Self-assembly and aggregation of human islet amyloid polypeptide (hIAPP, or amylin) into β-sheet-rich oligomers and fibrils have been implicated in pancreatic β-cell dysfunction and failure, contributing to the pathogenesis of type 2 diabetes (T2D). Substantial effort has gone into developing inhibitors, particularly short peptides, capable of targeting hIAPP and disrupting its amyloidogenic process, offering potential therapeutic strategies to prevent or slow T2D progression. Here, we demonstrate the effectiveness of the anti-amyloidogenic peptide QBP1 in halting the conformational conversion of hIAPP into β-structured aggregates, thereby preventing amyloidogenesis and its associated cytotoxicity. First, we evaluated the anti-amyloidogenic effects of QBP1 through cell-free in vitro aggregation experiments, including Thioflavin-T fluorescence, A11/OC dot blotting, and negative-stain electron microscopy. Circular dichroism and nuclear magnetic resonance spectroscopy corroborated that QBP1 delays hIAPP β-sheet formation and oligomerization, respectively, with an efficacy comparable to that of epigallocatechin-3-gallate. Second, we performed cell-based in vitro experiments to investigate cytoprotection in INS-1E β-cells by fusing QBP1 to the cell-penetrating peptide penetratin (Antp-QBP1). Viability assays, immunocytochemistry, and gene expression analysis showed that under amyloidogenic stress Antp-QBP1 preserves β-cell viability and metabolic homeostasis by preventing the formation of early toxic hIAPP intermediates. Finally, in silico experiments using molecular dynamics simulations revealed stable QBP1-hIAPP interactions mediated by van der Waals forces and π-H contacts involving hydrophobic and aromatic residues (e.g., W, F), supported by favorable non-polar solvation and structural complementarity. Taken together, these findings identify QBP1 as a promising candidate for strategies aimed at reducing islet amyloid burden and preserving β-cell integrity in T2D.
Tejero-Ojeda et al. (Wed,) studied this question.