TY - JOUR
T1 - Interaction of VIVO-8-hydroxyquinoline species with RNase A
T2 - the effect of metal ligands in the protein adduct stabilization
AU - Ferraro, Giarita
AU - Vitale, Luigi
AU - Sciortino, Giuseppe
AU - Pisanu, Federico
AU - Garribba, Eugenio
AU - Merlino, Antonello
N1 - Publisher Copyright:
© 2023 The Royal Society of Chemistry
PY - 2023/7/11
Y1 - 2023/7/11
N2 - Herein, we studied the interaction of bovine pancreatic ribonuclease (RNase A) with [VIVO(8-HQ)2] - a promising antitrypanosomal, antituberculosis, and antitumor vanadium complex (VC) formed by 8-hydroxyquinolinato (8-HQ), reaching IC50 values lower than cisplatin in HCT116 and A2780 cancer lines (0.99 and 0.96 μM vs. 15.0 and 3.4 μM) and the minimum inhibitory concentration (MIC) of 3.7 μM against strains of Mycobacterium tuberculosis. The system was investigated by spectroscopic (UV-vis absorption spectroscopy, circular dichroism, and electron paramagnetic resonance), computational (docking and DFT calculations), and X-ray crystallographic multi-technique approach. Crystallographic results at pH 5.1 demonstrate that upon interaction with the protein, one of the 8-HQ ligands is replaced by a water molecule and by Glu111 side-chain, resulting in the inhibition of the RNase A activity. EPR data confirm the formation of this adduct, with VIV coordinated by 8-HQ and by the couples (Glu-COO−; H2O) at pH 5.1, (His-N; H2O) at pH 7.4, and (His-N; OH−) or (Ser/Thr-O−, H2O) at pH 8.4. Computational data unveil the reasons behind the ligand exchange, not observed for similar complexes like [VIVO(picolinato)2] and not predicted by thermodynamic considerations. Overall, our results show that the VC-protein binding is defined not only by the thermodynamic stability of VC but also by other factors, such as the structure and steric requirements of the metal ligands, with important implications in the drug delivery strategies.
AB - Herein, we studied the interaction of bovine pancreatic ribonuclease (RNase A) with [VIVO(8-HQ)2] - a promising antitrypanosomal, antituberculosis, and antitumor vanadium complex (VC) formed by 8-hydroxyquinolinato (8-HQ), reaching IC50 values lower than cisplatin in HCT116 and A2780 cancer lines (0.99 and 0.96 μM vs. 15.0 and 3.4 μM) and the minimum inhibitory concentration (MIC) of 3.7 μM against strains of Mycobacterium tuberculosis. The system was investigated by spectroscopic (UV-vis absorption spectroscopy, circular dichroism, and electron paramagnetic resonance), computational (docking and DFT calculations), and X-ray crystallographic multi-technique approach. Crystallographic results at pH 5.1 demonstrate that upon interaction with the protein, one of the 8-HQ ligands is replaced by a water molecule and by Glu111 side-chain, resulting in the inhibition of the RNase A activity. EPR data confirm the formation of this adduct, with VIV coordinated by 8-HQ and by the couples (Glu-COO−; H2O) at pH 5.1, (His-N; H2O) at pH 7.4, and (His-N; OH−) or (Ser/Thr-O−, H2O) at pH 8.4. Computational data unveil the reasons behind the ligand exchange, not observed for similar complexes like [VIVO(picolinato)2] and not predicted by thermodynamic considerations. Overall, our results show that the VC-protein binding is defined not only by the thermodynamic stability of VC but also by other factors, such as the structure and steric requirements of the metal ligands, with important implications in the drug delivery strategies.
UR - https://www.scopus.com/pages/publications/85167504017
U2 - 10.1039/d3qi01023f
DO - 10.1039/d3qi01023f
M3 - Article
AN - SCOPUS:85167504017
SN - 2052-1545
VL - 10
SP - 5186
EP - 5198
JO - Inorganic Chemistry Frontiers
JF - Inorganic Chemistry Frontiers
IS - 17
ER -
