posted on 2024-09-27, 07:46authored byShenqing Zhang, Huaijiang Xiang, Youqi Tao, Juan Li, Shuyi Zeng, Qianhui Xu, Haonan Xiao, Shiran Lv, Caiwei Song, Yan Cheng, Martin Li, Zeyun Zhu, Shengnan Zhang, Bo Sun, Dan Li, ShengQi Xiang, Li Tan, Cong Liu
The amyloid fibrils of α-synuclein (α-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 α-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 α-syn monomer and fibril, preventing
the fibril from binding to the receptors. Furthermore, GSD-16-24 significantly
inhibits the association of α-syn fibrils with membrane receptors,
thereby reducing neuronal propagation and pro-inflammatory effects
of α-syn fibrils. Our findings introduce a novel approach to
mitigate the pathological effects of α-syn fibrils by targeting
their IDR with small molecules, offering potential leads for the development
of clinical drugs to treat PD.