Assisted enzyme replacement therapy

Abstract

Reagents and methods useful for the synthesis of conjugates comprising guanidinylated cyclic acetals are provided. Also provided are methods for increasing the cellular uptake of various therapeutic compounds and treatment modalities using these conjugates.

1 .- 45 . (canceled) 
     
     
         46 . A conjugate comprising a dimeric guanidinoglycoside coupled to a therapeutic compound useful for treating a viral infection, wherein each guanidinoglycoside of the dimeric guanidinoglycoside independently comprises an aminoglycoside antibiotic in which all of the ammonium groups have been converted into guanidinium groups. 
     
     
         47 . The conjugate of  claim 46 , wherein the dimeric guanidinoglycoside is coupled to the therapeutic compound through a linker. 
     
     
         48 . The conjugate of  claim 46 , wherein the therapeutic compound comprises a nucleoside. 
     
     
         49 . The conjugate of  claim 48 , wherein the nucleoside is selected from the group consisting of: 3′-azido-3′-deoxythymidine, 2′,3′-dideoxyinosine and 2′,3′-dideoxycytidine. 
     
     
         50 . The conjugate of  claim 46 , wherein the viral infection is a retroviral infection. 
     
     
         51 . The conjugate of  claim 50 , wherein the retroviral infection is selected from an HIV infection and a HBV infection. 
     
     
         52 . The conjugate of  claim 46 , wherein each guanidinoglycoside is independently selected from the group consisting of guanidino-amikacin, guanidino-gentamicin, guanidino-kanamycin, guanidino-neomycin, guanidino-netilmicin, guanidino-paromomycin, guanidino-streptomycin, and guanidino-tobramycin. 
     
     
         53 . The conjugate of  claim 46 , wherein the dimeric guanidinoglycoside comprises guanidinylated neomycin. 
     
     
         54 . The conjugate of  claim 46 , wherein the guanidinoglycoside is covalently bound to the nucleoside. 
     
     
         55 . The conjugate of  claim 46 , wherein each guanidinoglycoside of the dimeric glycoside is the same. 
     
     
         56 . The conjugate of  claim 46 , wherein each guanidinoglycoside is independently selected from the group consisting of guanidino-neomycin, guanidino-paromomycin, and guanidino-tobramycin. 
     
     
         57 . The conjugate of  claim 46 , wherein each guanidinoglycoside is guanidino-neomycin. 
     
     
         58 . A method for treating a viral infection in a mammal, the method comprising administering to the mammal a therapeutically effective amount of a conjugate comprising a dimeric guanidinoglycoside and an therapeutic compound useful for treating the disease, wherein each guanidinoglycoside of the dimeric guanidinoglycoside independently comprises an aminoglycoside antibiotic in which all of the ammonium groups have been converted into guanidinium groups. 
     
     
         59 . The method of  claim 58 , wherein the therapeutic compound comprises a nucleoside selected from the group consisting of: 3′-azido-3′-deoxythymidine, 2′,3′-dideoxyinosine and 2′,3′-dideoxycytidine. 
     
     
         60 . The method of  claim 58 , wherein the viral infection is selected from an HIV infection and a HBV infection. 
     
     
         61 . A method for increasing the cellular uptake of a therapeutic compound useful for treating a viral infection, the method comprising:
 a) coupling the therapeutic compound to a dimeric guanidinoglycoside to form a conjugate, wherein each guanidinoglycoside of the dimeric guanidinoglycoside independently comprises an aminoglycoside antibiotic in which all of the ammonium groups have been converted into guanidinium groups; and   b) delivering the conjugate to a cell.   
     
     
         62 . The method of  claim 61 , wherein the therapeutic compound comprises a nucleoside selected from the group consisting of: 3′-azido-3′-deoxythymidine, 2′,3′-dideoxyinosine and 2′,3′-dideoxycytidine. 
     
     
         63 . The method of  claim 61 , wherein the viral infection is selected from an HIV infection and a HBV infection.