α-Synuclein as a Target for Metallo-Anti-Neurodegenerative Agents.
Kaiming CaoYang ZhuZhuanghao HouManman LiuYanyan YangHongze HuYi DaiYu WangSiming YuanGuangming HuangJiaming MeiPeter J SadlerYang-Zhong LiuPublished in: Angewandte Chemie (International ed. in English) (2022)
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 Ru III complex trans-[ImH][RuCl 4 (Me 2 SO)(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.
Keyphrases
- magnetic resonance
- high resolution
- induced apoptosis
- binding protein
- protein protein
- multiple sclerosis
- solid state
- mass spectrometry
- amino acid
- drug induced
- ms ms
- diabetic rats
- genome wide
- small molecule
- emergency department
- blood brain barrier
- case control
- cell proliferation
- molecular dynamics simulations
- signaling pathway
- drug discovery
- radiation induced
- single cell
- anti inflammatory
- capillary electrophoresis
- stress induced