Targeting amylin fibrillation: Design and formulation of novel antidiabetic nutraceuticals.

Islet amyloid polypeptide (IAPP) fibrillation, is a key pathological feature of type 2 diabetes (T2D), contributing to β-cell dysfunction, impaired insulin secretion, and disease progression. Consequently, inhibition of IAPP fibrillation to minimize β-cell cytotoxicity is an important approach towards β-cell preservation and T2D management. Various anti-fibrillation compounds have been identified, including polyphenols, carbohydrates, peptides, and even polyphenol-peptide combinations targeting IAPP. Polyphenols are known for their antioxidant properties and mitigating oxidative stress, a key contributor to fibrillation-induced β-cell toxicity. Peptides and carbohydrates interact with IAPP through specific binding motifs to disrupt fibrillation pathways. Various tools have been employed to identify fibrillation inhibitors (i.e. thioflavin T (ThT) fluorescence assay, dynamic light scattering (DLS)), evaluate the effect of inhibitor binding on IAPP conformation (i.e., circular dichroism (CD) spectroscopy and molecular docking), and elucidate the effect of inhibitors in mitigating fibrillation-induced loss of cell functionality and viability (i.e. membrane leakage assays, cell viability, cellular oxidative stress, and glucose-stimulated insulin secretion). However, despite the advances in food-derived anti-fibrillation compounds, the relationship between inhibitor structure and activity remains underexplored. Studying structure-activity relationships enables the identification of key molecular features essential for inhibitory activity. Here, we discuss recent highlights in IAPP anti-fibrillation compounds and advances in understanding structure-activity relationships using quantitative structure-activity relationships analysis. Various amino acid descriptors such as FASGAI, z5 scales, and KideraFactors using penta- and hexapeptides with varying anti-fibrillation activity were used to develop models using partial least squared projection to latent structure analysis (PLS) to elucidate the structural features that contribute to inhibitor activity. Insights from this study highlight implications for our understanding of the fibrillation process as a whole. The findings provide insight into the preferred structural interactions of anti-IAPP fibrillation peptide inhibitors, paving the way toward the rational development of novel anti-diabetic nutraceuticals with anti-fibrillation mechanisms.