Diabetes Drug Discovery: hIAPP Polymorphic Amyloid Structures as Novel Therapeutic Targets.

Human islet amyloid peptide (hIAPP) aggregation is an early step in Diabetes Mellitus. We aimed to evaluate a family of pharmaco-chaperones to act as modulators that provide dynamic interventions and the multi-target capacity (native state, cytotoxic oligomers, protofilaments and fibrils of hIAPP) required to meet the treatment challenges of diabetes. We used a cross-functional approach that combines in silico and in vitro biochemical and biophysical methods to study the hIAPP aggregation-oligomerization process as to reveal novel potential anti-diabetic drugs. The family of pharmaco-chaperones are modulators of the oligomerization and fibre formation of hIAPP. When they interact with the amino acid in the amyloid-like steric zipper zone, they inhibit and/or delay the aggregation-oligomerization pathway by binding and stabilizing several amyloid structures of hIAPP. Moreover, they can protect cerebellar granule cells (CGC) from the cytotoxicity produced by the hIAPP oligomers. The modulation of proteostasis by the family of pharmaco-chaperones - is a promising potential approach to limit the onset and progression of diabetes and its comorbidities.