Structural and Mechanistic Insights into Development of Chemical Tools to Control Individual and Inter-Related Pathological Features in Alzheimer's Disease

Hyuck Jin Lee, Kyle J. Korshavn, Younwoo Nam, Juhye Kang, Thomas J. Paul, Richard A. Kerr, Il Seung Youn, Mehmet Ozbil, Kwang S. Kim, Brandon T. Ruotolo, Rajeev Prabhakar, Ayyalusamy Ramamoorthy, Mi Hee Lim

Research output: Contribution to journalArticle

16 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2706-2715
Number of pages10
JournalChemistry - A European Journal
Volume23
Issue number11
DOIs
StatePublished - 2017

Keywords

  • amyloid beta-peptides
  • chemical tools
  • metal ions
  • oxidative stress
  • structure–activity relationships

ASJC Scopus subject areas

  • Catalysis
  • Organic Chemistry

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    Lee, H. J., Korshavn, K. J., Nam, Y., Kang, J., Paul, T. J., Kerr, R. A., Youn, I. S., Ozbil, M., Kim, K. S., Ruotolo, B. T., Prabhakar, R., Ramamoorthy, A., & Lim, M. H. (2017). Structural and Mechanistic Insights into Development of Chemical Tools to Control Individual and Inter-Related Pathological Features in Alzheimer's Disease. Chemistry - A European Journal, 23(11), 2706-2715. https://doi.org/10.1002/chem.201605401