Inhibitor Development for α-Synuclein Fibril's Disordered Region to Alleviate Parkinson's Disease Pathology

The amyloid fibrils of alpha-synuclein (alpha-syn) are crucial in the pathology of Parkinson's disease (PD), with the intrinsically disordered region (IDR) of its C-terminal playing a key role in interacting with receptors like LAG3 and RAGE, facilitating pathological neuronal spread and inflammation. In this study, we identified Givinostat (GS) as an effective inhibitor that disrupts the interaction of alpha-syn fibrils with receptors such as LAG3 and RAGE through high-throughput screening. By exploring the structure-activity relationship and optimizing GS, we developed several lead compounds, including GSD-16-24. Utilizing solution-state and solid-state NMR, along with cryo-EM techniques, we demonstrated that GSD-16-24 binds directly to the C-terminal IDR of alpha-syn monomer and fibril, preventing the fibril from binding to the receptors. Furthermore, GSD-16-24 significantly inhibits the association of alpha-syn fibrils with membrane receptors, thereby reducing neuronal propagation and pro-inflammatory effects of alpha-syn fibrils. Our findings introduce a novel approach to mitigate the pathological effects of alpha-syn fibrils by targeting their IDR with small molecules, offering potential leads for the development of clinical drugs to treat PD.