The effects of platinum(IV) complexes on Aβ_1-42 aggregation: a synergistic inhibition upon axial coordination

Among novel metallodrugs, Pt(IV) complexes have been receiving increasing attention as alternatives to Pt(II) analogues since they exhibit superior kinetic inertness and, hence, fewer undesirable reactions. Pt(IV) complexes have been designed as prodrugs with mechanisms of action finely tuned by properties of the axial ligands. In this context, the insertion of known bioactive molecules as axial ligands to generate multi-target drugs (MTDs) is considered a valuable drug design strategy because of the possible synergistic effects between the metal centre and the organic moiety. By employing the repurposing of drugs in different diseases, in this study, the Pt(IV) complex (OC-6-44)-acetatodiamminedichlorido(4,5-dihydroxy-9,10-dioxo-9,10-dihydroanthracene-2-carboxylato)platinum(IV) was investigated for its ability to modulate the self-aggregation process of the amyloid peptide Aβ_1-42. Specifically, the complex features 4,5-dihydroxy-9,10-dioxo-9,10-dihydroanthracene-2-carboxylato (rhein) as a ligand that is a natural aromatic molecule already known as a discrete inhibitor of amyloid aggregation. Herein, several biophysical and microscopic assays, such as thioflavin T (ThT) fluorescence, dynamic light scattering (DLS) and scanning electron (SEM) and confocal microscopy, indicated that the Pt(IV) complex can inhibit and disassemble Aβ_1-42 aggregation to a greater extent with respect to rhein alone. This effect is likely due to the formation of π-π interactions between the rhein moiety and the side chains of the Aβ_1-42 peptide. This experimental evidence was confirmed by molecular docking studies of monomeric and tetrameric Aβ_1-42. Overall, the data support the application of Pt(IV) complexes as innovative neurotherapeutics.