A strategy for the development of new vanadium-based drugs is the preparation of complexes that target proteins and bear molecules involved in the cellular metabolism as ligands,likeα-hydroxycarboxylic acids.Based on...A strategy for the development of new vanadium-based drugs is the preparation of complexes that target proteins and bear molecules involved in the cellular metabolism as ligands,likeα-hydroxycarboxylic acids.Based on these premises,this study explores the solution behaviour of the dioxidovanadium(V)complex of malic acid,Cs_(2)[V^(V)_(2)O_(4)(mal)_(2)]·2H_(2)O,and its interaction with the model protein lysozyme(HEWL)at room and at physiological temperature using 51V nuclear magnetic resonance(NMR),electrospray ionisation-mass spectrometry(ESI-MS)and X-ray crystallography.The results show the coexistence in aqueous solution of various molecular species containing two or ten V^(V)centres.In solution these species are formed regardless of the presence of HEWL,while at 37℃the formation of[V^(V)_(10)O_(28)]^(6−)(V_(10))is precluded when the protein is present.Crystallographic data reveal that,when protein crystals are incubated with the V compound at room temperature(25℃)and at pH 4.0,[VIVO]^(2+),[V^(V)_(2)O_(5)(mal)]^(2−),[V^(V)_(10)O_(26)]^(2−)and[V^(V)_(10)O_(28)]^(6−)are bound to the protein,while at 37℃,under the same conditions,only[VIVO]^(2+)interacts with HEWL.[V^(V)_(10)O_(28)]^(6−)can bind the protein both covalently(as[V^(V)_(10)O_(26)]^(2−)ion)and non-covalently.Whereas the transformation of[V^(V)_(2)O_(4)(mal)_(2)]^(2−)to[V^(V)_(2)O_(5)(mal)]^(2−)is expected on the basis of thermodynamic considerations,the formation of V10 and of the V_(10)-HEWL adduct is not easily predictable.Docking calculations confirm the experimental results and highlight the role of protein-protein interaction in the stabilization of the revealed adduct.This study demonstrates that vanadium compounds can undergo transformation in solution,giving rise to species that interact with proteins through several binding modes and stabilization mechanisms.展开更多
基金This research was funded by MIUR PRIN 2022-Cod.2022JMFC3X“Protein Metalation by Anticancer Metal-based Drugs”MIUR PRIN 2022-Cod.2022APCTNA“TRILLI-TRansforming metal Ions and Low-cost LIgands into next generation metallodrugs.
文摘A strategy for the development of new vanadium-based drugs is the preparation of complexes that target proteins and bear molecules involved in the cellular metabolism as ligands,likeα-hydroxycarboxylic acids.Based on these premises,this study explores the solution behaviour of the dioxidovanadium(V)complex of malic acid,Cs_(2)[V^(V)_(2)O_(4)(mal)_(2)]·2H_(2)O,and its interaction with the model protein lysozyme(HEWL)at room and at physiological temperature using 51V nuclear magnetic resonance(NMR),electrospray ionisation-mass spectrometry(ESI-MS)and X-ray crystallography.The results show the coexistence in aqueous solution of various molecular species containing two or ten V^(V)centres.In solution these species are formed regardless of the presence of HEWL,while at 37℃the formation of[V^(V)_(10)O_(28)]^(6−)(V_(10))is precluded when the protein is present.Crystallographic data reveal that,when protein crystals are incubated with the V compound at room temperature(25℃)and at pH 4.0,[VIVO]^(2+),[V^(V)_(2)O_(5)(mal)]^(2−),[V^(V)_(10)O_(26)]^(2−)and[V^(V)_(10)O_(28)]^(6−)are bound to the protein,while at 37℃,under the same conditions,only[VIVO]^(2+)interacts with HEWL.[V^(V)_(10)O_(28)]^(6−)can bind the protein both covalently(as[V^(V)_(10)O_(26)]^(2−)ion)and non-covalently.Whereas the transformation of[V^(V)_(2)O_(4)(mal)_(2)]^(2−)to[V^(V)_(2)O_(5)(mal)]^(2−)is expected on the basis of thermodynamic considerations,the formation of V10 and of the V_(10)-HEWL adduct is not easily predictable.Docking calculations confirm the experimental results and highlight the role of protein-protein interaction in the stabilization of the revealed adduct.This study demonstrates that vanadium compounds can undergo transformation in solution,giving rise to species that interact with proteins through several binding modes and stabilization mechanisms.
