Feedback Prodrug

Abstract

Compounds and methods for use in selectively inhibiting a lytic enzyme based on feedback inhibition. The conjugated compound serves as a substrate for a lytic enzyme. Cleavage of the conjugated compound by the lytic enzyme releases an inhibitor of the enzyme.

1 . A conjugated compound comprising:
 a first constituent comprising an enzymatic substrate; and   a second constituent covalently linked to the first constituent, the second constituent comprising an inhibitor moiety that, when released from the conjugated compound, inhibits the activity of an enzyme;   
       wherein the covalent linkage between the first and second constituents can be cleaved by the enzyme to release the inhibitor moiety. 
     
     
         2 . The conjugated compound of  claim 1   wherein the enzymatic substrate comprises a carbohydrate moiety;   the inhibitor moiety inhibits the activity of a glycosidase;   
       and the covalent linkage between the first and second constituents can be cleaved by the glycosidase to release the inhibitor moiety. 
     
     
         3 . The conjugated compound of  claim 1   wherein the enzymatic substrate comprises a polypeptide moiety;   the inhibitor moiety inhibits the activity of a protease;   
       and the covalent linkage between the first and second constituents can be cleaved by the protease to release the inhibitor moiety. 
     
     
         4 . The conjugated compound of  claim 1   wherein the enzymatic substrate comprises a kinase substrate;   the inhibitor moiety inhibits the activity of a kinase;   
       and the covalent linkage between the first and second constituents can be cleaved by the kinase to release the inhibitor moiety. 
     
     
         5 . The conjugated compound of  claim 1  wherein the second constituent further comprises a linking group, such that the first constituent is covalently linked to a linking group, which in turn is covalently linked to the inhibitor moiety. 
     
     
         6 . The conjugated compound of  claim 1  wherein enzymatic cleavage of the covalent linkage between the first constituent and the second constituent releases the second constituent, which then self-fragments to yield the inhibitor moiety. 
     
     
         7 . The conjugated compound of  claim 1  wherein the first or second constituent further comprises a moiety that increases metabolic stability or facilitates cellular uptake. 
     
     
         8 . The conjugated compound of  claim 7  wherein the first or second constituent is acetylated. 
     
     
         9 . The conjugated compound of  claim 2  wherein the carbohydrate moiety is acetylated. 
     
     
         10 . The conjugated compound of  claim 2  wherein the inhibitor moiety comprises mannostatin A or a derivative thereof. 
     
     
         11 . A method for treating a disease or condition comprising administering to a subject in need thereof, a conjugated compound of  claim 1 . 
     
     
         12 . A method for treating a disease or condition selected from the group consisting of a cancer, a precancerous condition, diabetes, hepatitis, a viral infection, a bacterial infection, a fungal infection, a genetic disorder, and a lysosomal storage disease; the method comprising administering to a subject in need thereof, the conjugated compound of  claim 2 .