Nitrosated and nitrosylated heme proteins

Abstract

Nitrosylation of proteins and amino acid groups enables selective regulation of protein function, and also endows the proteins and amino acids with additional smooth muscle relaxant and platelet inhibitory capabilities. Thus, the invention relates to novel compounds achieved by nitrosylation of protein thiols. Such compounds include: S-nitroso-heme proteins, S-nitroso-t-PA, S-nitroso-cathepsin; S-nitroso-lipoproteins; and S-nitroso-immunoglobulins. The invention also relates to therapeutic use if S-nitroso-protein compounds for regulating protein function, cellular metabolism and effecting vasodilation, platelet inhibition, relaxation of non-vascular smooth muscle, and increasing blood oxygen transport by hemoglobin and myoglobin. The compounds are also used to deliver nitric oxide in its most bioactive form in order to achieve the effects described above, or for in vitro nitrosylation of molecules present in the body. The invention also relates to the nitrosylation of oxygen, carbon and nitrogen moieties present on proteins and amino acids, and the use thereof to achieve the above physiological effects.

1 . A method of promoting platelet inhibition or promoting vasodilation in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition comprising a nitrosated and/or nitrosylated heme protein, wherein the heme protein is nitrosated and/or nitrosylated at one or more thiol groups in the heme protein.  
   
   
       2 . The method of  claim 1 , wherein the pharmaceutical composition further comprises at least one of a nonionic surfactant, a phospholipid, an emulsifier, and a fatty acid.  
   
   
       3 . The method of  claim 1 , wherein the heme protein is hemoglobin.  
   
   
       4 . The method of  claim 3 , wherein the hemoglobin is a human hemoglobin.  
   
   
       5 . The method of  claim 3 , wherein the hemoglobin is bovine hemoglobin.  
   
   
       6 . A method of treating a hypoxic disorder in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition comprising a nitrosated and/or nitrosylated heme protein, wherein the heme protein is nitrosated and/or nitrosylated at one or more thiol groups in the heme protein.  
   
   
       7 . The method of  claim 6 , wherein the hypoxic disorder is the result of pneumothorax, an airway obstruction, paralysis of the respiratory muscles, a weakness of the respiratory muscles, or an inhibition of a respiratory center by a drug.  
   
   
       8 . The method of  claim 6 , further comprising at least one of a nonionic surfactant, a phospholipid, an emulsifier or a fatty acid.  
   
   
       9 . The method of  claim 6 , wherein the heme protein is hemoglobin.  
   
   
       10 . The method of  claim 9 , wherein the hemoglobin is a human hemoglobin.  
   
   
       11 . The method of  claim 9 , wherein the hemoglobin is bovine hemoglobin.  
   
   
       12 . A method of treating impaired alveolar gas diffusion in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition comprising a nitrosated and/or nitrosylated heme protein, wherein the heme protein is nitrosated and/or nitrosylated at one or more thiol groups in the heme protein.  
   
   
       13 . The method of  claim 12 , wherein the impaired alveolar gas diffusion is the result of interstital fibrosis, brochiole constriction, pulmonary edema, pneumonia, hemorrhage, drowning, anemia, carbon monoxide poisoning or an arteriovenous shunt.  
   
   
       14 . The method of  claim 12 , further comprising at least one of a nonionic surfactant, a phospholipid, an emulsifier or a fatty acid.  
   
   
       15 . The method of  claim 12 , wherein the heme protein is hemoglobin.  
   
   
       16 . The method of  claim 15 , wherein the hemoglobin is a human hemoglobin.  
   
   
       17 . The method of  claim 15 , wherein the hemoglobin is bovine hemoglobin.