Polyphenolic gallotannins inhibit amyloid aggregation and associated cytotoxicity primarily by interfering with secondary nucleation

Amyloidoses result from protein misfolding and aggregation into insoluble amyloid deposits, impairing organ function. These deposits are linked to diseases like Alzheimer's, Parkinson’s, and type 2 diabetes (T2DM). T2DM involves the pancreatic deposition of islet amyloid polypeptide (IAPP), a peptide hormone critical for glucose regulation. However, IAPP can misfold, forming cytotoxic aggregates in pancreatic islets and leading to β-cell dysfunction. Targeting IAPP aggregation is a promising treatment strategy for T2DM. Naturally occuring gallotannins are potential amyloid-aggregation inhibitors, although their effects are not fully understood. This study examines two gallotannins, corilagin and 1,3,6-tri-O-Galloyl-β-D-glucose (β-TGG), and their inhibitory effects on IAPP aggregation. Thioflavin T fluorescence, atomic force microscopy and circular dichroism showed that gallotannins delay IAPP self-assembly and reduce length and quantity of amyloid fibrils. By monitoring cell metabolism, release of cytosolic enzymes and production of reactive oxygen species, we showed that corilagin protects INS-1E pancreatic cells against IAPP toxicity and plasma membrane damage. Peptide-gallotannin interactions were further investigated using all-atom explicit solvent molecular dynamic simulations, revealing hydrogen bonds and π-π stacking interactions. Overall, these experimental and computational findings highlight the potent anti-aggregative and cytoprotective properties of gallotannins, thus, potential candidates to prevent or modulate the progression of amyloidoses.