Metallodrugs Having Improved Pharmacological Properties, and Methods of Manufacture and Use Thereof

Abstract

It is an object of the present invention to provide improved pharmacological properties to molecules which bind to a target with low affinity (hereinafter referred to as a “ligand moiety”) through linkage of such molecules to a metal binding moiety, thereby generating a combination molecule commonly referred to as a “metallodrug” or “metallotherapeutic.” The metal binding domain of metallodrugs typically catalyzes oxido-reductase chemistry or acts as a Lewis-Acid catalyst, resulting in modification of proteins and nucleic acids that are in close proximity due to binding of the ligand moiety to its target.

1 . A composition for catalytically inactivating a biochemical target of interest, comprising:
 a ligand moiety which binds to the biochemical target; and   a metal binding moiety,   wherein the ligand moiety and the metal binding moiety are covalently linked, wherein the ligand moiety is heterologous to the metal binding moiety, and wherein the composition binds to the biochemical target with an affinity of between about 10 4  M −1  and about 5×10 8  M −1 .   
     
     
         2 . The composition according to  claim 1 , wherein the metal binding moiety comprises a metal bound thereto, wherein said metal is redox-active in the bound state under oxidative conditions to generate one or more reactive oxygen species. 
     
     
         3 . The composition according to  claim 1 , wherein the metal binding moiety has a metal bound thereto, wherein said metal is active as a Lewis acid catalyst in the bound state under hydrolytic conditions. 
     
     
         4 . The composition according to  claim 1 , wherein said ligand moiety has an off rate (k off ) for its ligand which is similar to that for the catalytic turnover (k cat ) of the metal binding moiety. 
     
     
         5 . The composition according to  claim 1 , wherein the metal binding moiety comprises a metal bound thereto, wherein said metal is a cation of a metal selected from the group consisting of an alkaline earth metals, metals which give rise to cations with an incomplete d sub-shell, and lanthanide and actinide metals. 
     
     
         6 . The composition according to  claim 5 , wherein the metal is selected from the group consisting of Cu(II), Cu(III), Ni(II), Ni(III), Zn(II), Fe(II), Fe(III), Co(II), Co(III), Cr(II), and Cr(III), other second and third row transition metal ions, and non-transition metals such as Al(III). 
     
     
         7 . The composition according to  claim 1 , wherein the ligand moiety comprises a peptide or protein backbone, or pegylated form thereof. 
     
     
         8 . The composition according to  claim 1 , wherein the ligand moiety comprises a carbohydrate backbone, or pegylated form thereof. 
     
     
         9 . The composition according to  claim 1 , wherein the ligand moiety comprises a secondary metabolite, or pegylated form thereof. 
     
     
         10 . The composition according to  claim 1 , wherein the ligand moiety comprises a nucleic acid backbone, or pegylated form thereof. 
     
     
         11 . The composition according to  claim 1 , wherein the ligand moiety comprises a protein nucleic acid backbone, or pegylated form thereof. 
     
     
         12 . The composition according to  claim 1 , wherein the ligand moiety comprises an organic molecular motif selected from the group consisting of an aptamer, a small organic molecule, a peptidomimetic, a dendrimer, an antibiotic, a secondary metabolite, an antibody (or antibody fragment), and a pegylated form thereof. 
     
     
         13 . The composition according to  claim 1 , wherein the metal binding moiety comprises an organic chelating ligand. 
     
     
         14 . The composition according to  claim 13 , wherein said organic chelating ligand coordinates a metal using amine and carboxylate functionalities on the organic chelating ligand. 
     
     
         15 . The composition according to  claim 13 , wherein said organic chelating ligand coordinates a metal using the coordination chemistry of a compound selected from the group consisting of diethylenetriaminepentaacetic acid (DTPA), ethylenediamine tetraacetic acid (EDTA), N,N-bis(carboxymethyl)glycine (NTA), diethylenetriaminepentaacetate (DTPA), 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), Mercaptoacetylglycine (MAG3), 1,4,8,11-Tetraazacyclotetradecane (CYCLAM), 1,4,7,10-tetraazacyclododecane, cyclen, 1,4,7-triazacyclononane (TACN), and hydrazinonicotinamide (HYNIC). 
     
     
         16 . The composition according to  claim 1 , wherein the metal binding moiety comprises a peptide chelating ligand. 
     
