Synthetic peptide and peptide conjugates and related tissue coupling methods via transglutaminase enzyme

Abstract

Peptides and conjugates thereof comprising one or more bioactive agents which can be coupled to a tissue via a transglutaminase and related methods.

We claim: 
     
         1 . A method of using transglutaminase activity to deliver a therapeutic agent, said method comprising:
 providing a peptide conjugate compound comprising a prodrug component of a therapeutic agent; a peptide component comprising at least one of a lysinyl and a glutaminyl substrate for a transglutaminase; and a terminal linear monomethoxy poly(ethylene)glycol component coupled to said peptide component; and   contacting said compound and a tissue substrate comprising at least one of a lysinyl and a glutaminyl substrate for a transglutaminase, said contact in the presence of a transglutaminase enzyme, each of said contact and said enzyme presence at least partially sufficient to bind said compound and said tissue substrate.   
     
     
         2 . The method of  claim 1  wherein said compound comprises a prodrug of a glucocorticoid. 
     
     
         3 . The method of  claim 2  wherein said glucocorticoid is hydrocortisone. 
     
     
         4 . The method of  claim 1  wherein said tissue substrate comprises an extracellular matrix component. 
     
     
         5 . The method of  claim 4  wherein said compound is bound to one of a cartilage tissue and a meniscus tissue. 
     
     
         6 . The method of  claim 1  wherein said enzyme is endogenous to said tissue substrate. 
     
     
         7 . The method of  claim 1  wherein said compound comprises a component coupling said agent to said peptide component, said coupling component hydrolyzable under physiological conditions, said method comprising hydrolyzing said compound to release said therapeutic agent. 
     
     
         8 . A method of using transglutaminase activity to deliver a glucocorticoid, said method comprising:
 providing a peptide conjugate compound comprising a prodrug component of a glucocorticoid; a peptide component comprising at least one of a lysinyl and a glutaminyl substrate for a transglutaminase; a component coupling said agent to said peptide, said coupling component hydrolysable under physiological conditions; and a terminal linear monomethoxy poly(ethylene)glycol component coupled to said peptide component;   contacting said compound and a tissue substrate comprising at least one of a lysinyl and a glutaminyl substrate for a transglutaminase, said contact in the presence of a transglutaminase enzyme, each of said contact and said enzyme presence at least partially sufficient to bind said compound and said tissue substrate; and   hydrolyzing said compound, to release said glucocorticoid from said compound.   
     
     
         9 . The method of  claim 8  wherein said glucocorticoid is hydrocortisone. 
     
     
         10 . The method of  claim 8  wherein said compound is bound to one of a cartilage tissue and a meniscus tissue. 
     
     
         11 . The method of  claim 8  wherein said enzyme is endogenous to said tissue substrate. 
     
     
         12 . A method of using transglutaminase activity to deliver a therapeutic agent, said method comprising:
 providing a peptide conjugate compound comprising a prodrug component of a therapeutic agent; a peptide component comprising a lysinyl substrate for a transglutaminase, said substrate comprising a GFKG sequence; and   contacting said compound and a tissue substrate comprising a glutaminyl substrate for a transglutaminase, said contact in the presence of a transglutaminase enzyme, each of said contact and said enzyme presence at least partially sufficient to bind said compound and said tissue substrate.   
     
     
         13 . The method of  claim 12  wherein said compound comprises a prodrug of a glucocorticoid. 
     
     
         14 . The method of  claim 13  wherein said glucocorticoid is hydrocortisone. 
     
     
         15 . The method of  claim 12  wherein said tissue substrate comprises an extracellular matrix component. 
     
     
         16 . The method of  claim 15  wherein said compound is bound to one of a cartilage tissue and a meniscus tissue. 
     
     
         17 . The method of  claim 12  wherein said enzyme is endogenous to said tissue substrate. 
     
     
         18 . A method of using transglutaminase activity to deliver a glucocorticoid, said method comprising:
 providing a peptide conjugate compound comprising a prodrug component of a glucocorticoid; a peptide component comprising a lysinyl substrate for a transglutaminase, said substrate comprising a GFKG sequence; and   contacting said compound and a tissue substrate comprising a glutaminyl substrate for a transglutaminase, said contact in the presence of a transglutaminase enzyme, each of said contact and said enzyme presence at least partially sufficient to bind said compound and said tissue substrate.   
     
     
         19 . The method of  claim 18  wherein said glucocorticoid is hydrocortisone. 
     
     
         20 . The method of  claim 19  wherein said compound is bound to one of a cartilage tissue and a meniscus tissue, said enzyme endogenous to said tissue substrate.