title: Structural and Mechanistic Insights into Development of Chemical Tools to Control Individual and Inter-Related Pathological Features in Alzheimer's Disease.
abstract: To elucidate the involvement of individual and inter-related pathological factors [i.e., amyloid-β (Aβ), metals, and oxidative stress] in the pathogenesis of Alzheimer's disease (AD), chemical tools have been developed. Characteristics required for such tool construction, however, have not been clearly identified; thus, the optimization of available tools or new design has been limited. Here, key structural properties and mechanisms that can determine tools' regulatory reactivities with multiple pathogenic features found in AD are reported. A series of small molecules was built up through rational structural selection and variations onto the framework of a tool useful for in vitro and in vivo metal-Aβ investigation. Variations include: (i) location and number of an Aβ interacting moiety; (ii) metal binding site; and (iii) denticity and structural flexibility. Detailed biochemical, biophysical, and computational studies were able to provide a foundation of how to originate molecular formulas to devise chemical tools capable of controlling the reactivities of various pathological components through distinct mechanisms. Overall, this multidisciplinary investigation illustrates a structure-mechanism-based strategy of tool invention for such a complicated brain disease.
authors.affiliation: School of Life Sciences, Ulsan National Institute of Science and Technology (UNIST), Ulsan, 44919, Republic of Korea.
authors.forename: Hyuck Jin
authors.initials: HJ
authors.lastname: Lee
authors.affiliation: Department of Chemistry, University of Michigan, Ann Arbor, Michigan, 48109, USA.
authors.forename: Kyle J
authors.initials: KJ
authors.lastname: Korshavn
authors.affiliation: Department of Chemistry, UNIST, Ulsan, 44919, Republic of Korea.
authors.forename: Younwoo
authors.initials: Y
authors.lastname: Nam
authors.affiliation: Department of Chemistry, UNIST, Ulsan, 44919, Republic of Korea.
authors.forename: Juhye
authors.initials: J
authors.lastname: Kang
authors.affiliation: Department of Chemistry, University of Miami, Coral Gables, Florida, 33146, USA.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Paul
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: Department of Chemistry, UNIST, Ulsan, 44919, Republic of Korea.
authors.forename: Il Seung
authors.initials: IS
authors.lastname: Youn
authors.affiliation: Department of Chemistry, University of Miami, Coral Gables, Florida, 33146, USA.
authors.forename: Mehmet
authors.initials: M
authors.lastname: Ozbil
authors.affiliation: Department of Chemistry, UNIST, Ulsan, 44919, Republic of Korea.
authors.forename: Kwang S
authors.initials: KS
authors.lastname: Kim
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, University of Miami, Coral Gables, Florida, 33146, USA.
authors.forename: Rajeev
authors.initials: R
authors.lastname: Prabhakar
authors.affiliation: Department of Chemistry, University of Michigan, Ann Arbor, Michigan, 48109, USA.|Biophysics, University of Michigan, Ann Arbor, Michigan, 48109, USA.
authors.forename: Ayyalusamy
authors.initials: A
authors.lastname: Ramamoorthy
authors.affiliation: Department of Chemistry, UNIST, Ulsan, 44919, Republic of Korea.
authors.forename: Mi Hee
authors.identifier: http://orcid.org/0000-0003-3377-4996
authors.initials: MH
authors.lastname: Lim
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology*; D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002712:Chlorides / Q000737:chemistry; D003300:Copper / Q000737:chemistry; D006801:Humans; D008670:Metals / Q000737:chemistry / Q000378:metabolism; D018384:Oxidative Stress; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D021241:Spectrometry, Mass, Electrospray Ionization; D013053:Spectrophotometry; D017967:Zinc Compounds / Q000737:chemistry
chemical_list: D016229:Amyloid beta-Peptides; D002712:Chlorides; D008670:Metals; D054852:Small Molecule Libraries; D017967:Zinc Compounds; D003300:Copper; C016837:zinc chloride; C029892:cupric chloride
keywords: amyloid beta-peptides; chemical tools; metal ions; oxidative stress; structure-activity relationships