PDpep1.3 is a peptide optimised from a hit from a high-throughput screen to identify protein-protein interaction inhibitors that reduce alpha-synuclein oligomer levels and their associated cytotoxicity. PDpep1.3 disrupts the direct interaction between the C-terminal region of alpha-synuclein and CHarged Multivesicular body Protein 2B (CHMP2B), a component of the endosomal sorting complex required for transport-III (ESCRT-III). alpha-Synuclein impedes endolysosomal activity via this interaction with CHMP2B, inhibiting its own degradation, and blockade of it with PDpep1.3 restores endolysosomal function and decreases alpha-synuclein levels in human cells. In vivo, PDpep1.3 protects dopaminergic neurons from alpha-synuclein-mediated degeneration in Parkinson€(TM)s disease models in rats.
