Development of Nanomolar Affinity Miniprotein Inhibitors Targeting α-Synuclein Aggregation as Promising Therapeutic Agents for Parkinson’s Disease

Abstract

<p>Parkinson’s disease (PD) is a debilitating neurodegenerative disorder characterized by the accumulation of α-synuclein (α-syn) aggregates in the brain. Developing effective therapies targeting α-syn has been challenging due to its intrinsically disordered nature. In this study, through screening a phage-displayed small ubiquitin-like modifier 1 (SUMO1)(15-55)-biased library, we identified a 41-amino acid miniprotein, PD-6, as a novel nanomolar affinity binder of α-syn. PD-6 had good cell membrane permeability and serum stability. It effectively inhibited α-syn aggregation in SH-SY5Y cells. In <em>Caenorhabditis elegans</em> PD models, PD-6 rescued dopaminergic neuron loss and motor dysfunction to provide protection against neurodegeneration. The binding mode of PD-6 with α-syn was revealed by nuclear magnetic resonance investigation.<br></p>