Lipoprotein targeting protease inhibitors and uses

Abstract

Described herein is the design and construction of a class of lipoprotein targeting protease inhibitors. Small peptides with protease inhibitor activity are conjugated to hydrophobic, lipoprotein targeting molecules using, for instance, amine reactive chemistry. Methods of use of the resultant lipoprotein targeting protease inhibitor (antiprotease) molecules are also described. Also described is the production and use of protease inhibitor enriched HDL particles, as well as A1AT-peptide-enriched HDL particles, and their use in various therapeutic contexts.

1 . A method, comprising administering to a subject a composition comprising: 
       
         
           
                 
                 
               
                     
                   (SEQ ID NO: 4) 
                 
                     
                   VitE-AAPV; 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 5) 
                 
                     
                   VitE-PEG-AAPV; 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 6) 
                 
                     
                   VitE-PEG-AAPV-CMK; 
                 
                     
                   or 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 7) 
                 
                     
                   VitE-AAPV-CMK. 
                 
             
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         2 . The method of  claim 1 , wherein the vitamin E (VitE) is selected from the group consisting of alpha-tocopherol, beta-tocopherol, gamma-tocopherol, delta-tocopherol, alpha-tocotrienol, beta-tocotrienol, gamma-tocotrienol, and delta-tocotrienol 
     
     
         3 . The method of  claim 1 , wherein the composition further comprises a pharmaceutically acceptable carrier. 
     
     
         4 . The method of  claim 3 , wherein the pharmaceutically acceptable carrier is a lipid. 
     
     
         5 . The method of  claim 1 , wherein the composition is administered in a liposome or reconstituted high density lipoprotein. 
     
     
         6 . The method of  claim 1 , wherein the method is a method of treating alpha-1-antitrypsin (A1AT) deficiency, hyperlipidemia, atherosclerosis, restenosis, peripheral vascular disease, acute coronary syndrome, reperfusion myocardial injury, asthma, chronic pulmonary obstructive disorder, and/or emphysema. 
     
     
         7 . The method of  claim 1 , wherein the composition is administered to the subject by injection or infusion. 
     
     
         8 . The method of  claim 7 , wherein the composition is administered to the subject intravenously, subcutaneously, intra-arterially, or intrapericardially. 
     
     
         9 . The method of  claim 1 , wherein the composition is incorporated in an implantable device. 
     
     
         10 . The method of  claim 9 , wherein the implantable device is a stent.