Broad-spectrum suppression and disassembly of α-synuclein variant aggregates mediated by a ruthenium metallodrug via conserved metal coordination

Abstract

Inhibiting α-synuclein (α-Syn) aggregation is a promising therapeutic strategy for Parkinson's disease (PD); however, its structural disorder and the heterogeneity of aggregates across familial variants pose significant challenges. Here, we demonstrate that NAMI-A, a ruthenium-based compound, effectively inhibits aggregation of wild-type and pathogenic familial α-Syn variants. Biophysical and biochemical analyses revealed that NAMI-A binds α-Syn via coordination to conserved regions, preventing the structural transition to β-sheets and inhibiting aggregation. Notably, NAMI-A dismantles pre-formed aggregates of diverse structures from various pathogenic variants. Cellular assays confirmed that NAMI-A significantly reduces α-Syn-induced cytotoxicity in neuronal cells by attenuating ROS generation. This work establishes that metallo-agents can act as broad-spectrum therapeutic agents to overcome mutation-dependent limitations for PD treatment.