α-Synuclein as a Target for Metallo-Anti-Neurodegenerative Agents

Angew Chem Int Ed Engl. 2023 Jan 2;62(1):e202215360. doi: 10.1002/anie.202215360. Epub 2022 Nov 30.

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 (Me2 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.

Keywords: Ligand Substitution Kinetics; Parkinson's Disease; Protein Aggregation Inhibition; Protein Target Sites; Ruthenium Complex.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Organometallic Compounds* / chemistry
  • Parkinson Disease* / pathology
  • Rats
  • Ruthenium* / chemistry
  • Ruthenium* / pharmacology
  • alpha-Synuclein / chemistry

Substances

  • alpha-Synuclein
  • imidazolium-bis(imidazole)dimethylsulfoxideimidazotetrachlororuthenate(III)
  • Ruthenium
  • Organometallic Compounds