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Title: A Redox-Active, Compact Molecule for Cross-Linking Amyloidogenic Peptides into Nontoxic, Off-Pathway Aggregates: In Vitro and In Vivo Efficacy and Molecular Mechanisms

Journal Article · · Journal of the American Chemical Society
DOI:https://doi.org/10.1021/jacs.5b10043· OSTI ID:1354250
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Chemical reagents targeting and controlling amyloidogenic peptides have received much attention for helping identify their roles in the pathogenesis of protein-misfolding disorders. Herein, we report a novel strategy for redirecting amyloidogenic peptides into nontoxic, off-pathway aggregates, which utilizes redox properties of a small molecule (DMPD, N,N-dimethyl-p-phenylenediamine) to trigger covalent adduct formation with the peptide. In addition, for the first time, biochemical, biophysical, and molecular dynamics simulation studies have been performed to demonstrate a mechanistic understanding for such an interaction between a small molecule (DMPD) and amyloid-β (Aβ) and its subsequent anti-amyloidogenic activity, which, upon its transformation, generates ligand–peptide adducts via primary amine-dependent intramolecular cross-linking correlated with structural compaction. Furthermore, in vivo efficacy of DMPD toward amyloid pathology and cognitive impairment was evaluated employing 5xFAD mice of Alzheimer’s disease (AD). Such a small molecule (DMPD) is indicated to noticeably reduce the overall cerebral amyloid load of soluble Aβ forms and amyloid deposits as well as significantly improve cognitive defects in the AD mouse model. Overall, our in vitro and in vivo studies of DMPD toward Aβ with the first molecular-level mechanistic investigations present the feasibility of developing new, innovative approaches that employ redox-active compounds without the structural complexity as next-generation chemical tools for amyloid management.

Research Organization:
Brookhaven National Laboratory (BNL), Upton, NY (United States)
Sponsoring Organization:
USDOE Office of Science (SC), Basic Energy Sciences (BES)
DOE Contract Number:
SC00112704
OSTI ID:
1354250
Report Number(s):
BNL-112766-2016-JA¿¿¿
Journal Information:
Journal of the American Chemical Society, Vol. 137, Issue 46; ISSN 0002-7863
Publisher:
American Chemical Society (ACS)
Country of Publication:
United States
Language:
English

References (62)

