Amyloid binding and beyond: a new approach for Alzheimer's disease drug discovery targeting Abo–PrPC binding and downstream pathways

Amyloid b oligomers (Abo) are the main toxic species in Alzheimer's disease, which have been targeted for single drug treatment with very little success. In this work we report a new approach for identifying functional Abo binding compounds. A tailored library of 971 fluorine containing compounds was selected by a computational method, developed to generate molecular diversity. These compounds were screened for Abo binding by a combined 19F and STD NMR technique. Six hits were evaluated in three parallel biochemical and functional assays. Two compounds disrupted Abo binding to its receptor PrPC in HEK293 cells. They reduced the pFyn levels triggered by Abo treatment in neuroprogenitor cells derived from human induced pluripotent stem cells (hiPSC). Inhibitory effects on pTau production in cortical neurons derived from hiPSC were also observed. These drug-like compounds connect three of the pillars in Alzheimer's disease pathology, i.e. prion, Ab and Tau, affecting three different pathways through specific binding to Abo and are, indeed, promising candidates for further development