Star Polymers Reduce Islet Amyloid Polypeptide Toxicity via Accelerated Amyloid Aggregation

Abstract

Protein aggregation into amyloid fibrils is a ubiquitous phenomenon across the spectrum of neurodegenerative disorders and type 2 diabetes. A common strategy against amyloidogenesis is to minimize the populations of toxic oligomers and protofibrils by inhibiting protein aggregation with small molecules or nanoparticles. However, melanin synthesis in nature is realized by accelerated protein fibrillation to circumvent accumulation of toxic intermediates. Accordingly, we designed and demonstrated the use of star-shaped poly(2-hydroxyethyl acrylate) (PHEA) nanostructures for promoting aggregation while ameliorating the toxicity of human islet amyloid polypeptide (IAPP), the peptide involved in glycemic control and the pathology of type 2 diabetes. The binding of PHEA elevated the β-sheet content in IAPP aggregates while rendering a new morphology of “stelliform” amyloids originating from the polymers. Atomistic molecular dynamics simulations revealed that the PHEA arms served as rodlike scaffolds for IAPP binding and subsequently accelerated IAPP aggregation by increased local peptide concentration. The tertiary structure of the star nanoparticles was found to be essential for driving the specific interactions required to impel the accelerated IAPP aggregation. This study sheds new light on the structure–toxicity relationship of IAPP and points to the potential of exploiting star polymers as a new class of therapeutic agents against amyloidogenesis.

Half a century of amyloids: past, present and future

“…23,[263][264][265][266][267][268][269][270][271][272][273] In recent years, it has been increasingly realized that, as with molecular inhibitors, the endpoint of amyloidosis mitigation with nanoparticles is not necessarily inhibition of protein fibrillization per se, but suppression of protein toxicity. Indeed, accelerated protein assembly may reduce the population of toxic oligomers and protofibrils, 253,274 analogous to Pmel17 aggregation in melanin synthesis in the skin. 275 However, no systematic understanding is currently available to predict whether an exogenous substance, nanoparticles included, inhibits or accelerates protein aggregation, and if accelerated protein aggregation leads to a beneficial or a detrimental effect on cell viability.…”

Cationic polymethacrylate-copolymer acts as an agonist for β-amyloid and antagonist for amylin fibrillation

“…The successive failures of small molecule compounds directs researchers to develop new antiamyloidogenic molecules such as polymers, peptoids, nanoparticles, molecular chaperones etc. [18][19][20] Among them, several polymers characterized by their ionic properties have been tested to investigate their activities on amyloidogenic aggregation. Notably, amine containing polymers, polyamino acids, cationic surfactants and cellular polyamines have been observed to modulate A aggregation.…”

“…Notably, amine containing polymers, polyamino acids, cationic surfactants and cellular polyamines have been observed to modulate A aggregation. [21][22][23] Similarly, controlled aggregation kinetics and toxicity of hIAPP using starpolymers and polymer-nanodiscs have been studied recently 19,24 . Here we demonstrate the modulation of amyloid aggregation pathways for hIAPP and A40 using a polymethacrylate (PMAQA) derived copolymer ( Fig.…”

Polymer Brushes via Surface-Initiated Electrochemically Mediated ATRP: Role of a Sacrificial Initiator in Polymerization of Acrylates on Silicon Substrates

“…The homopolymer brushes demonstrated water contact angles (WCA) of 61.9 ± 1.2°, comparable to literature data for PHEA brushes [ 74 ]. The chemical structure of the PHEA chains synthesized in solution ( Table 1 , entry 1) was confirmed by 1 H NMR ( Figure S8 ): δ (ppm) = 4.66–4.80 (1H, O H –, c), 3.89–4.07 (2H, –C H 2 –, a), 3.49–3.63 (2H, –C H 2 –, b), 2.14–2.38 (1H, –C H =, α), 1.34–1.90 (2H, –C H 2 –, β) [ 75 , 76 ].…”