Prion protein-derived cell-penetrating peptide inhibits type II diabetes-associated islet amyloid polypeptide aggregation and cytotoxicity

ABSTRACT Islet amyloid polypeptide (IAPP) is a 37-residue peptide hormone co-packaged and co-secreted with insulin by pancreatic β-cells. A pathological hallmark of type II diabetes is the self-assembly of IAPP into β-sheet rich amyloid fibers, which is associated with β-cell impairment. Previously, we showed that a cell-penetrating peptide (CPP) construct, consisting of a hydrophobic signal sequence coupled to a polycationic nuclear localization signal (NLS)-like sequence, exhibited potent anti-prion activity and antagonism of Alzheimer’s disease-associated amyloid-β (Aβ) peptide aggregation and neurotoxicity. Here, we have extended this approach towards type II diabetes by assessing the efficacy of the CPP construct, designated as NCAM1-PrP, in inhibiting IAPP oligomerization, fiber formation and associated cytotoxicity. Using complementary in vitro and in silico experiments, we show that NCAM1-PrP effectively modulates IAPP’s toxic structures into non-toxic conformations. This study underlines the potential of our designed CPP-based therapeutic approach as a versatile tool in the battle against amyloid-associated pathologies.