Implications of Protein Interaction in the Speciation of Potential V^IVO–Pyridinone Drugs

Abstract

Vanadium complexes (VCs) are promising agents for the treatment, among others, of diabetes and cancer. The development of vanadium-based drugs is mainly limited by a scarce knowledge of the active species in the target organs, which is often determined by the interaction of VCs with biological macromolecules like proteins. Here, we have studied the binding of [VIVO(empp)2] (where Hempp is 1-methyl-2-ethyl-3-hydroxy-4(1H)-pyridinone), an antidiabetic and anticancer VC, with the model protein hen egg white lysozyme (HEWL) by electrospray ionization-mass spectrometry (ESI-MS), electron paramagnetic resonance (EPR), and X-ray crystallography. ESI-MS and EPR techniques reveal that, in aqueous solution, both the species [VIVO(empp)2] and [VIVO(empp)(H2O)]+, derived from the first one upon the loss of a empp(−) ligand, interact with HEWL. Crystallographic data, collected under different experimental conditions, show covalent binding of [VIVO(empp)(H2O)]+ to the side chain of Asp48, and noncovalent binding of cis-[VIVO(empp)2(H2O)], [VIVO(empp)(H2O)]+, [VIVO(empp)(H2O)2]+, and of an unusual trinuclear oxidovanadium(V) complex, [VV 3O6(empp)3(H2O)], with accessible sites on the protein surface. The possibility of covalent and noncovalent binding with different strength and of interaction with various sites favor the formation of adducts with the multiple binding of vanadium moieties, allowing the transport in blood and cellular fluids of more than one metal-containing species with a possible amplification of the biological effects.

Interaction of Vanadium Complexes with Proteins: Revisiting the Reported Structures in the Protein Data Bank (PDB) since 2015

“…Structure C, obtained at a pH of 7.5, contains a similar [V IV O(empp) 2 (H 2 O)] adduct, but a second [V IV O(empp) 2 (H 2 O) 2 ] + adduct is also found to be H-bonded to the side chain of Arg125. Altogether, supported by ESI-MS and EPR data, these results emphasize the speciation of [V IV OL 2 ] compounds upon protein interactions and the possible binding of different V-fragments, which is important to better understanding their transport in the bloodstream and possible binding to proteins inside cells [ 133 ].…”

“…In the last years, some SC-XRD studies of oxidovanadium(IV and V) complexes bound to proteins have been reported, namely involving the V IV O 2+ center. The first SC-XRD structure involving the oxidovanadium(IV) ion was reported in 2014 [ 104 ] and a few others have been reported since 2021 [ 16 , 75 , 132 , 133 , 134 ]. Table 4 summarizes the six VCs’ organic ligands bound to three different model proteins (lysozyme, RNase and trypsin) in the PDB, published since 2015, which will be discussed in the next sections.…”

Stabilization and Binding of [V4O12]4− and Unprecedented [V20O54(NO3)]n− to Lysozyme upon Loss of Ligands and Oxidation of the Potential Drug VIVO(acetylacetonato)2

“…Although the understanding of the POVs binding to proteins is a crucial step for elucidating the mechanism of biological action of these compounds, this research field, due to its high complexity, has been scarcely investigated [14,15] . In our continuous efforts to characterize the interaction of proteins with metal complexes, [16–19] we have recently studied the structures of the adducts formed upon reaction of proteins with V IV OL 2 compounds, where L − is a monoanionic bidentate organic ligand [20–22] . Crystallography works reporting the structures of these adducts are rare [20–24] and the few studies carried out on these systems revealed binding preference of V containing fragments, in particular V IV OL + and V IV OL 2 , for Asn, Asp, Glu and His side chains.…”

Halogenated non-innocent vanadium(v) Schiff base complexes: chemical and anti-proliferative properties

“…[3][4][5][6] Non-innocent Schiff base V-catecholates have interesting electronic properties with the potential for redox taking place not only on the metal center but also on the ligand. 3,[7][8][9] The subclass of non-innocent Schiff base V-catecholates have recently been discovered to have desirable pharmaceutical properties [3][4][5][6][8][9][10][11][12][13][14][15][16] which expanded the known anti-diabetic and anti-cancer properties of vanadium complexes. 3,4,6,[8][9][10][11][12][13][14][15][16][17][18] The reported antiproliferative properties of the class of non-innocent Schiff base V-catecholates were reported to surpass the efficacy of cisplatin against in human chondrosarcoma (SW1353) bone cells, T98G glioblastoma cells, aggressive mesenchymal-like MDA-MB-231 cells, A549 (lung), and PANC-1 (pancreas) cancer cell lines, and HFF-1 (human foreskin fibroblasts) normal cells.…”