FUNCTIONAL AND STRUCTURAL CHARACTERIZATION OF BIOLOGICALLY ACTIVE COMPOUNDS AND PROTEIN INTERACTIONS ASSOCIATED TO NEURODEGENERATIVE DISEASES

This thesis presents a comprehensive investigation into the interactions between natural compounds—such as polyphenols, alkaloids, and vitamins—and their interplay with metal ions and amyloidogenic proteins, particularly amyloid beta, in the context of oxidative stress and neurodegenerative diseases. Through the integration of advanced spectroscopic techniques, cell-based assays, and deep-learning approach, the research contributes to an enhanced understanding of the molecular mechanisms underlying these interactions and explores their potential therapeutic implications. Key findings include the dual role of rosmarinic acid and other hydroxycinnamic acids as both antioxidants and copper-binding agents. Among them, rosmarinic acid demonstrated superior efficacy by forming stable Cu(II) complexes that modulate oxidative processes and reduce reactive oxygen species (ROS) generation. Similarly, rosemary extract, rich in rosmarinic and carnosic acids, exhibited synergistic antioxidant and neuroprotective effects, emphasizing the relevance of polyphenol-rich natural extracts in complex pathologies such as Alzheimer’s disease. Studies on the alkaloids lycorine and galantamine revealed their ability to interact with the N-terminal region of amyloid-beta, mitigating aggregation and ROS production. Lycorine, in particular, formed ternary complexes with Cu(II) and amyloid beta, significantly altering redox activity and reducing neurotoxicity. These interactions were characterized using NMR and UV-Vis spectroscopy, showing that lycorine stabilizes the resulting complexes and inhibits ROS catalysis. Investigations into vitamin–metal ion systems, such as folic acid and vitamin C with Cu(II), highlighted their complex behavior in modulating oxidative pathways. Folic acid showed specific coordination through its pteridine ring, while vitamin C exhibited both antioxidant and prooxidant effects depending on the environment. Furthermore, the structural role of copper in modulating α-synuclein conformation and aggregation in membrane-like environments was explored. The formation of a Cu(I)-mediated dimer of α-synuclein stabilized its α-helical structure while reducing redox activity, offering new insights into its role in Parkinson’s disease and metal-protein interactions.