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

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• 作者：Jeffrey S. Derrick ; Richard A. Kerr ; Younwoo Nam ; Shin Bi Oh ; Hyuck Jin Lee ; Kaylin G. Earnest ; Nayoung Suh ; Kristy L. Peck ; Mehmet Ozbil ; Kyle J. Korshavn ; Ayyalusamy Ramamoorthy ; Rajeev Prabhakar ; Edward J. Merino ; Jason Shearer ; Joo-Yong Lee ; Brandon T. Ruotolo ; Mi Hee Lim
• 刊名：Journal of the American Chemical Society
• 出版年：2015
• 出版时间：November 25, 2015
• 年：2015
• 卷：137
• 期：46
• 页码：14785-14797
• 全文大小：774K
• ISSN：1520-5126

文摘

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