Peptide-peptidase inhibitor conjugates and methods of using same

Abstract

Peptide-peptidase inhibitor conjugate molecules are disclosed. These conjugate molecules are useful as agents for the treatment and prevention of metabolic and cardiovascular diseases, disorders, and conditions. Such diseases, conditions and disorders include, but are not limited to, hypertension, dyslipidemia, cardiovascular disease, eating disorders, insulin-resistance, obesity, and diabetes mellitus of any kind, and other diabetes-related disorders.

1 . A peptide-peptidase inhibitor conjugate comprising a peptide covalently linked to a peptidase inhibitor. 
     
     
         2 . The conjugate according to  claim 1  wherein the peptide is an analog, derivative or hybrid of a native peptide hormone. 
     
     
         3 . The conjugate according to  claim 1  wherein the peptidase inhibitor reduces the activity of a regulatory peptidase. 
     
     
         4 . The conjugate according to  claim 1  wherein the peptidase inhibitor is selected from a group consisting of an angiotensin converting enzyme inhibitor, a vasopeptidase inhibitor, endothelial converting enzyme inhibitor, human neutral endopeptidase inhibitor, dipeptidyl peptidase IV inhibitor, aminopeptidase inhibitor, cysteine protease inhibitor, serine protease inhibitor, and carboxypeptidase inhibitor. 
     
     
         5 . The conjugate according to  claim 1  wherein the plasma half-life of the conjugate is greater than the plasma half-life of the peptide not conjugated to the peptidase inhibitor. 
     
     
         6 . The conjugate according to  claim 1 , wherein the peptide is a hybrid peptide hormone. 
     
     
         7 . The conjugate according to  claim 6 , Wherein the hybrid peptide hormone comprises one or more hormone portions selected from the group consisting of GLP-1, a GLP-2, a GIP, an exendin, a PYY, an amylin, a calcitonin, a leptin, and analogs thereof. 
     
     
         8 . The conjugate according to  claim 2 , wherein the peptide is selected from a group consisting of a GLP-1, a GLP-2, a GIP, an exendin, a PYY, an amylin, a calcitonin, a leptin, and analogs thereof. 
     
     
         9 . The conjugate according to  claim 2 , wherein the peptide is a agonist of the hormone. 
     
     
         10 . The conjugate according to  claim 2 , wherein the peptide is an antagonist of the hormone. 
     
     
         11 . The use of a peptide-peptidase inhibitor conjugate of  claim 1  for the preparation of a pharmaceutical composition for decreasing degradation of a peptidase-sensitive peptide in a subject. 
     
     
         12 . The use of a peptide-peptidase inhibitor conjugate of  claim 1  for the preparation of a pharmaceutical composition for increasing plasma concentration of a biologically active, peptidase-sensitive peptide in a subject. 
     
     
         13 . (canceled) 
     
     
         14 . A method of decreasing degradation of a peptidase-sensitive peptide in a subject comprising administering a composition comprising the peptide-peptidase inhibitor conjugate compound according to  claim 1  to a subject in an amount effective to decrease degradation of a peptidase-sensitive peptide. 
     
     
         15 . A method of increasing plasma concentration of a biologically active, peptidase-sensitive peptide in a subject comprising administering a composition comprising the peptide-peptidase inhibitor according to  claim 1  to a subject in an amount effective to increase plasma half-life of a biologically active, peptidase-sensitive peptide.