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.