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Multivalent Polymer–Peptide Conjugates: A General Platform for Inhibiting Amyloid Beta Peptide Aggregation

Journal Article · · ACS Macro Letters
 [1];  [2];  [2];  [2];  [2];  [2];  [2];  [2];  [2];  [2]
  1. Univ. of Illinois at Urbana-Champaign, IL (United States); University of Illinois at Urbana-Champaign
  2. Univ. of Illinois at Urbana-Champaign, IL (United States)
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Protein aggregation is implicated in multiple deposition diseases including Alzheimer's Disease, which features the formation of toxic aggregates of amyloid beta (Aβ) peptides. Many inhibitors have been developed to impede or reverse Aβ aggregation. Multivalent inhibitors, however, have been largely overlooked despite the promise of high inhibition efficiency endowed by the multivalent nature of Aβ aggregates. In this work, we report the success of multivalent polymer peptide conjugates (mPPCs) as a general class of inhibitors of the aggregation of Aβ40. Significantly delayed onset of fibril formation was realized using mPPCs prepared with three peptide/peptoid ligands covering a range of polymer molecular weights (MWs) and ligand loadings. Dose dependence studies showed that the nature of the ligands is a key factor in mPPC inhibition potency. The negatively charged ligand LPFFD leads to more efficient mPPCs compared to mPPCs with the neutral ligands, and is most effective at 7% ligand loading across different MWs. Molecular dynamics simulations along with dynamic light scattering experiments suggest that mPPCs form globular structures in solution due to ligand ligand interactions. Such interactions are key to the spatial proximity of ligands and thus to the multivalency effect of mPPC inhibition. Finally, excess ligand ligand interactions, however, reduce the accessibility of mPPC ligands to Aβ peptides, and impair the overall inhibition potency.

Research Organization:
Univ. of Illinois at Urbana-Champaign, IL (United States)
Sponsoring Organization:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22); US Air Force Office of Scientific Research (AFOSR); National Institutes of Health (NIH); National Science Foundation (NSF)
Grant/Contract Number:
FG02-07ER46471
OSTI ID:
1607404
Journal Information:
ACS Macro Letters, Journal Name: ACS Macro Letters Journal Issue: 10 Vol. 8; ISSN 2161-1653
Publisher:
American Chemical Society (ACS)Copyright Statement
Country of Publication:
United States
Language:
English

References (31)

Multivalency as a Chemical Organization and Action Principle journal September 2012
Reactive Amphiphilic Conjugated Polymers for Inhibiting Amyloid β Assembly journal April 2019
Branched KLVFF Tetramers Strongly Potentiate Inhibition of β-Amyloid Aggregation journal October 2007
Gold-Nanoparticle-Based Multifunctional Amyloid-β Inhibitor against Alzheimer’s Disease journal November 2014
Inhibition of Alzheimer's Amyloidosis by Peptides That Prevent β-Sheet Conformation journal September 1996
Inhibitors of Fibril Formation and Cytotoxicity of β-Amyloid Peptide Composed of KLVFF Recognition Element and Flexible Hydrophilic Disrupting Element journal January 2002
Studies on the in Vitro Assembly of Aβ 1–40: Implications for the Search for Aβ Fibril Formation Inhibitors journal June 2000
Seeding “one-dimensional crystallization” of amyloid: A pathogenic mechanism in Alzheimer's disease and scrapie? journal June 1993
Alzheimer's disease: Initial report of the purification and characterization of a novel cerebrovascular amyloid protein journal May 1984
Chemical kinetics for drug discovery to combat protein aggregation diseases journal March 2014
Polymer−Peptide Conjugates Convert Amyloid into Protein Nanobundles through Fragmentation and Lateral Association journal September 2019
Toward a Rational Design to Regulate β-Amyloid Fibrillation for Alzheimer’s Disease Treatment journal January 2018
Rationally Designed Peptides and Peptidomimetics as Inhibitors of Amyloid-β (Aβ) Aggregation: Potential Therapeutics of Alzheimer’s Disease journal January 2017
Synthesis of Copolymers Containing an Active Ester of Methacrylic Acid by RAFT:  Controlled Molecular Weight Scaffolds for Biofunctionalization journal April 2006
Influencing Receptor−Ligand Binding Mechanisms with Multivalent Ligand Architecture journal December 2002
Chemical Probes That Selectively Recognize the Earliest Aβ Oligomers in Complex Mixtures journal November 2010
Multivalent Macromolecules Redirect Nucleation-Dependent Fibrillar Assembly into Discrete Nanostructures journal February 2014
Chiral Metallohelical Complexes Enantioselectively Target Amyloid β for Treating Alzheimer’s Disease journal August 2014
Inhibition of Amyloid β Protein Fibrillation by Polymeric Nanoparticles journal October 2008
Polymer–Peptide Conjugates Disassemble Amyloid β Fibrils in a Molecular-Weight Dependent Manner journal March 2017
The Neuronal Tau Protein Blocks in Vitro Fibrillation of the Amyloid-β (Aβ) Peptide at the Oligomeric Stage journal April 2018
Versatile and Efficient Targeting Using a Single Nanoparticulate Platform: Application to Cancer and Alzheimer’s Disease journal July 2012
Amyloid β-sheet mimics that antagonize protein aggregation and reduce amyloid toxicity journal September 2012
β-sheet breaker peptides inhibit fibrillogenesis in a rat brain model of amyloidosis: Implications for Alzheimer's therapy journal July 1998
Heteromultivalent peptide recognition by co-assembly of cyclodextrin and calixarene amphiphiles enables inhibition of amyloid fibrillation journal November 2018
Rationally Designed Peptidomimetic Modulators of Aβ Toxicity in Alzheimer's Disease journal January 2015
Avoiding compositional drift during the RAFT copolymerization of N-(2-hydroxypropyl)methacrylamide and N-acryloxysuccinimide: towards uniform platforms for post-polymerization modification journal January 2015
Bridging the gap between molecular dynamics and hydrodynamics in nanoscale Brownian motions journal January 2019
Arrest of -Amyloid Fibril Formation by a Pentapeptide Ligand journal April 1996
Computational and Experimental Studies on β-Sheet Breakers Targeting Aβ1–40 Fibrils journal April 2014
Self-Structuring in Water of Polyamidoamino Acids with Hydrophobic Side Chains Deriving from Natural α-Amino Acids journal November 2018

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37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY