Peptide Inhibitors of Alpha-Synuclein Aggregation

A hallmark of synucleinopathies, including Parkinson's disease, is the aggregation of alpha-synuclein, a regulatory protein that modulates presynaptic vesicle dynamics. Amyloid-type aggregates, whose structure is stabilized by intramolecular contacts of beta-strands from the N-terminal and central regions of alpha-synuclein, exhibit pronounced neurotoxicity. Peptides that exhibit affinity for these regions have been shown to impede the contacts that are characteristic of the pathogenic conformation of alpha-synuclein and thereby prevent its aggregation. These peptides have the potential to function as neuroprotectors, and thus may offer therapeutic benefits in the treatment of Parkinson's disease. In recent years, several dozen promising peptides that block alpha-synuclein aggregation have been identified. The protective effect of several leading peptides has been confirmed in animal models of Parkinson's disease; however, due to delivery challenges, the search for alternative penetrating peptides remains a pressing issue. This review examines key strategies for the rational design of peptide inhibitors of alpha-synuclein aggregation and approaches to their testing, and it summarises data on the mechanism of action of the most fully characterised effective inhibitors.