Divergent Disassembly of PrP106-126 Aggregates Driven by Isomeric Polyoxometalate Hybrids.
The misfolding and aggregation of the prion protein into amyloid fibrils is primarily driven and stabilized by hydrophobic interactions, rendering the aggregates highly resistant to disaggregation and posing a significant therapeutic challenge. To address this issue, we design two compounds by covalently grafting isomeric ortho-vanillin or vanillin onto a MnMo6 cluster. The resulting o-Va-MnMo6 exhibits markedly superior disassembly activity, reducing neurotoxic PrP106-126 aggregates by 85% versus 49% for Va-MnMo6. The enhanced efficacy arises from the ortho-methoxy group of o-Va-MnMo6, which engages hydrophobic Ala113 via van der Waals interactions, whilst its hydroxyl group forms a hydrogen bond with the M112-A113 backbone. Concurrently, the polyoxometalate moiety electrostatically interacts with Lys110. The multipoint binding enables the molecule to straddle the contiguous K110HMA113 domain, effectively disrupting the aggregation core. In contrast, Va-MnMo6 interacts primarily with His111 via hydrogen bonding, lacking critical hydrophobic contact. Molecular dynamics simulations confirm that both compounds initially anchor electrostatically to Lys110, after which their differing ligands guide them to distinct sites, resulting in the divergent potencies.