Comparative Analysis of the Inhibitory Mechanism of Aβ_1-42 Aggregation by Diruthenium Complexes

There is a growing interest in the search for metal-based therapeutics for protein misfolding disorders such as Alzheimer's disease (AD). A novel and largely unexplored class of metallodrugs is constituted by paddlewheel diruthenium complexes, which exhibit unusual water solubility and stability and unique coordination modes to proteins. Here, we investigate the ability of the complexes [Ru₂Cl(DPhF)(O₂CCH₃)₃]·H₂O (1), [Ru₂Cl(DPhF)₂(O₂CCH₃)₂]·H₂O (2), and K₂[Ru₂(DPhF)(CO₃)₃]·3H₂O (3) (DPhF^- = N,N'-diphenylformamidinate) to interfere with the amyloid aggregation of the Aβ_1-42 peptide. These compounds differ in charge and steric hindrance due to the coordination of a different number of bulky ligands. The mechanisms of action of the three complexes were studied by employing a plethora of physicochemical and biophysical techniques as well as cellular assays. All these studies converge on different mechanisms of inhibition of amyloid fibrillation: complexes 1 and 2 show a clear inhibitory effect due to an exchange ligand process in the Ru₂ unit aided by aromatic interactions. Complex 3 shows no inhibition of aggregation, probably due to its negative charge in solution. This study demonstrates that slight variations in the ligands surrounding the bimetallic core can modulate the amyloid aggregation inhibition and supports the use of paddlewheel diruthenium complexes as promising therapeutics for Alzheimer's disease.