Mechanism of Amyloid Inhibition by Small Molecules

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DESCRIPTION (provided by applicant): The primary goal of this research proposal is to derive a model for the activity of small molecule amyloid inhibitors. Data for this model will be collected in three parallel but related approaches, which take advantage of the well-characterized amyloidogenic protein NM. The first approach will detail the structure-activity relationships, which govern inhibition of amyloid formation by the small molecules Congo Red (CR) and 4,5- dianilinophthalimide (DAPH) and their analogues, cataloguing what chemical aspects of these molecules contribute to their potency. The second approach will establish the molecular mechanism by which CR and DAPH prevent NM aggregation by investigating their effects on specific steps in the NM aggregation pathway. The third approach will identify the binding sites of small molecule NM inhibitors using epitope mapping and cross-linking experiments with functionalized CR and DAPH analogues. The data collected in these approaches will inform a detailed mechanistic and structural model for the inhibition of NM aggregation and fiber formation. A precise model of how small molecules bind to NM and inhibit its aggregation will be a critical first step in understanding the molecular basis of amyloid inhibition by small molecules.