Open AccessA Redox-Active, Compact Molecule for Cross-Linking Amyloidogenic Peptides into Nontoxic, Off-Pathway Aggregates: In Vitro and In Vivo Efficacy and Molecular Mechanisms
Author(s) -
Jeffrey S. Derrick,
Richard A. Kerr,
Younwoo Nam,
SeJoon Oh,
Hyuck Jin Lee,
Kaylin G. Earnest,
Nayoung Suh,
Kristy L. Peck,
Mehmet Özbi̇l,
Kyle J. Korshavn,
Ayyalusamy Ramamoorthy,
Rajeev Prabhakar,
Edward J. Merino,
Jason Shearer,
Joo Yong Lee,
Brandon T. Ruotolo,
Mi Hee Lim
Publication year - 2015
Publication title -
journal of the american chemical society
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.115
H-Index - 612
eISSN - 1520-5126
pISSN - 0002-7863
DOI - 10.1021/jacs.5b10043
Subject(s) - chemistry , in vivo , peptide , small molecule , amyloid (mycology) , in vitro , biophysics , adduct , ligand (biochemistry) , combinatorial chemistry , biochemistry , receptor , organic chemistry , inorganic chemistry , microbiology and biotechnology , biology
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.