     
         17 . The composition according to  claim 16 , wherein said peptide chelating ligand coordinates a metal using terminal amine and/or amino acid sidechains, and/or deprotonated backbone amide, and/or backbone carbonyl functionalities on the peptide chelating ligand. 
     
     
         18 . The composition according to  claim 16 , wherein said peptide chelating ligand is an ATCUN motif. 
     
     
         19 . The composition according to  claim 1 , wherein the biochemical target is selected from the group consisting of a bacterial component, a viral component, a fungal component, a mammalian cellular component, a protozoan component, a serum component, an extracellular matrix component, a cancer cell component, and a pathogen-derived toxin. 
     
     
         20 . The composition according to  claim 1 , wherein the biochemical target is a cellular or serum component selected from the group consisting of a cell receptor, a cytokine, a hormone, an enzyme, and a misfolded or polymeric form of a naturally occurring molecule. 
     
     
         21 . The composition according to  claim 1 , wherein when the composition is bound to the biochemical target, the metal binding moiety is within 20 nm, and preferably within 20 Å, of the biochemical target. 
     
     
         22 . A method of improving the efficacy of a current or candidate therapeutic molecule which is a ligand to a biochemical target, comprising:
 covalently conjugating said current or candidate therapeutic molecule and which lacks a metal-binding domain, to a metal binding moiety.   
     
     
         23 . The method according to  claim 22 , wherein the metal binding moiety comprises a metal bound thereto, wherein said metal is redox-active in the bound state under oxidative conditions to generate one or more reactive oxygen species. 
     
     
         24 . The composition according to  claim 22 , wherein the metal binding moiety has a metal bound thereto, wherein said metal is active as a Lewis acid catalyst in the bound state under hydrolytic conditions. 
     
     
         25 . The method according to  claim 22 , wherein said current or candidate therapeutic molecule has an off rate (k off ) for its ligand which is similar to that for the catalytic turnover (k cat ) of the metal binding moiety. 
     
     
         26 . The method according to  claim 22 , wherein the ligand moiety comprises a peptide or protein backbone, or pegylated form thereof. 
     
     
         27 . The method according to  claim 22 , wherein the ligand moiety comprises a carbohydrate backbone, or pegylated form thereof. 
     
     
         28 . The method according to  claim 22 , wherein the ligand moiety comprises a secondary metabolite, or pegylated form thereof. 
     
     
         29 . The method according to  claim 22 , wherein the ligand moiety comprises a nucleic acid backbone, or pegylated form thereof. 
     
     
         30 . The method according to  claim 22 , wherein the ligand moiety comprises a protein nucleic acid backbone, or pegylated form thereof. 
     
     
         31 . The method according to  claim 22 , wherein the ligand moiety comprises an organic molecular motif selected from the group consisting of an aptamer, a small organic molecule, a peptidomimetic, a dendrimer, an antibiotic, a secondary metabolite, an antibody, and a pegylated form thereof. 
     
     
         32 . The method according to  claim 22 , wherein the metal binding moiety comprises an organic chelating ligand. 
     
     
         33 . The method according to  claim 32 , wherein said organic chelating ligand coordinates a metal using amine and carboxylate functionalities on the organic chelating ligand. 
     
     
         34 . The method according to  claim 32 , wherein said organic chelating ligand coordinates a metal using the coordination chemistry of a compound selected from the group consisting of diethylenetriaminepentaacetic acid (DTPA), ethylenediamine tetraacetic acid (EDTA), N,N-bis(carboxymethyl)glycine (NTA), diethylenetriaminepentaacetate (DTPA), 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), Mercaptoacetylglycine (MAG3), 1,4,8,11-Tetraazacyclotetradecane (CYCLAM), 1,4,7,10-tetraazacyclododecane, cyclen, 1,4,7-triazacyclononane (TACN), and hydrazinonicotinamide (HYNIC). 
     
     
         35 . The method according to  claim 22 , wherein the metal binding moiety comprises a peptide chelating ligand. 
     
     
         36 . The method according to  claim 35 , wherein said peptide chelating ligand coordinates a metal using terminal amine and/or amino acid sidechains, and/or deprotonated backbone amide, and/or backbone carbonyl functionalities on the peptide chelating ligand. 
     
