Inhibition of hIAPP Amyloid Aggregation and Pancreatic β-Cell Toxicity by OH-Terminated PAMAM Dendrimer

Abstract

Human islet amyloid polypeptide (hIAPP, or amylin) forms amyloid deposits in the islets of Langerhans, a phenomenon that is associated with type-2 diabetes impacting millions of people worldwide. Accordingly, strategies against hIAPP aggregation are essential for the prevention and eventual treatment of the disease. Here, it is shown that generation-3 OH-terminated poly(amidoamine) dendrimer, a polymeric nanoparticle, can effectively halt the aggregation of hIAPP and shut down hIAPP toxicity in pancreatic MIN6 and NIT-1 cells as well as in mouse islets. This finding is supported by high-throughput dynamic light scattering experiment and thioflavin T assay, where the rapid evolution of hIAPP nucleation and elongation processes is halted by the addition of the dendrimer up to 8 h. Discrete molecular dynamics simulations further reveal that hIAPP residues bound strongly with the dendrimer near the c-terminal portion of the peptide, where the amyloidogenic sequence (residues 22-29) locates. Furthermore, simulations of hIAPP dimerization reveal that binding with the dendrimer significantly reduces formation of interpeptide contacts and hydrogen bonds, thereby prohibiting peptide self-association and amyloidosis. This study points to a promising nanomedicinal strategy for combating type-2 diabetes and may have broader implications for targeting neurological disorders whose distinct hallmark is also amyloid fibrillation.

Star Polymers Reduce Islet Amyloid Polypeptide Toxicity via Accelerated Amyloid Aggregation

“…10−13 For example, antiprion activity has been demonstrated by phosphorus dendrimers, maltose-based glycodendrimers (mPPI), poly(propyleneimine) PPI, and poly(ethylenimine) hyperbranched polymers. 12−20 Of the myriad forms of polymeric NPs, hyperbranched polymers and dendrimers have demonstrated strong efficacies as antiamyloid agents, 11,12,15,21−26 though anti-IAPP applications have only been explored recently. PPI glycodendrimers and lysine dendrimers have been investigated as anti-Aβ aggregation agents, 22,23 and hyperbranched PEG-based polymers with a dopamine moiety were found to be capable of inhibiting α-synuclein (αS) aggregation.…”

“…11 Anionic low-generation dendrimers have been shown to modulate IAPP fibrillization and associated toxicity, 24 and inhibition of IAPP fibrillization and toxicity in vitro and ex vivo has recently been demonstrated by our team with OH-terminated polyamidoamine dendrimers (PAMAM-OH). 26 …”

Brazilin inhibits fibrillogenesis of human islet amyloid polypeptide, disassembles mature fibrils, and alleviates cytotoxicity

“…18,19 Among these, small organic molecules have received special interest because of their high permeability through the blood-brain barrier and potentially low cytotoxicity. 20 Several natural compounds have been found to prevent hIAPP brillization or to transform the mature brils into unstructured, off-pathway aggregates.…”

Modulating protein amyloid aggregation with nanomaterials

“…Further computational studies indicated that PAMAM dendrimers could encapsulate one or two hIAPP monomers within their core subsequently forming a unimolecular micelle that shielded amyloid contact from free hIAPP, thus terminating the amyloid fibrillization pathway. 53 …”

“…Chem. 2014; 289, 31066-31076 51 ; Nanoscale 2015, 7 , 18725–18737 52 ; Small , 2016, 12 , 1615–1626, 53 copyright 2016 John Wiley & Sons.…”