Protein Misfolding, Functional Amyloid, and Human Disease journal June 2006
Alzheimer's Disease: From Pathology to Therapeutic Approaches journal April 2009
Tools of the Trade: Investigations into Design Strategies of Small Molecules to Target Components in Alzheimer's Disease journal March 2015
The value and limitations of transgenic mouse models used in drug discovery for Alzheimer's disease: an update journal February 2012
Neurodegenerative diseases and oxidative stress journal March 2004
Metal ions and amyloid fiber formation in neurodegenerative diseases. Copper, zinc and iron in Alzheimer's, Parkinson's and prion diseases journal October 2012
Misfolded proteins in Alzheimer's disease and type II diabetes journal January 2012
Bioinorganic Chemistry of Alzheimer’s Disease journal June 2012
The chemistry of Alzheimer’s disease journal January 2009
Metals in Neurobiology: Probing Their Chemistry and Biology with Molecular Imaging journal May 2008
Metal Ions and Intrinsically Disordered Proteins and Peptides: From Cu/Zn Amyloid-β to General Principles journal May 2014
Werner coordination chemistry and neurodegeneration journal January 2013
The art of building multifunctional metal-binding agents from basic molecular scaffolds for the potential application in neurodegenerative diseases journal October 2012
The Ongoing Search for Small Molecules to Study Metal-Associated Amyloid-β Species in Alzheimer’s Disease journal July 2014
Minding metals: Tailoring multifunctional chelating agents for neurodegenerative disease journal January 2010
Small Molecule Modulators of Copper-Induced Aβ Aggregation journal October 2009
Design of small molecules that target metal-A  species and regulate metal-induced A  aggregation and neurotoxicity journal December 2010
Insights into antiamyloidogenic properties of the green tea extract (-)-epigallocatechin-3-gallate toward metal-associated amyloid-  species journal February 2013
Rational Design of a Structural Framework with Potential Use to Develop Chemical Reagents That Target and Modulate Multiple Facets of Alzheimer’s Disease journal December 2013
A rationally designed small molecule for identifying an in vivo link between metal–amyloid-β complexes and the pathogenesis of Alzheimer's disease journal January 2015
Site-specific Inhibitory Mechanism for Amyloid β42 Aggregation by Catechol-type Flavonoids Targeting the Lys Residues journal August 2013
Inhibition of alpha-synuclein fibrillization by dopamine analogs via reaction with the amino groups of alpha-synuclein. Implication for dopaminergic neurodegeneration journal July 2005
Effects of Phenyl- and Methyl-Substituents on p -Phenylenediamine, an Electrochemical and Spectral Study journal June 2009
Determination of formaldehyde using a kinetic-spectrophotometric method. Part II. Oxidation of N-methyl-substituted-1,4-phenylenediamines with hydrogen peroxide journal January 1990
On-line electrochemical–mass spectrometry study of the mechanism of oxidation of N,N-dimethyl-p-phenylenediamine in aqueous electrolytes journal April 2004
In silico search for an endogenous anti-Alzheimer’s molecule — Screening amino acid metabolic pathways journal October 2012
Intraneuronal beta-Amyloid Aggregates, Neurodegeneration, and Neuron Loss in Transgenic Mice with Five Familial Alzheimer's Disease Mutations: Potential Factors in Amyloid Plaque Formation journal October 2006
How Do Metabolites Differ from Their Parent Molecules and How Are They Excreted? journal January 2013
A small molecule that displays marked reactivity toward copper– versus zinc–amyloid-β implicated in Alzheimer's disease journal January 2014
Unraveling the Photoluminescence Response of Light-Switching Ruthenium(II) Complexes Bound to Amyloid-β journal July 2013
Cotinine Reduces Amyloid-β Aggregation and Improves Memory in Alzheimer's Disease Mice journal May 2011
The Amyloid-β Peptide of Alzheimer’s Disease Binds Cu I in a Linear Bis-His Coordination Environment: Insight into a Possible Neuroprotective Mechanism for the Amyloid-β Peptide journal December 2008
Benzoquinone imines. Part II. Hydrolysis of p-benzoquinone monoimine and p-benzoquinone di-imine journal January 1969
Spectroelectrochemistry for a coupled chemical reaction in the channel cell journal March 1999
The Frequency of 1,4-Benzoquinone-Lysine Adducts in Cytochrome c Correlate with Defects in Apoptosome Activation journal April 2011
Quinone Electrophiles Selectively Adduct “Electrophile Binding Motifs” within Cytochrome c journal September 2007
When quinones meet amino acids: chemical, physical and biological consequences journal April 2006
Covalent Binding of Benzoquinone to Reduced Ribonuclease.Adduct Structures and Stoichiometry journal March 1994
Therapeutics for Alzheimer’s disease based on the metal hypothesis journal July 2008
The Alzheimer’s therapeutic PBT2 promotes amyloid-β degradation and GSK3 phosphorylation via a metal chaperone activity: Metal chaperone activity of PBT2 journal August 2011
Naturally secreted oligomers of amyloid β protein potently inhibit hippocampal long-term potentiation in vivo journal April 2002
Common Structure of Soluble Amyloid Oligomers Implies Common Mechanism of Pathogenesis journal April 2003
Distinct Pools of β-Amyloid in Alzheimer Disease–Affected Brain: A Clinicopathologic Study journal July 2008
GROMACS: Fast, flexible, and free journal January 2005
A biomolecular force field based on the free enthalpy of hydration and solvation: The GROMOS force-field parameter sets 53A5 and 53A6 journal January 2004
Solution Structure of Amyloid β-Peptide(1−40) in a Water−Micelle Environment. Is the Membrane-Spanning Domain Where We Think It Is? † , ‡ journal August 1998
AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading journal January 2009
Density‐functional thermochemistry. III. The role of exact exchange journal April 1993
Models@Home: distributed computing in bioinformatics using a screensaver based approach journal February 2002
Settle: An analytical version of the SHAKE and RATTLE algorithm for rigid water models journal October 1992
LINCS: A linear constraint solver for molecular simulations journal September 1997
Particle mesh Ewald: An N ⋅log( N ) method for Ewald sums in large systems journal June 1993
Quiet high-resolution computer models of a plasma journal February 1974
A partially folded structure of amyloid-beta(1–40) in an aqueous environment journal July 2011
Inhibition of Amyloid Peptide Fibrillation by Inorganic Nanoparticles: Functional Similarities with Proteins journal April 2011
N-Terminal Deletions Modify the Cu 2+ Binding Site in Amyloid-β journal March 2005
Amyloid-β Binds Cu 2+ in a Mononuclear Metal Ion Binding Site journal October 2004
Cu(II) Binding to Monomeric, Oligomeric, and Fibrillar Forms of the Alzheimer’s Disease Amyloid-β Peptide † journal April 2008
The Copper(II) Adduct of the Unstructured Region of the Amyloidogenic Fragment Derived from the Human Prion Protein is Redox-Active at Physiological pH journal January 2007
Ion mobility–mass spectrometry analysis of large protein complexes journal June 2008
Collision Cross Sections of Proteins and Their Complexes: A Calibration Framework and Database for Gas-Phase Structural Biology journal November 2010
Tissue plasminogen activator arrests Alzheimer's disease pathogenesis journal March 2014

Cited By (12)

Structure-mechanism-based engineering of chemical regulators targeting distinct pathological factors in Alzheimer’s disease journal October 2016
Calprotectin influences the aggregation of metal-free and metal-bound amyloid-β by direct interaction journal January 2018
Computational Study of the Aza-Michael Addition of the Flavonoid (+)-Taxifolin in the Inhibition of β-Amyloid Fibril Aggregation journal March 2018
Towards an understanding of amyloid-β oligomers: characterization, toxicity mechanisms, and inhibitors journal January 2017
A Unified View of Assessing the Pro-oxidant versus Antioxidant Nature of Amyloid Beta Conformers journal October 2018
Structural and Mechanistic Insights into Development of Chemical Tools to Control Individual and Inter-Related Pathological Features in Alzheimer's Disease journal January 2017
Destabilization of amyloid fibrils on interaction with MoS 2 -based nanomaterials journal January 2019
N , N ′-Diacetyl- p -phenylenediamine restores microglial phagocytosis and improves cognitive defects in Alzheimer’s disease transgenic mice journal November 2019
A Broader‐scope Analysis of the Catalytic Reduction of Nitrophenols and Azo Dyes with Noble Metal Nanoparticles journal May 2019
Minor Structural Variations of Small Molecules Tune Regulatory Activities toward Pathological Factors in Alzheimer's Disease journal October 2017
A cationic polymethacrylate-copolymer acts as an agonist for β-amyloid and an antagonist for amylin fibrillation journal January 2019
Tailoring Hydrophobic Interactions between Probes and Amyloid-β Peptides for Fluorescent Monitoring of Amyloid-β Aggregation journal May 2018

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