Structure-Activity Analysis of Small Molecules That Selectively Remodel Soluble Oligomers and Fibrils of Amyloid Aß

Misfolded proteins associated with diverse aggregation disorders assemble not only into a single toxic conformer, but rather a suite of aggregated conformers with unique biochemical properties and toxicities. To what extent small molecules can target and neutralize specific types of aggregates is poorly understood. Therefore, we have investigated the capacity of aromatic small molecules to recognize and remodel five conformers (monomers, soluble oligomers, off-pathway aggregates, fibrillar oligomers and amyloid fibrils) of the Aß1-42 peptide associated with Alzheimer's disease. We find that a class of aromatic molecules remodels a subset of these misfolded conformers into an alternative aggregated species that is non-toxic. Moreover, we have elucidated structure-activity relationships that describe the variable remodeling activities of these aromatic molecules. We expect that these and related small molecules with similar conformational specificity will aid in illuminating the conformational epitopes responsible for Aß-mediated toxicity.