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.
abstract: 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.
authors.affiliation: Department of Chemistry, Ulsan National Institute of Science and Technology (UNIST) , Ulsan 44919, Korea.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Derrick
authors.affiliation: Department of Chemistry, University of Michigan , Ann Arbor, Michigan 48109, United States.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Kerr
authors.affiliation: Department of Chemistry, Ulsan National Institute of Science and Technology (UNIST) , Ulsan 44919, Korea.
authors.forename: Younwoo
authors.initials: Y
authors.lastname: Nam
authors.affiliation: Asan Institute for Life Sciences, Asan Medical Center , Seoul 05505, Korea.
authors.forename: Shin Bi
authors.initials: SB
authors.lastname: Oh
authors.affiliation: Department of Chemistry, Ulsan National Institute of Science and Technology (UNIST) , Ulsan 44919, Korea.|Department of Chemistry, University of Michigan , Ann Arbor, Michigan 48109, United States.
authors.forename: Hyuck Jin
authors.initials: HJ
authors.lastname: Lee
authors.affiliation: Department of Chemistry, University of Cincinnati , Cincinnati, Ohio 45221, United States.
authors.forename: Kaylin G
authors.initials: KG
authors.lastname: Earnest
authors.affiliation: Asan Institute for Life Sciences, Asan Medical Center , Seoul 05505, Korea.
authors.forename: Nayoung
authors.initials: N
authors.lastname: Suh
authors.affiliation: Department of Chemistry, University of Nevada , Reno 89557, United States.
authors.forename: Kristy L
authors.initials: KL
authors.lastname: Peck
authors.affiliation: Department of Chemistry, University of Miami , Coral Gables, Florida 33146, United States.
authors.forename: Mehmet
authors.initials: M
authors.lastname: Ozbil
authors.affiliation: Department of Chemistry, University of Michigan , Ann Arbor, Michigan 48109, United States.
authors.forename: Kyle J
authors.initials: KJ
authors.lastname: Korshavn
authors.affiliation: Department of Chemistry, University of Michigan , Ann Arbor, Michigan 48109, United States.|Biophysics, University of Michigan , Ann Arbor, Michigan 48109, United States.
authors.forename: Ayyalusamy
authors.initials: A
authors.lastname: Ramamoorthy
authors.affiliation: Department of Chemistry, University of Miami , Coral Gables, Florida 33146, United States.
authors.forename: Rajeev
authors.initials: R
authors.lastname: Prabhakar
authors.affiliation: Department of Chemistry, University of Cincinnati , Cincinnati, Ohio 45221, United States.
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Merino
authors.affiliation: Department of Chemistry, University of Nevada , Reno 89557, United States.
authors.forename: Jason
authors.initials: J
authors.lastname: Shearer
authors.affiliation: Asan Institute for Life Sciences, Asan Medical Center , Seoul 05505, Korea.|Department of Convergence Medicine, University of Ulsan College of Medicine , Seoul 05505, Korea.
authors.forename: Joo-Yong
authors.initials: JY
authors.lastname: Lee
authors.affiliation: Department of Chemistry, University of Michigan , Ann Arbor, Michigan 48109, United States.
authors.forename: Brandon T
authors.initials: BT
authors.lastname: Ruotolo
authors.affiliation: Department of Chemistry, Ulsan National Institute of Science and Technology (UNIST) , Ulsan 44919, Korea.
authors.forename: Mi Hee
authors.initials: MH
authors.lastname: Lim
mesh_terms: D000682:Amyloid / Q000737:chemistry*; D016229:Amyloid beta-Peptides / Q000737:chemistry*; D002460:Cell Line; D006801:Humans; D066298:In Vitro Techniques; D056004:Molecular Dynamics Simulation; D010084:Oxidation-Reduction
chemical_list: D000682:Amyloid; D016229:Amyloid beta-Peptides