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Title: Polymer–Peptide Conjugates Disassemble Amyloid β Fibrils in a Molecular-Weight Dependent Manner

Amyloid aggregation and deposition are associated with many intractable human diseases. Although the inhibition of amyloid protein aggregation has been well-studied, the disaggregation and dissolution of existing amyloid fibrils is less known. Taking a fibrillar assembly of amyloid β (Aβ) peptide as the model system, in this paper we report multivalent polymer–peptide conjugates (mPPCs) that disassemble preformed Aβ fibrils into dispersible sub-100 nm structures. Atomic force microscopy and dynamic light scattering studies show that the disassembly rate of preformed Aβ fibrils is controlled by the molecular weight of mPPCs. Rate equations on fibril disappearance are deduced from a simple model, which indicate that the disassembly reaction is first-order in the concentration of Aβ fibrils and a pseudo-first-order reaction in the concentration of peptide moieties on mPPCs, respectively. We eliminate the possibility that the disassembly occurs by the association between mPPCs and Aβ monomer/oligomers based on circular dichroism and Thioflavin T fluorescence assays. It is mostly likely that the mPPCs disassemble Aβ fibrils through a direct interaction. Finally, the mPPCs may thus offer a general macromolecular design concept that breaks down existing amyloid fibrils in a predictable fashion.
Authors:
ORCiD logo [1] ;  [2] ;  [3] ; ORCiD logo [1]
  1. Univ. of Illinois, Urbana, IL (United States). Dept. of Chemistry. Beckman Inst. for Advanced Science and Technology
  2. Univ. of Illinois, Urbana, IL (United States). Dept. of Chemistry
  3. Univ. of Illinois, Urbana, IL (United States). Beckman Inst. for Advanced Science and Technology
Publication Date:
Grant/Contract Number:
FG02-07ER46471
Type:
Accepted Manuscript
Journal Name:
Journal of the American Chemical Society
Additional Journal Information:
Journal Volume: 139; Journal Issue: 12; Journal ID: ISSN 0002-7863
Publisher:
American Chemical Society (ACS)
Research Org:
Univ. of Illinois at Urbana-Champaign, IL (United States)
Sponsoring Org:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES
OSTI Identifier:
1425495