Star Polymers Reduce Islet Amyloid Polypeptide Toxicity via Accelerated Amyloid Aggregation

Emily H Pilkington, May Lai, Xinwei Ge, William J Stanley, Bo Wang, Miaoyi Wang, Aleksandr Kakinen, Mark-Antoine Sani, Michael R Whittaker, Esteban N. Gurzov, Feng Ding, John Quinn, Thomas P Davis, Pu Chun Ke

Research output: Contribution to journalArticleResearchpeer-review

33 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)4249-4260
Number of pages12
JournalBiomacromolecules
Volume18
Issue number12
DOIs
Publication statusPublished - 11 Dec 2017

Cite this