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. 2023 May 29;62(21):8407-8417.
doi: 10.1021/acs.inorgchem.3c01041. Epub 2023 May 17.

Implications of Protein Interaction in the Speciation of Potential VIVO-Pyridinone Drugs

Giarita Ferraro  1 , Maddalena Paolillo  1 , Giuseppe Sciortino  2 , Federico Pisanu  3 , Eugenio Garribba  3 , Antonello Merlino  1
Affiliations

Implications of Protein Interaction in the Speciation of Potential VIVO-Pyridinone Drugs

Giarita Ferraro et al. Inorg Chem. .

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, [VV3O6(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.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Scheme 1
Scheme 1. Pyridinone Ligands That Form Pharmacologically Active VIVO2+ Complexes
Figure 1
Figure 1
Concentration distribution curves of the species formed as a function of pH in the system VIVO2+/Hempp 1/2 with vanadium concentration of 50 μM. The water ligands bound to vanadium are omitted for clarity.
Figure 2
Figure 2
Deconvoluted positive-ion mode spectra recorded on the system containing [VIVO(empp)2] and HEWL. (A) Free protein at pH 7.0; (B) [VIVO(empp)2]/HEWL 2/1 at pH 4.0 with a vanadium concentration of 50 μM; (C) [VIVO(empp)2]/HEWL 2/1 at pH 7.0 with a vanadium concentration of 50 μM.
Figure 3
Figure 3
High-field region of the anisotropic X-band EPR spectra recorded at 120 K and pH 7.0 in an aqueous solution containing: (A) [VIVO(empp)2]; (B) [VIVO(empp)2]/HEWL 2/1; (C) [VIVO(empp)2]/HEWL 1/2. Vanadium concentration is 1.0 mM. The MI = 7/2 resonances of [VIVO(empp)2], cis-[VIVO(empp)2], and of the adduct HEWL–[VIVO(empp)]+ with a covalent binding are indicated with 1a, 1b, and 2, respectively. The interaction of [VIVO(empp)2] (1a) and cis-[VIVO(empp)2] (1b) with HEWL could be noncovalent since this does not change the spin Hamiltonian parameters, while that of [VIVO(empp)]+ could be covalent.
Figure 4
Figure 4
Overall structures of the adducts formed upon reaction of [VIVO(empp)2] with HEWL under different experimental conditions: (A) structure A, derived from a crystal grown in 1.1 M sodium chloride, 0.1 M sodium acetate at pH 4.0; (B) structure B, derived from a crystal grown in 0.8 M succinic acid at pH 7.0; (C) structure C, derived from a crystal grown in 2.0 M sodium formate, 0.1 M Hepes at pH 7.5. Vanadium atoms are in green. Coordinates and structure factors were deposited in the PDB under the accession codes 8OM8, 8OMS, 8OMT.
Figure 5
Figure 5
Vanadium binding sites in structure A: (A) noncovalent binding of [(VV3O6)(empp)3(H2O)]; (B) covalent coordination of [VIVO(empp)(H2O)]+ to the side chain of Asp48. 2Fo-Fc electron density maps are reported at 1.0 σ level in gray.
Figure 6
Figure 6
Vanadium binding site in structure B: noncovalent binding of cis-[VIVO(empp)2(H2O)]. 2Fo-Fc electron density maps are reported at 1.0 σ level in gray.
Figure 7
Figure 7
Vanadium binding site in structure C: (A) noncovalent binding of cis-[VIVO(empp)2(H2O)]; (B) noncovalent binding of [VIVO(empp)(H2O)2]+. 2Fo-Fc electron density maps are reported at 1.0 σ level in gray.
Figure 8
Figure 8
Superimposition of the structures of the adducts formed by HEWL with [VIVO(malt)2] and [VIVO(empp)2]. [VIVO(malt)2] fragments and vanadium atoms derived from [VIVO(malt)2] are in yellow, [VIVO(empp)2] fragments and [(VV3O6)(empp)3(H2O)] are in blue.
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References

