Paolillo, Maddalena (2025) Interaction between vanadium-based compounds and proteins. [Tesi di dottorato]

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Abstract

Vanadium compounds (VCs) have attracted growing interest because of their catalytic and biological properties, including the treatment of diabetes, cancer, and cardiovascular and neurodegenerative diseases. Their pharmacological potential is strongly linked to the ability to interact with biomolecules, in particular proteins, which mediate their transport, distribution and activation in vivo. Understanding VC–protein interactions at the molecular level is therefore crucial for rational drug design. The aim of this PhD project was to provide a structural characterization of the interaction between different VCs and proteins, considering both model proteins (like lysozyme (HEWL)) and physiologically relevant proteins (like human transferrin (hTF)). Complexes of different oxidation states and architectures were studied, including V(IV)O complexes with bidentate ligands (Hempp = 1-methyl-2-ethyl-3-hydroxy-4(1H)-pyridinone, Hdhp =1,2-dimethyl-3-hydroxy-4(1H)-pyridinone, 8-HQ = 8-hydroxyquinolinato, acac = acetylacetonate) and tridentate ligands (xant = xanthurenic acid, dipic = dipicolinic acid), V(V)O2-hydrazonate derivatives, and dinuclear V(V) complexes with α-hydroxycarboxylic acids (mal = malic acid, lact = lactic acid). A combined approach involving spectroscopic (UV-Vis, CD, fluorescence, 51V NMR), spectrometric (ESI-MS), and crystallographic techniques was employed to investigate the reactivity of these VCs with proteins. V(IV)O complexes with bidentate and tridentate ligands showed simultaneous covalent and non-covalent binding to HEWL and gave rise to unexpected multinuclear species. V(V)O2-hydrazonate derivatives formed supramolecular dimers stabilized by stacking interactions upon binding to HEWL. Dinuclear V(V) complexes with α-hydroxycarboxylates exhibited ligand-dependent behaviour. In crystallo, HEWL bound different V-containing fragments. Temperature and crystallization conditions significantly modulated the formation of multinuclear vanadates. The first crystal structure of an adduct formed by human transferrin with the Fe3+ bound at the C-lobe only (FeC-hTF) with a VC was also obtained: FeC-hTF can stabilize a divanadate(V) ion. Overall, this Ph.D. thesis revealed unprecedented structural aspects of VC–protein recognition. Unexpected molecular species and binding events were highlighted. The results provided a significant advancement in the understanding of the mechanisms at the basis of the V-compound recognition by proteins opening new perspectives for the rational development of V-based therapeutics.

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