α-Helical peptidic scaffolds to target α-synuclein toxic species with nanomolar affinity

alpha -Synuclein aggregation is a key driver of neurodegeneration in Parkinson's disease and related syndromes. Accordingly, obtaining a molecule that targets alpha -synuclein toxic assemblies with high affinity is a long-pursued objective. Here, we exploit the biophysical properties of toxic oligomers and amyloid fibrils to identify a family of alpha -helical peptides that bind to these alpha -synuclein species with low nanomolar affinity, without interfering with the monomeric functional protein. This activity is translated into a high anti-aggregation potency and the ability to abrogate oligomer-induced cell damage. Using a structure-guided search we identify a human peptide expressed in the brain and the gastrointestinal tract with analogous binding, anti-aggregation, and detoxifying properties. The chemical entities we describe here may represent a therapeutic avenue for the synucleinopathies and are promising tools to assist diagnosis by discriminating between native and toxic alpha -synuclein species. alpha -Synuclein (alpha S) aggregation is a driver of several neurodegenerative disorders. Here, the authors identify a class of peptides that bind toxic alpha S oligomers and amyloid fibrils but not monomeric functional protein, and prevent further alpha S aggregation and associated cell damage.

Automated summary

Researchers have identified a class of peptides that can bind toxic α-synuclein oligomers and amyloid fibrils without interfering with monomeric functional protein, preventing further aggregation and associated cell damage.