Comparative Analysis of the Inhibitory Mechanism of Aß1-42 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 Aß1-42 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.

A Diruthenium Metallodrug as a Potent Inhibitor of Amyloid-ß Aggregation: Synergism of Mechanisms of Action.

The physical and chemical properties of paddlewheel diruthenium compounds are highly dependent on the nature of the ligands surrounding the bimetallic core. Herein, we compare the ability of two diruthenium compounds, [Ru2Cl(D-p-FPhF)(O2CCH3)3]·H2O (1) (D-p-FPhF- = N,N'-bis(4-fluorophenyl)formamidinate) and K3[Ru2(O2CO)4]·3H2O (2), to act as inhibitors of amyloid aggregation of the Aß1-42 peptide and its peculiar fragments, Aß1-16 and Aß21-40. A wide range of biophysical techniques has been used to determine the inhibition capacity against aggregation and the possible mechanism of action of these compounds (Thioflavin T fluorescence and autofluorescence assays, UV-vis absorption spectroscopy, circular dichroism, nuclear magnetic resonance, mass spectrometry, and electron scanning microscopy). Data show that the most effective inhibitory effect is shown for compound 1. This compound inhibits fiber formation and completely abolishes the cytotoxicity of Aß1-42. The antiaggregatory capacity of this complex can be explained by a binding mechanism of the dimetallic units to the peptide chain along with π-π interactions between the formamidinate ligand and the aromatic side chains. The results suggest the potential use of paddlewheel diruthenium complexes as neurodrugs and confirm the importance of the steric and charge effects on the properties of diruthenium compounds.

From the Discovery of Targets to Delivery Systems: How to Decipher and Improve the Metallodrugs' Actions at a Molecular Level.

Metals are indispensable for the life of all organisms, and their dysregulation leads to various disorders due to the disruption of their homeostasis. Nowadays, various transition metals are used in pharmaceutical products as diagnostic and therapeutic agents because their electronic structure allows them to adjust the properties of molecules differently from organic molecules. Therefore, interest in the study of metal-drug complexes from different aspects has been aroused, and numerous approaches have been developed to characterize, activate, deliver, and clarify molecular mechanisms. The integration of these different approaches, ranging from chemoproteomics to nanoparticle systems and various activation strategies, enables the understanding of the cellular responses to metal drugs, which may form the basis for the development of new drugs and/or the modification of currently used drugs. The purpose of this review is to briefly summarize the recent advances in this field by describing the technological platforms and their potential applications for identifying protein targets for discovering the mechanisms of action of metallodrugs and improving their efficiency during delivery.

The endocannabinoidome mediator N-oleoylglycine is a novel protective agent against 1-methyl-4-phenyl-pyridinium-induced neurotoxicity.

N-oleoylglycine (OlGly) is a lipid mediator that belongs to the expanded version of the endocannabinoid (eCB) system, the endocannabinoidome (eCBome), which has recently gained increasing attention from the scientific community for its protective effects in a mouse model of mild traumatic brain injury. However, the effects of OlGly on cellular models of Parkinson's disease (PD) have not yet been investigated, whilst other lipoaminoacids have been reported to have beneficial effects. Moreover, the protective effects of OlGly seem to be mediated by direct activation of proliferator-activated receptor alpha (PPARα), which has already been investigated as a therapeutic target for PD. Therefore, this study aims to investigate the possible protective effects of OlGly in an in vitro model obtained by treating the neuroblastoma cell line, SH-SY5Y (both differentiated and not) with 1-methyl-4-phenyl-pyridinium (MPP+), which mimics some cellular aspects of a PD-like phenotype, in the presence or absence of the PPARα antagonist, GW6471. Our data show that MPP+ increases mRNA levels of PPARα in both non differentiated and differentiated cells. Using assays to assess cell metabolic activity, cell proliferation, and pro-inflammatory markers, we observed that OlGly (1 nM), both as treatment (1 h) and pre-treatment (4 h), is able to protect against neuronal damage induced by 24 h MPP+ exposure through PPARα. Moreover, using a targeted lipidomics approach, we demonstrate that OlGly exerts its effects also through the modulation of the eCBome. Finally, treatment with OlGly was able also to reduce increased IL-1ß induced by MPP+ in differentiated cells. In conclusion, our results suggest that OlGly could be a promising therapeutic agent for the treatment of MPP+-induced neurotoxicity.