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

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. Herein, we report key structural properties and mechanisms that can determine tools' regulatory reactivities with multiple pathogenic features found in AD. We built up a series of small molecules via rational structural selection and variations [(i) location and number of an Aβ interacting moiety; (ii) metal binding site; (iii) denticity and structural flexibility] onto the framework of a tool useful for in vitro and in vivo metal-Aβ investigation. Detailed biochemical, biophysical, and computational studies using our chemical series 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, our multidisciplinary investigations illustrate a structure-mechanism-based strategy of tool invention for such a complicated brain disease, AD.