中国科学院机构知识库网格
Chinese Academy of Sciences Institutional Repositories Grid
首页 机构 成果 学者
  
  1. CAS IR Grid
  2. 上海药物研究所
  3. 中国科学院上海药物研究所
  4. 新药研究国家重点实验室
Pharmacological characterization of the small molecule 03A10 as an inhibitor of α-synuclein aggregation for Parkinson's disease treatment

文献类型：期刊论文

作者Wang, Qing7,8; Yao, Sheng4,5,6,7; Yang, Ze-xian7,8; Zhou, Chen3; Zhang, Yu8; Zhang, Ye7,8; Zhang, Lei8; Li, Jin-tian2,7; Xu, Zhi-jian2; Zhu, Wei-liang2,7
刊名ACTA PHARMACOLOGICA SINICA
出版日期2023-06-01
卷号44期号:6页码:1122-1134
关键词Parkinson's disease alpha-synuclein aggregation protein-protein interaction 03A10 MPTP/p model enema inoculation model
DOI10.1038/s41401-022-01039-6
文献子类Article
英文摘要Aggregation of alpha-synuclein, a component of Lewy bodies (LBs) or Lewy neurites in Parkinson's disease (PD), is strongly linked with disease development, making it an attractive therapeutic target. Inhibiting aggregation can slow or prevent the neurodegenerative process. However, the bottleneck towards achieving this goal is the lack of such inhibitors. In the current study, we established a high-throughput screening platform to identify candidate compounds for preventing the aggregation of alpha-synuclein among the natural products in our in-house compound library. We found that a small molecule, 03A10, i.e., (+)-desdimethylpinoresinol, which is present in the fruits of Vernicia fordii (Euphorbiaceae), modulated aggregated alpha-synuclein, but not monomeric alpha-synuclein, to prevent further elongation of alpha-synuclein fibrils. In alpha-synuclein-overexpressing cell lines, 03A10 (10 mu M) efficiently prevented alpha-synuclein aggregation and markedly ameliorated the cellular toxicity of alpha-synuclein fibril seeds. In the MPTP/probenecid (MPTP/p) mouse model, oral administration of 03A10 (0.3 mg & BULL; kg(-1 )& BULL;d(-1), 1 mg & BULL;kg(-1 )& BULL;d(-1), for 35 days) significantly alleviated behavioral deficits, tyrosine hydroxylase (TH) neuron degeneration and p-alpha-synuclein aggregation in the substantia nigra (SN). As the Braak hypothesis postulates that the prevailing site of early PD pathology is the gastrointestinal tract, we inoculated alpha-synuclein preformed fibrils (PFFs) into the mouse colon. We demonstrated that alpha-synuclein PFF inoculation promoted alpha-synuclein pathology and neuroinflammation in the gut and brain; oral administration of 03A10 (5 mg & BULL; kg(-1) & BULL;d(-1), for 4 months) significantly attenuated olfactory deficits, alpha-synuclein accumulation and neuroinflammation in the olfactory bulb and SN. We conclude that 03A10 might be a promising drug candidate for the treatment of PD.
WOS关键词LEWY BODY ; PATHOLOGY ; FIBRILS ; VISUALIZATION ; DYSFUNCTION ; SEED
WOS研究方向Chemistry ; Pharmacology & Pharmacy
语种英语
WOS记录号WOS:000926534800001
出版者NATURE PUBL GROUP
源URL[http://119.78.100.183/handle/2S10ELR8/309721]  
专题新药研究国家重点实验室
通讯作者Zhang, Nai-xia; Ye, Yang; Feng, Lin-yin
作者单位1.ShanghaiTech Univ, Sch Life Sci & Technol, 393 Middle Huaxia Rd, Shanghai 201203, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, CAS Key Lab Receptor Res,State Key Lab Drug Res, Shanghai 201203, Peoples R China;
3.Chinese Acad Sci, Shanghai Inst Mat Med, Analyt Res Ctr Organ & Biol Mol, 555 Zu Chong Zhi Rd, Shanghai 201203, Peoples R China;
4.Chinese Acad Sci, Inst Drug Discovery Innovat, Zhongshan Inst Drug Discovery, Zhongshan 528400, Peoples R China;
5.Chinese Acad Sci, Shanghai Inst Mat Med, Nat Prod Chem Dept, 555 Zu Chong Zhi Rd, Shanghai 201203, Peoples R China;
6.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, 555 Zu Chong Zhi Rd, Shanghai 201203, Peoples R China;
7.Univ Chinese Acad Sci, 19 Yuquan Rd, Beijing 100049, Peoples R China;
8.Chinese Acad Sci, Shanghai Inst Mat Med, Ctr Neurol & Psychiat Res & Drug Discovery CNPRDD, CAS Key Lab Receptor Res, 555 Zu Chong Zhi Rd, Shanghai 201203, Peoples R China;
推荐引用方式
GB/T 7714		 Wang, Qing,Yao, Sheng,Yang, Ze-xian,et al. Pharmacological characterization of the small molecule 03A10 as an inhibitor of α-synuclein aggregation for Parkinson's disease treatment[J]. ACTA PHARMACOLOGICA SINICA,2023,44(6):1122-1134.
APA Wang, Qing.,Yao, Sheng.,Yang, Ze-xian.,Zhou, Chen.,Zhang, Yu.,...&Feng, Lin-yin.(2023).Pharmacological characterization of the small molecule 03A10 as an inhibitor of α-synuclein aggregation for Parkinson's disease treatment.ACTA PHARMACOLOGICA SINICA,44(6),1122-1134.
MLA Wang, Qing,et al."Pharmacological characterization of the small molecule 03A10 as an inhibitor of α-synuclein aggregation for Parkinson's disease treatment".ACTA PHARMACOLOGICA SINICA 44.6(2023):1122-1134.

入库方式： OAI收割

来源：上海药物研究所

浏览0
下载0
收藏0
其他版本

除非特别说明，本系统中所有内容都受版权保护，并保留所有权利。