Piano-Stool Ru (II) Complexes as Modulators of Human Prion Protein PrP_106-126 Aggregation

Prion diseases are neurodegenerative disorders caused by the accumulation of misfolded prion proteins, leading to neurotoxicity and neuronal death. Creutzfeldt-Jakob disease (CJD) in humans and Bovine spongiform encephalopathy (BSE) in animals are among the most prominent prion disorders. Therefore, the search for molecules that can serve as drugs for prion diseases has gained significant attention. In our study, we synthesised and characterised two piano-stool ruthenium complexes, RuBT and RuBI, based on benzazole-quinoline scaffolds. Molecular structures of RuBT and RuBI were determined by X-ray crystallography. The anti-aggregation effects of the complexes on PrP_106-126 aggregation were studied through ThT assay, CD, TEM, and AFM. Seeded aggregation assays demonstrated their ability to modulate seed-induced fibril formation. The interaction between the complexes and PrP_106-126 was analysed using molecular docking and UV-visible spectroscopy. Molecular docking analysis showed good binding affinity with the PrP_106-126. To demonstrate bioavailability and transport, the DNA and HSA binding affinities of complexes were computed. The complexes exhibited neuroprotective effects in HT-22 cells by reducing damage induced by PrP_106-126. They also showed anticancer activity on human neuroblastoma SH-SY5Y cells. These findings suggest that these complexes facilitate future studies on full-length prion proteins and advanced disease models.