PQK7: A novel peptide inhibitor targeting alpha-synuclein fibrillogenesis in Parkinson's disease

Abstract

The accumulation of alpha-synuclein (⍺-Syn) fibrils plays a central role in the progression of Parkinson's disease (PD) and related neurodegenerative disorders. In this context, the development of peptide inhibitors designed to inhibit ⍺-Syn through computational methods has emerged as a promising area of research. This study focused on developing a peptide inhibitor, PQK7, designed based on the key residues of NAC region of ⍺-Syn fibrils involved in its aggregation. Using molecular docking and dynamics simulations, PQK7 was shown to bind key residues in the NAC region of ⍺-Syn (Val-74, Ala-76, Val-77, Thr-81, Ser-87, Ile-88, and Ala-89), effectively disrupting the formation of fibrils. MD simulations indicated that the PQK7-⍺-Syn complex reaches a stable conformation, which showed increased fluctuations and reduced β-sheet content, suggests that PQK7 interferes with ⍺-Syn fibrillation at the molecular level. In vitro assays like ThT fluorescence assay, AFM imaging, CD specotroscopy, and SDS-PAGE analysis confirmed that PQK7 significantly reduces ⍺-Syn fibril formation, particularly at substoichiometric concentrations, while keeping ⍺-Syn monomers in a soluble state. Additionally, PQK7-⍺-Syn treatment in SH-SY5Y cells reduced the toxicity of ⍺-Syn aggregates, restoring normal cell cycle progression and reducing apoptosis and oxidative stress. Our findings suggest that PQK7 holds potential as a therapeutic agent for PD, acting as an anti-oligomeric inhibitor that targets early ⍺-Syn aggregates without affecting the protein's normal function.