     
         37 . The method according to  claim 35 , wherein said peptide chelating ligand is an ATCUN motif. 
     
     
         38 . The method according to  claim 22 , wherein the biochemical target is selected from the group consisting of a bacterial component, a viral component, a fungal component, a human cellular component, a protozoan component, a serum component, an extracellular matrix component, a cancer cell component, and a pathogen-derived toxin. 
     
     
         39 . The method according to  claim 22 , wherein the biochemical target is a cellular or serum component selected from the group consisting of a cell receptor, a cytokine, a hormone, an enzyme, and a misfolded or polymeric form of a naturally occurring molecule. 
     
     
         40 . The method according to  claim 22 , wherein when the composition is bound to the biochemical target, the metal binding moiety is within 20 nm, and preferably within 20 Å, of the biochemical target. 
     
     
         41 . A method for therapeutically inactivating a biochemical target, comprising:
 administering to a subject in need thereof a composition according to  claim 1  under wherein the composition binds to, and generates reactive oxygen species proximate to, the biochemical target, wherein the concentration of reactive oxygen species generated conformationally and/or functionally alters the biochemical target to therapeutic effect.   
     
     
         42 . A method for therapeutically inactivating a biochemical target, comprising:
 administering to a subject in need thereof a composition according to  claim 1  under conditions wherein the composition binds to, and is active as a Lewis acid catalyst in the bound state under hydrolytic conditions.   
     
     
         43 . A method for sterilization by inactivating a biochemical target, comprising:
 administering to a subject in need thereof a composition according to  claim 1  under conditions wherein the composition binds to, and generates reactive oxygen species proximate to, the biochemical target, wherein the concentration of reactive oxygen species generated conformationally and/or functionally alters the biochemical target to therapeutic effect.   
     
     
         44 . A method for sterilization by inactivating a biochemical target, comprising:
 administering to a subject in need thereof a composition according to  claim 1  under conditions wherein the composition binds to, and is active as a Lewis acid catalyst proximate to the biochemical target, wherein the concentration of reactive species generated conformationally and/or functionally alters the biochemical target to therapeutic effect.   
     
     
         45 . A method for catalytically inactivating a biochemical target of interest, comprising:
 a ligand moiety which binds to the biochemical target with an affinity of between about 10 4  M −1  and about 5×10 8  M −1 .   
     
     
         46 . The method according to  claim 45 , wherein the metal binding moiety has a metal bound thereto, wherein said metal is active as a Lewis acid catalyst in the bound state under hydrolytic conditions. 
     
     
         47 . The method according to  claim 45 , wherein the metal binding moiety comprises a metal bound thereto, wherein said metal is a cation of a metal selected from the group consisting of an alkaline earth metals, metals which give rise to cations with an incomplete d sub-shell, and actinide metals. 
     
     
         48 . The method according to  claim 46 , wherein the metal is selected from the group consisting of Cu(II), Cu(III), Ni(II), Ni(III), Zn(II), Fe(II), Fe(III), Co(II), Co(III), Cr(II), and Cr(III), and other second and third row transition metal ions, and non-transition metals. 
     
     
         49 . A pharmaceutical composition, comprising
 a. one or more compositions according to  claim 1  and/or one or more salt form of the composition according to  claim 1 , and   b. one or more pharmaceutically acceptable excipients or carriers.   
     
     
         50 . The pharmaceutical composition according to  claim 49 , wherein the composition is in a therapeutically effective amount. 
     
     
         51 . A method for reducing the biological activities in a patient or for treating infection or condition in a patient, comprising administrating to the patient a therapeutically effective amount of the pharmaceutical composition according to  claim 49 . 
     
     
         52 . The method in accordance to  claim 51 , further comprising administering one or more additional therapeutically active agents prior to, after, or simultaneously with the pharmaceutical composition. 
     
     
         53 . A method for treating a disease in a patient, comprising providing to the patient a therapeutically effective amount of the pharmaceutical composition comprising
 a. one or more compositions according to  claim 1  and/or one or more salt form of the composition according to  claim 1 , and   b. one or more pharmaceutically acceptable excipients or carriers.   
     
     
         54 . The method according to  claim 53 , further comprising administering one or more additional therapeutically active agents prior to, after, or simultaneously with the pharmaceutical composition.