Structural and Mechanistic Insights into Development of Chemical Tools to Control Individual and Inter‐Related Pathological Features in Alzheimer's Disease. Issue 11 (26th January 2017)

• Record Type: Journal Article
• Authors: Lee, Hyuck Jin; Korshavn, Kyle J.; Nam, Younwoo; Kang, Juhye; Paul, Thomas J.; Kerr, Richard A.; Youn, Il Seung; Ozbil, Mehmet; Kim, Kwang S.; Ruotolo, Brandon T.; Prabhakar, Rajeev; Ramamoorthy, Ayyalusamy; Lim, Mi Hee
• Is Part Of: Chemistry. Volume 23:Issue 11(2017)
• Page Start: 2706
• Page End: 2715
• Publication Date: 2017-01-26
• Subjects: amyloid beta-peptides -- chemical tools -- metal ions -- oxidative stress -- structure–activity relationships; Chemistry -- Periodicals; 540
• DOI: 10.1002/chem.201605401
• Languages: English
• ISSNs: 0947-6539

Abstract

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. Abstract : Inventing smart chemical tools : A structure‐mechanism‐based design strategy is demonstrated to be useful for constructing chemical tools able to regulate the actions of diverse pathological factors in Alzheimer's disease.