    1. Barry N. P. E.; Sadler P. J. Exploration of the medical periodic table: towards new targets. Chem. Commun. 2013, 49, 5106–5131. 10.1039/c3cc41143e. - DOI - PubMed
    2. Medici S.; Peana M.; Nurchi V. M.; Lachowicz J. I.; Crisponi G.; Zoroddu M. A. Noble metals in medicine: Latest advances. Coord. Chem. Rev. 2015, 284, 329–350. 10.1016/j.ccr.2014.08.002. - DOI
    3. Metal-based Anticancer Agents. Casini A.; Anne V.; Meier-Menches S. M., Eds.; RSC: Croydon, England, 2019.
    4. Anthony E. J.; Bolitho E. M.; Bridgewater H. E.; Carter O. W. L.; Donnelly J. M.; Imberti C.; Lant E. C.; Lermyte F.; Needham R. J.; Palau M.; Sadler P. J.; Shi H.; Wang F.-X.; Zhang W.-Y.; Zhang Z. Metallodrugs are unique: opportunities and challenges of discovery and development. Chem. Sci. 2020, 11, 12888–12917. 10.1039/D0SC04082G. - DOI - PMC - PubMed
    5. Frei A.; Zuegg J.; Elliott A. G.; Baker M.; Braese S.; Brown C.; Chen F.; G Dowson C.; Dujardin G.; Jung N.; King A. P.; Mansour A. M.; Massi M.; Moat J.; Mohamed H. A.; Renfrew A. K.; Rutledge P. J.; Sadler P. J.; Todd M. H.; Willans C. E.; Wilson J. J.; Cooper M. A.; Blaskovich M. A. T. Metal complexes as a promising source for new antibiotics. Chem. Sci. 2020, 11, 2627–2639. 10.1039/C9SC06460E. - DOI - PMC - PubMed
    6. Yousuf I.; Bashir M.; Arjmand F.; Tabassum S. Advancement of metal compounds as therapeutic and diagnostic metallodrugs: Current frontiers and future perspectives. Coord. Chem. Rev. 2021, 445, 214104.10.1016/j.ccr.2021.214104. - DOI
    7. Fotopoulou E.; Titilas I.; Ronconi L. Metallodrugs as Anticancer Chemotherapeutics and Diagnostic Agents: A Critical Patent Review (2010–2020). Recent Pat. Anti-Cancer Drug Discovery 2022, 17, 42–54. 10.2174/1574892816666210907101146. - DOI - PubMed
    8. Miranda V. M. Medicinal inorganic chemistry: an updated review on the status of metallodrugs and prominent metallodrug candidates. Rev. Inorg. Chem. 2022, 42, 29–52. 10.1515/revic-2020-0030. - DOI
    1. Mjos K. D.; Orvig C. Metallodrugs in Medicinal Inorganic Chemistry. Chem. Rev. 2014, 114, 4540–4563. 10.1021/cr400460s. - DOI - PubMed
    1. Levina A.; Crans D. C.; Lay P. A. Speciation of metal drugs, supplements and toxins in media and bodily fluids controls in vitro activities. Coord. Chem. Rev. 2017, 352, 473–498. 10.1016/j.ccr.2017.01.002. - DOI
    2. Pessoa J. C.; Correia I. Misinterpretations in Evaluating Interactions of Vanadium Complexes with Proteins and Other Biological Targets. Inorganics 2021, 9, 17.10.3390/inorganics9020017. - DOI
    1. Pessoa J. C.; Etcheverry S.; Gambino D. Vanadium compounds in medicine. Coord. Chem. Rev. 2015, 301, 24–48. 10.1016/j.ccr.2014.12.002. - DOI - PMC - PubMed
    2. Kioseoglou E.; Petanidis S.; Gabriel C.; Salifoglou A. The chemistry and biology of vanadium compounds in cancer therapeutics. Coord. Chem. Rev. 2015, 301-302, 87–105. 10.1016/j.ccr.2015.03.010. - DOI
    3. Rehder D. Perspectives for vanadium in health issues. Future Med. Chem. 2016, 8, 325–338. 10.4155/fmc.15.187. - DOI - PubMed
