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

Michael W. Beck, Jeffrey S. Derrick, Richard A. Kerr, Shin Bi Oh, Woo Jong Cho, Shin Jung C. Lee, Yonghwan Ji, Jiyeon Han, Zahra Aliakbar Tehrani, Nayoung Suh, Sujeong Kim, Scott D. Larsen, Kwang S. Kim (), Joo-Yong Lee (), Brandon T. Ruotolo () and Mi Hee Lim ()
Additional contact information
Michael W. Beck: Ulsan National Institute of Science and Technology (UNIST)
Jeffrey S. Derrick: Ulsan National Institute of Science and Technology (UNIST)
Richard A. Kerr: University of Michigan
Shin Bi Oh: Asan Institute for Life Sciences, Asan Medical Center
Woo Jong Cho: School of Life Sciences, Ulsan National Institute of Science and Technology (UNIST)
Shin Jung C. Lee: Ulsan National Institute of Science and Technology (UNIST)
Yonghwan Ji: Ulsan National Institute of Science and Technology (UNIST)
Jiyeon Han: Ulsan National Institute of Science and Technology (UNIST)
Zahra Aliakbar Tehrani: Ulsan National Institute of Science and Technology (UNIST)
Nayoung Suh: Asan Institute for Life Sciences, Asan Medical Center
Sujeong Kim: Asan Institute for Life Sciences, Asan Medical Center
Scott D. Larsen: University of Michigan
Kwang S. Kim: Ulsan National Institute of Science and Technology (UNIST)
Joo-Yong Lee: Asan Institute for Life Sciences, Asan Medical Center
Brandon T. Ruotolo: University of Michigan
Mi Hee Lim: Ulsan National Institute of Science and Technology (UNIST)

Nature Communications, 2016, vol. 7, issue 1, 1-13

Abstract: Abstract 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.

Date: 2016
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DOI: 10.1038/ncomms13115

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