Inhibition of synucleinopathic seeding by rationally designed inhibitors

Seeding, in the context of amyloid disease, is the sequential transfer of pathogenic protein aggregates from cell-to-cell within affected tissues. The structure of pathogenic seeds provides the molecular basis and enables rapid conversion of soluble protein into fibrils. To date, there are no inhibitors that specifically target seeding of Parkinson’s disease (PD)-associated a-synuclein (a-syn) fibrils, in part, due to lack of information of the structural properties of pathological seeds. Here we design small peptidic inhibitors based on the atomic structure of the core of a-syn fibrils. The inhibitors prevent a-syn aggregation in vitro and in cell culture models with binding affinities of 0.5 mM to a-syn fibril seeds. The inhibitors also show efficacy in preventing seeding by human patient-derived a-syn fibrils. Our results suggest that pathogenic seeds of a-syn contain steric zippers and suggest a therapeutic approach targeted at the spread and progression that may be applicable for PD and related synucleinopathies.