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Journal of the American Chemical Society

Journal of the American Chemical Society

IF: 14.4
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Inhibitor Development for α-Synuclein Fibril’s Disordered Region to Alleviate Parkinson’s Disease Pathology

Published:27 September 2024 DOI: 10.1021/jacs.4c08869
Shenqing 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

Abstract

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.

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Materials
Procduct Name CAS Molecular Formula Supplier Price
FASUDIL 103745-39-7 C14H17N3O2S 195 suppliers $29.00-$923.00
FASUDIL 103745-39-7 C14H17N3O2S 195 suppliers $29.00-$923.00
FASUDIL 103745-39-7 C14H17N3O2S 195 suppliers $29.00-$923.00
FASUDIL 103745-39-7 C14H17N3O2S 195 suppliers $29.00-$923.00

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