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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

Chemical reagents targeting and controlling amyloidogenic peptides have received much attention for helping identify their roles in the pathogenesis of protein-misfolding disorders. In this paper, 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. Altogether 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 complexitymore » as next-generation chemical tools for amyloid management.« less
Authors:
 [1] ;  [2] ;  [1] ;  [3] ;  [4] ;  [5] ;  [3] ;  [6] ;  [7] ;  [2] ;  [2] ;  [7] ;  [5] ;  [6] ;  [8] ;  [2] ;  [1]
  1. Ulsan National Institute of Science and Technology (UNIST), Ulsan (Korea)
  2. Univ. of Michigan, Ann Arbor, MI (United States)
  3. Asan Medical Center, Seoul (Korea)
  4. Ulsan National Institute of Science and Technology (UNIST), Ulsan (Korea); Univ. of Michigan, Ann Arbor, MI (United States)
  5. Univ. of Cincinnati, Cincinnati, OH (United States)
  6. Univ. of Nevada, Reno, NV (United States)
  7. Univ. of Miami, Coral Gables, FL (United States)
  8. Asan Medical Center, Seoul (Korea); Univ. of Ulsan College of Medicine, Seoul (Korea)
Publication Date:
Grant/Contract Number:
AC02-98CH10886
Type:
Accepted Manuscript
Journal Name:
Journal of the American Chemical Society
Additional Journal Information:
Journal Volume: 137; Journal Issue: 46; Journal ID: ISSN 0002-7863
Publisher:
American Chemical Society (ACS)
Research Org:
Univ. of Michigan, Ann Arbor, MI (United States)
Sponsoring Org:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22)
Country of Publication:
United States
Language:
English
Subject:
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; 59 BASIC BIOLOGICAL SCIENCES
OSTI Identifier:
1345989