Elsevier, Copyright © 2023 Elsevier.

Figure 3

Sequences of insulin chains A and B with colors (green for chain A and cyan for chain B) highlighting hydrophobic regions that can be exposed and promote fibrillation.

Figure 4

Molecular models of insulin interacting with different peptide inhibitors. (a) DNPQS. (b) ELAQM. Both are reprinted from [87], Copyright © 2023, with permission from Elsevier. (c) Ferrocenyl-FF. (d) Ferrocenyl-FY. Both are reprinted from [88], with permission from the Royal Society of Chemistry. (e) Ferrocenyl-FFD. (f) Ferrocenyl-FFF. (g) Ferrocenyl-FFK. (h) Ferrocenyl-FFY. (e–h) They are reprinted from [89], with permission from the Royal Society of Chemistry. (i) NFGAIL. Reprinted from [91], Copyright © 2023, with permission from Elsevier. (j) NIVNVSLVK. Reproduced from [92] under a Creative Commons license, © 2023 Banerjee et al. (k) VIFYW. (l) VVVVV. (k,l) Both are reprinted from [93] under a Creative Commons license, © 2023 Siddiqi, Alam, Iqbal, Majid, Malik, Nusrat, Alam, Ajmal, Uversky, and Khan.