Inhibitor Development\nfor α‑Synuclein\nFibril’s Disordered Region to Alleviate Parkinson’s\nDisease Pathology

The amyloid fibrils of α-synuclein (α-syn)\nare crucial\nin the pathology of Parkinson’s disease (PD), with the intrinsically\ndisordered region (IDR) of its C-terminal playing a key role in interacting\nwith receptors like LAG3 and RAGE, facilitating pathological neuronal\nspread and inflammation. In this study, we identified Givinostat (GS)\nas an effective inhibitor that disrupts the interaction of α-syn\nfibrils with receptors such as LAG3 and RAGE through high-throughput\nscreening. By exploring the structure–activity relationship\nand optimizing GS, we developed several lead compounds, including\nGSD-16-24. Utilizing solution-state and solid-state NMR, along with\ncryo-EM techniques, we demonstrated that GSD-16-24 binds directly\nto the C-terminal IDR of α-syn monomer and fibril, preventing\nthe fibril from binding to the receptors. Furthermore, GSD-16-24 significantly\ninhibits the association of α-syn fibrils with membrane receptors,\nthereby reducing neuronal propagation and pro-inflammatory effects\nof α-syn fibrils. Our findings introduce a novel approach to\nmitigate the pathological effects of α-syn fibrils by targeting\ntheir IDR with small molecules, offering potential leads for the development\nof clinical drugs to treat PD.