Disassembly of Prion Protein Fragment 106-126 Aggregates Driven by an Organopalladium-Modified Polyoxometalate

Prion disorders are characterized by the pathological misfolding of cellular prion proteins into the infectious and aggregated isoforms (PrP^Sc). Due to the dynamic folding-unfolding equilibrium of prion protein, therapeutic strategies targeting PrP^Sc often suffer from reversible binding and incomplete efficacy. Herein, an organopalladium-modified polyoxometalate (Pd-MnMo₆) is synthesized by covalently grafting [Pd(tpy)Cl] onto Mn-Anderson (denoted as MnMo₆). The Pd-MnMo₆ effectively disassembles 92.8% of preformed PrP106-126 fibrils and exhibits significant cytoprotection effect in SH-SY5Y cells. This protection effect is evidenced by the attenuation of PrP106-126 aggregates-induced cytotoxicity, suppression of excessive reactive oxygen species production, and mitigation of mitochondrial membrane depolarization. Mechanism studies reveal that Pd-MnMo₆ interacts with PrP106-126 through multiple interaction modes: electrostatic interaction, hydrogen bonding, π-π stacking and metal coordination. Analysis of the dynamic binding between Pd-MnMo₆ and a PrP106-126 decamer reveals that electrostatic attraction drives the initial approach of Pd-MnMo₆ to the PrP106-126 N-terminus, enabling subsequent π-π stacking (between the tpy ligand and histidine residues) and Pd coordination to methionine sites. This synergistic interaction network disrupts the dynamic folding equilibrium of PrP106-126, leading to irreversible binding and effective disassembly of PrP106-126 aggregates.