Structure-mechanism-based engineering of chemical regulators targeting distinct pathological factors in Alzheimer's disease

• Published in: Nature communications Vol. 7; no. 1; pp. 13115 - 13
• Main Authors: Beck, Michael W, Derrick, Jeffrey S, Kerr, Richard A, Oh, Shin Bi, Cho, Woo Jong, Lee, Shin Jung C, Ji, Yonghwan, Han, Jiyeon, Tehrani, Zahra Aliakbar, Suh, Nayoung, Kim, Sujeong, Larsen, Scott D, Kim, Kwang S, Lee, Joo-Yong, Ruotolo, Brandon T, Lim, Mi Hee
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 13.10.2016; Nature Portfolio
• Subjects: Alzheimer Disease - drug therapy; Alzheimer Disease - genetics; Alzheimer Disease - metabolism; Alzheimer's disease; Amyloid - antagonists & inhibitors; Amyloid - metabolism; Amyloid beta-Peptides - antagonists & inhibitors; Amyloid beta-Peptides - metabolism; Animals; Chemistry; Design; Drug Design; Free Radicals - antagonists & inhibitors; Free Radicals - metabolism; Humans; Life sciences; Metals; Metals - antagonists & inhibitors; Metals - metabolism; Mice, Inbred C57BL; Mice, Transgenic; Molecular Structure; Pathogenesis; Pathology; Permeability; Protein Aggregates - drug effects; Proteins; Reactive Oxygen Species - antagonists & inhibitors; Reactive Oxygen Species - metabolism; Small Molecule Libraries - chemistry; Small Molecule Libraries - pharmacology; South Korea; Ann Arbor Michigan; United States > US; Michigan
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms13115

The absence of effective therapeutics against Alzheimer's disease (AD) is a result of the limited understanding of its multifaceted aetiology. Because of the lack of chemical tools to identify pathological factors, investigations into AD pathogenesis have also been insubstantial. Here we report chemical regulators that demonstrate distinct specificity towards targets linked to AD pathology, including metals, amyloid-β (Aβ), metal-Aβ, reactive oxygen species, and free organic radicals. We obtained these chemical regulators through a rational structure-mechanism-based design strategy. We performed structural variations of small molecules for fine-tuning their electronic properties, such as ionization potentials and mechanistic pathways for reactivity towards different targets. We established in vitro and/or in vivo efficacies of the regulators for modulating their targets' reactivities, ameliorating toxicity, reducing amyloid pathology, and improving cognitive deficits. Our chemical tools show promise for deciphering AD pathogenesis and discovering effective drugs.