    4. Leon I. E.; Cadavid-Vargas J. F.; Di Virgilio A. L.; Etcheverry S. B. Vanadium, ruthenium and copper compounds: a new class of nonplatinum metallodrugs with anticancer activity. Curr. Med. Chem. 2017, 24, 112–148. 10.2174/0929867323666160824162546. - DOI - PubMed
    5. Crans D. C.; Yang L.; Haase A.; Yang X.. Health Benefits of Vanadium and Its Potential as an Anticancer Agent, Met. Ions Life Sci. In Metallo-Drugs Development & Action of Anticancer Agents ;Sigel A., Sigel H., Freisinger E., Sigel R. K. O., Eds.; Walter de Gruyter GmbH: Berlin, Germany, 2018; Vol. 18, pp 251–279. - PubMed
    6. Crans D. C.; LaRee H.; Cardiff G.; Posner B. I.. Developing Vanadium as an Antidiabetic or Anticancer Drug: A Clinical and Historical Perspective In Essential Metals in Medicine: Therapeutic Use and Toxicity of Metal Ions in the Clinic; Carver P. L., Ed.; De Gruyter GmbH: Berlin, 2019; pp 203–230. - PubMed
    7. Treviño S.; Díaz A.; Sánchez-Lara E.; Sanchez-Gaytan B. L.; Perez-Aguilar J. M.; González-Vergara E. Vanadium in Biological Action: Chemical, Pharmacological Aspects, and Metabolic Implications in Diabetes Mellitus. Biol. Trace Elem. Res. 2019, 188, 68–98. 10.1007/s12011-018-1540-6. - DOI - PMC - PubMed
    8. Treviño S.; Diaz A. Vanadium and insulin: Partners in metabolic regulation. J. Inorg. Biochem. 2020, 208, 111094.10.1016/j.jinorgbio.2020.111094. - DOI - PubMed
    9. Aureliano M.; Gumerova N. I.; Sciortino G.; Garribba E.; Rompel A.; Crans D. C. Polyoxovanadates with emerging biomedical activities. Coord. Chem. Rev. 2021, 447, 214143.10.1016/j.ccr.2021.214143. - DOI
    10. Selvaraj S.; Krishnan U. M. Vanadium–Flavonoid Complexes: A Promising Class of Molecules for Therapeutic Applications. J. Med. Chem. 2021, 64, 12435–12452. 10.1021/acs.jmedchem.1c00405. - DOI - PubMed
    11. Amante C.; De Sousa-Coelho A. L.; Aureliano M. Vanadium and Melanoma: A Systematic Review. Metals 2021, 11, 828.10.3390/met11050828. - DOI
    12. Sharfalddin A. A.; Al-Younis I. M.; Mohammed H. A.; Dhahri M.; Mouffouk F.; Abu Ali H.; Anwar M. J.; Qureshi K. A.; Hussien M. A.; Alghrably M.; Jaremko M.; Alasmael N.; Lachowicz J. I.; Emwas A.-H. Therapeutic Properties of Vanadium Complexes. Inorganics 2022, 10, 244.10.3390/inorganics10120244. - DOI
    13. Aureliano M.; Gumerova N. I.; Sciortino G.; Garribba E.; McLauchlan C. C.; Rompel A.; Crans D. C. Polyoxidovanadates’ interactions with proteins: An overview. Coord. Chem. Rev. 2022, 454, 214344.10.1016/j.ccr.2021.214344. - DOI
    1. Thompson K. H.; Lichter J.; LeBel C.; Scaife M. C.; McNeill J. H.; Orvig C. Vanadium treatment of type 2 diabetes: A view to the future. J. Inorg. Biochem. 2009, 103, 554–558. 10.1016/j.jinorgbio.2008.12.003. - DOI - PubMed
    2. Thompson K. H.; Orvig C. Vanadium in diabetes: 100 years from Phase 0 to Phase I. J. Inorg. Biochem. 2006, 100, 1925–1935. 10.1016/j.jinorgbio.2006.08.016. - DOI - PubMed