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α-Synuclein as a target for metallo-anti-neurodegenerative agents
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Cao, Kaiming, Zhu, Yang, Hou, Zhuanghao, Liu, Manman, Yang, Yanyan, Hu, Hongze, Dai, Yi, Wang, Yu, Yuan, Siming, Huang, Guangming, Mei, Jiaming, Sadler, Peter J. and Liu, Yangzhong (2023) α-Synuclein as a target for metallo-anti-neurodegenerative agents. Angewandte Chemie International Edition, 62 (1). e202215360. doi:10.1002/anie.202215360 ISSN 1433-7851.
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Official URL: https://doi.org/10.1002/anie.202215360
Abstract
The unique thermodynamic and kinetic coordination chemistry of ruthenium allows it to modulate key adverse aggregation and membrane interactions of α-synuclein (α-syn) associated with Parkinson's disease. We show that the low-toxic RuIII complex trans-[ImH][RuCl4(Me2SO)(Im)] (NAMI-A) has dual inhibitory effects on both aggregation and membrane interactions of α-syn with submicromolar affinity, and disassembles pre-formed fibrils. NAMI-A abolishes the cytotoxicity of α-syn towards neuronal cells and mitigates neurodegeneration and motor impairments in a rat model of Parkinson's. Multinuclear NMR and MS analyses show that NAMI-A binds to residues involved in protein aggregation and membrane binding. NMR studies reveal the key steps in pro-drug activation and the effect of activated NAMI-A species on protein folding. Our findings provide a new basis for designing ruthenium complexes which could mitigate α-syn-induced Parkinson's pathology differently from organic agents.
Item Type: | Journal Article | ||||||||||||||||||||||||
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Divisions: | Faculty of Science, Engineering and Medicine > Science > Chemistry | ||||||||||||||||||||||||
SWORD Depositor: | Library Publications Router | ||||||||||||||||||||||||
Journal or Publication Title: | Angewandte Chemie International Edition | ||||||||||||||||||||||||
Publisher: | Wiley - V C H Verlag GmbH & Co. KGaA | ||||||||||||||||||||||||
ISSN: | 1433-7851 | ||||||||||||||||||||||||
Official Date: | 2 January 2023 | ||||||||||||||||||||||||
Dates: |
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Volume: | 62 | ||||||||||||||||||||||||
Number: | 1 | ||||||||||||||||||||||||
Number of Pages: | 10 | ||||||||||||||||||||||||
Article Number: | e202215360 | ||||||||||||||||||||||||
DOI: | 10.1002/anie.202215360 | ||||||||||||||||||||||||
Status: | Peer Reviewed | ||||||||||||||||||||||||
Publication Status: | Published | ||||||||||||||||||||||||
Access rights to Published version: | Restricted or Subscription Access | ||||||||||||||||||||||||
Copyright Holders: | Wiley-VCH GmbH | ||||||||||||||||||||||||
Date of first compliant deposit: | 31 January 2023 | ||||||||||||||||||||||||
Date of first compliant Open Access: | 30 November 2023 | ||||||||||||||||||||||||
RIOXX Funder/Project Grant: |
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