Lipid-conjugated Ru(iii) complexes as inhibitors of pathological peptide aggregation in neurodegenerative disorders

Neurodegenerative diseases (NDs), characterized by the progressive loss of neuronal homeostasis and function, represent an increasing global health burden. Their severity and profound impact on quality of life highlight the urgent need for effective and targeted therapeutic strategies. Recent studies have drawn attention to the potential of certain Ru(iii) complexes, including NAMI-A and KP1019, as promising therapeutic candidates for NDs. Originally developed as anticancer agents, these compounds have demonstrated remarkable activity in inhibiting the aggregation of model misfolded proteins, which represent a common pathological feature of various neurological disorders. Herein, searching for Ru(iii) complexes which could be effective as anti-neurodegenerative agents, we selected AziRu - a NAMI-A-like compound - and some of its lipid-conjugated derivatives, previously explored as anticancer drug candidates, and tested them for their ability to interfere with the self-aggregation of selected model peptides involved in the pathogenesis of NDs, such as Alzheimer's disease (AD), Parkinson's disease (PD) and prion diseases. Among them, the Ru(iii) complexes we named MyriPyRu and PalmiPyRu, bearing myristic and palmitic acid-based tails, respectively, emerged as promising candidates. These complexes effectively modulated and inhibited the aggregation of amyloid peptides linked to AD pathogenesis with IC₅₀ values in the low micromolar range (ca. 5 μM for both compounds). More detailed studies on their interaction with AD peptides revealed their capacity to be coordinated by histidine residues in the N-terminal region. Biological investigations on human neuroblastoma-derived cells indicated no relevant cytotoxicity at concentrations comparable to those that caused anti-aggregation effects. Overall, these findings are highly promising, as MyriPyRu or PalmiPyRu could be the starting compounds to evolve further modified derivatives functionalized with specific targeting moieties for amyloid peptides, potentially paving the way to a new generation of Ru(iii)-based anti-amyloid agents for the treatment of Alzheimer's disease.