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 IC