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Pharmacological characterization of the small molecule 03A10 as an inhibitor of α-synuclein aggregation for Parkinson’s disease treatment

Qing Wang1,2, Sheng Yao2,3,4, Ze-xian Yang1,2, Chen Zhou5, Yu Zhang1, Ye Zhang1,2, Lei Zhang1, Jin-tian Li2,6,7, Zhi-jian Xu6,7, Wei-liang Zhu2,6,7, Nai-xia Zhang2,5, Yang Ye2,3,8, Lin-yin Feng1,2
1 CAS Key Laboratory of Receptor Research, Center for Neurological and Psychiatric Research and Drug Discovery (CNPRDD), Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China
2 University of Chinese Academy of Sciences, No.19 A Yuquan Road, Beijing 100049, China
3 State Key Laboratory of Drug Research and Natural Products Chemistry Department, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China
4 Zhongshan Institute of Drug Discovery, Institution for Drug Discovery Innovation, Chinese Academy of Science, Zhongshan 528400, China
5 Analytical Research Center for Organic and Biological Molecules, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China
6 CAS Key Laboratory of Receptor Research, State Key Laboratory of Drug Research
7 Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
8 School of Life Science and Technology, ShanghaiTech University, 393 Middle Huaxia Road, Shanghai 201203, China
Correspondence to: Nai-xia Zhang: nxzhang@simm.ac.cn, Yang Ye: yye@mail.shcnc.ac.cn, Lin-yin Feng: lyfeng@simm.ac.cn,
DOI: 10.1038/s41401-022-01039-6
Received: 18 August 2022
Accepted: 5 December 2022
Advance online: 10 January 2023

Abstract

Aggregation of α-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 α-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 α-synuclein, but not monomeric α-synuclein, to prevent further elongation of α-synuclein fibrils. In α-synuclein-overexpressing cell lines, 03A10 (10 μM) efficiently prevented α- synuclein aggregation and markedly ameliorated the cellular toxicity of α-synuclein fibril seeds. In the MPTP/probenecid (MPTP/p) mouse model, oral administration of 03A10 (0.3 mg· kg−1 ·d−1, 1 mg ·kg−1 ·d−1, for 35 days) significantly alleviated behavioral deficits, tyrosine hydroxylase (TH) neuron degeneration and p-α-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 α-synuclein preformed fibrils (PFFs) into the mouse colon. We demonstrated that α-synuclein PFF inoculation promoted α-synuclein pathology and neuroinflammation in the gut and brain; oral administration of 03A10 (5 mg· kg−1 ·d−1, for 4 months) significantly attenuated olfactory deficits, α-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.
Keywords: Parkinson’s disease; α-synuclein aggregation; protein‒protein interaction; 03A10; MPTP/p model; enema inoculation model

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