Structure-based Discovery of Small Molecule Inhibitors of the Autocatalytic Proliferation of Α-Synuclein Aggregates

The presence of amyloid fibrils of alpha-synuclein is closely associated with Parkinson's disease and related synucleino-pathies. It is still very challenging, however, to systematically discover small molecules that prevent the formation of these aberrant aggregates. Here, we describe a structure-based approach to identify small molecules that specifically inhibit the surface-catalyzed secondary nucleation step in the aggregation of alpha- synuclein by binding to the surface of the amyloid fibrils. The resulting small molecules are screened using a range of kinetic and thermodynamic assays for their ability to bind alpha-synuclein fibrils and prevent the further generation of alpha-synuclein oligomers. This study demonstrates that the combination of structure-based and kinetic-based drug discovery methods can lead to the identification of small molecules that selectively inhibit the autocatalytic proliferation of alpha-synuclein aggregates.