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

作者：Derrick Jeffrey S; Kerr Richard A; Nam Younwoo; Oh Shin Bi; Lee Hyuck Jin; Earnest Kaylin G; Suh Nayoung; Peck Kristy L; Ozbil Mehmet; Korshavn Kyle J; Ramamoorthy Ayyalusamy; Prabhakar Rajeev; Merino Edward J; Shearer Jason^*; Lee Joo Yong; Ruotolo Brandon T; Lim Mi Hee

来源：Journal of the American Chemical Society, 2015, 137(46): 14785-14797.

DOI：10.1021/jacs.5b10043

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-beta (A beta) and its subsequent anti-amyloidogenic activity, which, upon its transformation, generates ligandpeptide 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 Alzheimers disease (AD). Such a small molecule (DMPD) is indicated to noticeably reduce the overall cerebral amyloid load of soluble A beta 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 A beta 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.

• 出版日期2015-11-25