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Star polymers reduce IAPP toxicity via accelerated amyloid aggregation
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Pilkington, Emily H., Lai, May, Ge, Xinwei, Stanley, William J., Wang, Bo, Wang, Miaovi, Kakinen, Aleksandr, Sani, Marc-Antonie, Whittaker, Michael R., Gurov, Esteban, Ding, Feng, Quinn, John F., Davis, Thomas P. and Ke, Pu Chun (2017) Star polymers reduce IAPP toxicity via accelerated amyloid aggregation. Biomacromolecules . doi:10.1021/acs.biomac.7b01301 ISSN 1525-7797.
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Official URL: http://doi.org/10.1021/acs.biomac.7b01301
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 the 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 beta-sheet content in IAPP aggregates while rendered a new morphology of ‘stelliform’ amyloids originating from the polymers. Atomistic molecular dynamics simulations revealed that the PHEA arms served as rod-like 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 to drive the specific interactions required to impel the accelerated IAPP aggregation. This study shed 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.
Item Type: | Journal Article | ||||||||||||||||||||||||||||||
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Subjects: | Q Science > QD Chemistry | ||||||||||||||||||||||||||||||
Divisions: | Faculty of Science, Engineering and Medicine > Science > Chemistry | ||||||||||||||||||||||||||||||
Library of Congress Subject Headings (LCSH): | Star-branched polymers, Non-insulin-dependent diabetes -- Physiological aspects, Oligomers, Nanoparticles, Melanins -- Synthesis | ||||||||||||||||||||||||||||||
Journal or Publication Title: | Biomacromolecules | ||||||||||||||||||||||||||||||
Publisher: | American Chemical Society | ||||||||||||||||||||||||||||||
ISSN: | 1525-7797 | ||||||||||||||||||||||||||||||
Official Date: | 16 October 2017 | ||||||||||||||||||||||||||||||
Dates: |
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DOI: | 10.1021/acs.biomac.7b01301 | ||||||||||||||||||||||||||||||
Status: | Peer Reviewed | ||||||||||||||||||||||||||||||
Publication Status: | Published | ||||||||||||||||||||||||||||||
Access rights to Published version: | Open Access (Creative Commons) | ||||||||||||||||||||||||||||||
Date of first compliant deposit: | 23 November 2017 | ||||||||||||||||||||||||||||||
Date of first compliant Open Access: | 23 November 2017 | ||||||||||||||||||||||||||||||
RIOXX Funder/Project Grant: |
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