Small-molecule sequestration of amyloid-beta. as a drug discovery strategy for Alzheimer's disease

Disordered proteins are challenging therapeutic targets, and no drug is currently in clinical use that modifies the properties of their monomeric states. Here, we identify a small molecule, called 10074-G5, capable of binding and sequestering the intrinsically disordered amyloid- (A) peptide in its monomeric, soluble state. Our analysis reveals that this compound interacts with A and inhibits both the primary and secondary nucleation pathways in its aggregation process. We characterize this interaction using biophysical experiments and integrative structural ensemble determination methods. We observe that this small molecule has the remarkable effect of increasing the conformational entropy of monomeric A while decreasing its hydrophobic surface area. We also show that it rescues a Caenorhabditis elegans model of A-associated toxicity in a manner consistent with the mechanism of action identified from the in silico and in vitro studies. These results illustrate the strategy of targeting the monomeric states of disordered proteins with small molecules to alter their behavior for therapeutic purposes.