title: Structure-mechanism-based engineering of chemical regulators targeting distinct pathological factors in Alzheimer's disease.
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.
authors.affiliation: Department of Chemistry, Ulsan National Institute of Science and Technology (UNIST), Ulsan 44919, Republic of Korea.|Department of Chemistry, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Michael W
authors.identifier: 0000-0002-1737-0951
authors.initials: MW
authors.lastname: Beck
authors.affiliation: Department of Chemistry, Ulsan National Institute of Science and Technology (UNIST), Ulsan 44919, Republic of Korea.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Derrick
authors.affiliation: Department of Chemistry, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Kerr
authors.affiliation: Asan Institute for Life Sciences, Asan Medical Center, Seoul 05505, Republic of Korea.
authors.forename: Shin Bi
authors.initials: SB
authors.lastname: Oh
authors.affiliation: School of Life Sciences, Ulsan National Institute of Science and Technology (UNIST), Ulsan 44919, Republic of Korea.
authors.forename: Woo Jong
authors.initials: WJ
authors.lastname: Cho
authors.affiliation: Department of Chemistry, Ulsan National Institute of Science and Technology (UNIST), Ulsan 44919, Republic of Korea.
authors.forename: Shin Jung C
authors.initials: SJ
authors.lastname: Lee
authors.affiliation: Department of Chemistry, Ulsan National Institute of Science and Technology (UNIST), Ulsan 44919, Republic of Korea.
authors.forename: Yonghwan
authors.initials: Y
authors.lastname: Ji
authors.affiliation: Department of Chemistry, Ulsan National Institute of Science and Technology (UNIST), Ulsan 44919, Republic of Korea.
authors.forename: Jiyeon
authors.initials: J
authors.lastname: Han
authors.affiliation: Department of Chemistry, Ulsan National Institute of Science and Technology (UNIST), Ulsan 44919, Republic of Korea.
authors.forename: Zahra Aliakbar
authors.initials: ZA
authors.lastname: Tehrani
authors.affiliation: Asan Institute for Life Sciences, Asan Medical Center, Seoul 05505, Republic of Korea.
authors.forename: Nayoung
authors.initials: N
authors.lastname: Suh
authors.affiliation: Asan Institute for Life Sciences, Asan Medical Center, Seoul 05505, Republic of Korea.
authors.forename: Sujeong
authors.initials: S
authors.lastname: Kim
authors.affiliation: Department of Medicinal Chemistry, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Scott D
authors.initials: SD
authors.lastname: Larsen
authors.affiliation: Department of Chemistry, Ulsan National Institute of Science and Technology (UNIST), Ulsan 44919, Republic of Korea.
authors.forename: Kwang S
authors.identifier: 0000-0002-6929-5359
authors.initials: KS
authors.lastname: Kim
authors.affiliation: Asan Institute for Life Sciences, Asan Medical Center, Seoul 05505, Republic of Korea.|Department of Convergence Medicine, University of Ulsan College of Medicine, Seoul 05505, Republic of Korea.
authors.forename: Joo-Yong
authors.initials: JY
authors.lastname: Lee
authors.affiliation: Department of Chemistry, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Brandon T
authors.initials: BT
authors.lastname: Ruotolo
authors.affiliation: Department of Chemistry, Ulsan National Institute of Science and Technology (UNIST), Ulsan 44919, Republic of Korea.
authors.forename: Mi Hee
authors.initials: MH
authors.lastname: Lim
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D000682:Amyloid / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D015195:Drug Design; D005609:Free Radicals / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D008670:Metals / Q000037:antagonists & inhibitors / Q000378:metabolism; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D015394:Molecular Structure; D066329:Protein Aggregates / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors / Q000378:metabolism; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000682:Amyloid; D016229:Amyloid beta-Peptides; D005609:Free Radicals; D008670:Metals; D066329:Protein Aggregates; D017382:Reactive Oxygen Species; D054852:Small Molecule Libraries