Journal
CHEMISTRY-A EUROPEAN JOURNAL
Volume 23, Issue 11, Pages 2706-2715Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/chem.201605401
Keywords
amyloid beta-peptides; chemical tools; metal ions; oxidative stress; structure-activity relationships
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Funding
- National Research Foundation (NRF) of Korea grant - Korean government [NRF-2014R1A2A2A01004877, 2016R1A5A1009405, NRF-2014S1A2A2028270]
- Research Fund of Ulsan National Institute of Science and Technology (UNIST) [1.170014.01]
- University of Michigan Protein Folding Disease Initiative
- NIH grant
- James and Esther King Biomedical Research Program of the Florida State Health Department Award [DOH] [08KN-11]
- National Honor Scientist Program of NRF of Korea [2010-0020414]
- Global Ph.D. fellowship program through the National Research Foundation of Korea (NRF) - Ministry of Education [NRF-2015HIA2A1030823]
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To elucidate the involvement of individual and inter-related pathological factors [i.e., amyloid-beta (A beta), 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-A beta investigation. Variations include: (i) location and number of an A beta 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.
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