2. Academic Validation
  3. Inhibitor Development for α-Synuclein Fibril's Disordered Region to Alleviate Parkinson's Disease Pathology

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

  • J Am Chem Soc. 2024 Sep 27. doi: 10.1021/jacs.4c08869.
Shenqing Zhang 1 2,  Huaijiang Xiang 3 4,  Youqi Tao 1 2,  Juan Li 5,  Shuyi Zeng 1 2,  Qianhui Xu 3 4,  Haonan Xiao 1 2,  Shiran Lv 3 4,  Caiwei Song 3 4,  Yan Cheng 3,  Martin Li 1 2,  Zeyun Zhu 3,  Shengnan Zhang 3,  Bo Sun 6,  Dan Li 1 2,  ShengQi Xiang 5,  Li Tan 3,  Cong Liu 3 7
Affiliations

Affiliations

  • 1 Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai 200030, China.
  • 2 Zhangjiang Institute for Advanced Study, Shanghai Jiao Tong University, Shanghai 201203, China.
  • 3 Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 201210, China.
  • 4 University of Chinese Academy of Sciences, Shijingshan District, Beijing 100049, China.
  • 5 MOE Key Lab for Cellular Dynamics, School of Life Sciences, University of Science and Technology of China, 96 Jinzhai Road, Hefei, 230026 Anhui, China.
  • 6 School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
  • 7 State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China.
PMID: 39327912 DOI: 10.1021/jacs.4c08869
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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