Poly-Arginine R18 Peptide Inhibits Heat-Induced Lysozyme Protein Aggregation: Implications for a Possible Therapeutic Role in Parkinson’s Disease

Abstract: A key pathological feature of neurodegenerative disorders such as Parkinson’s disease is the generation of misfolded and aggregated proteins. Cationic arginine-rich peptides (CARPs), which include poly-arginine peptides, have shown potent neuroprotective capabilities in various neurological injury models, and may have a potential therapeutic role in chronic neurodegenerative disorders. The present study sought to investigate whether the CARP, Poly-arginine-18 (R18), could prevent protein aggregation. Poly-arginine R18 (R18), along with L-arginine (Arg) were evaluated for interactions with the protein, lysozyme, using in silico molecular docking simulations. An in vitro heat-induced lysozyme aggregation assay was also established, and used to examine the ability of Arg and R18 to inhibit protein aggregation of the protein. In silico binding affinity studies found that Arg and R18 bound the C-terminal region of lysozyme via multiple hydrogen bonds, providing evidence for a direct protein-protein interaction. In addition, both Arg and R18 reduced heat-induced lysozyme aggregation in vitro, but R18 was more effective at lower concentrations. This study demonstrates that the R18 polyarginine peptide can bind to lysozyme and prevent aggregation through a direct protein interaction. Such functionality has potential implications for promoting protein solubility and, thus, treating disorders associated with abnormal protein aggregation, including synucleinopathies such as Parkinson’s disease.