Transporters Comprising Spaced Arginine Moieties

Abstract

The present invention provides compositions and methods for enhancing transport of biologically active compounds across biological membranes and across and into animal epithelial or endothelial tissues. The composition includes a biologically active agent and a transport moiety. The transport moiety includes a structure selected from the group consisting of (ZYZ) n Z, (ZY) n Z, (ZYY) n Z and (ZYYY) n Z. Subunit “Z” is L-arginine or D-arginine, and subunit “Y” is an amino acid that does not comprise an amidino or guanidino moiety. Subscript “n” is an integer ranging from 2 to 10. The method for enhancing transport involves the administration of the aforementioned composition.

1 . A composition comprising a biologically active compound and a transport moiety, wherein the transport moiety comprises a structure selected from the group consisting of (ZYZ) n Z, (ZY) n Z, (ZYY) n Z and (ZYYY) n Z, wherein each Z is L-arginine or D-arginine, and each Y is independently an amino acid that does not comprise an amidino or guanidino moiety, and wherein n is an integer of from 2 to 10. 
   
   
       2 . The composition according to  claim 1 , wherein each Y is independently selected from the group consisting of alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, serine, threonine, valine, tryptophan, hydroxyproline, tyrosine, γ-amino butyric acid, β-alanine, sarcosine and ε-amino caproic acid. 
   
   
       3 . The composition according to  claim 1 , wherein the transport moiety comprises the structure (ZYZ) n Z, and wherein n is an integer ranging from 2 to 5. 
   
   
       4 . The composition according to  claim 1 , wherein the transport moiety comprises the structure (ZY) n Z, and wherein n is an integer ranging from 4 to 10. 
   
   
       5 . The composition according to  claim 1 , wherein the transport moiety comprises the structure (ZYY) n Z, and wherein n is an integer ranging from 4 to 10. 
   
   
       6 . The composition according to  claim 1 , wherein the transport moiety comprises the structure (ZYYY) n Z, and wherein n is an integer ranging from 4 to 10. 
   
   
       7 . The composition according to  claim 1 , wherein the transport moiety is attached to the biologically active compound by a linking moiety to form a conjugate. 
   
   
       8 . The composition according to  claim 1 , wherein Y is a gene-encoded amino acid. 
   
   
       9 . The composition according to  claim 1 , wherein Y is an amino acid other than a gene-encoded amino acid. 
   
   
       10 . The composition according to  claim 3 , wherein each Y is independently selected from the group consisting of glycine, γ-amino butyric acid, β-alanine and ε-amino caproic acid, and n is 3 or 4. 
   
   
       11 . The composition according to  claim 4 , wherein each Y is independently selected from the group consisting of glycine, γ-amino butyric acid, β-alanine and ε-amino caproic acid, and n is 6, 7 or 8. 
   
   
       12 . The composition according to  claim 5 , wherein each Y is independently selected from the group consisting of glycine, γ-amino butyric acid, β-alanine and ε-amino caproic acid, and n is 6, 7 or 8. 
   
   
       13 . The composition according to  claim 6 , wherein each Y is independently selected from the group consisting of glycine, γ-amino butyric acid, β-alanine and ε-amino caproic acid, and n is 6, 7 or 8. 
   
   
       14 . The composition according to  claim 7 , wherein the conjugate has the following structure: 
     
       
         
         
             
             
         
       
       wherein:
 R 1  is the biologically active compound; 
 X is a linkage between a functional group on the biologically active compound and a functional group on the linker between R 1  and R 3 ; 
 Y is a linkage between a functional group on the transport moiety and a functional group on the linker between R 1  and R 3 ; 
 A is N or CH; 
 R 2  is hydrogen, alkyl, aryl, arylalkyl, acyl or allyl; 
 R 3  is a transport moiety; 
 k and m are independently either 1 or 2; and 
 n is an integer of from 1 to 10. 
 
     
   
   
       15 . The composition according to  claim 14 , wherein each of X and Y is independently selected from the group consisting of —C(O)O—, —C(O)NH—, —OC(O)NH—, —S—S—, —C(S)O—, —C(S)NH—, —NHC(O)NH—, —SO 2 NH—, —SONH—, phosphate, phosphonate and phosphinate. 
   
   
       16 . The composition according to  claim 14 , wherein each of X and Y is independently selected from the group consisting of —C(O)O—, —C(O)NH—, —OC(O)NH— and —NHC(O)NH—. 
   
   
       17 . The composition according to  claim 7 , wherein the conjugate has the following structure: 
     
       
         
         
             
             
         
       
       wherein:
 R 1  is the biologically active compound; 
 X is a linkage between a functional group on the biologically active compound and a functional group on the linker between R 1  and R 3 ; 
 Y is a linkage between a functional group on the transport moiety and a functional group on the linker between R 1  and R 3 ; 
 R 3  is a transport moiety; 
 R 4  is S, O, NR 6  or CR 7 R 8 ; 
 R 5  is OH, SH or NHR 6 ; 
 R 6  is hydrogen, alkyl, aryl, arylalkyl, acyl or allyl; 
 R 7  and R 8  are independently hydrogen, alkyl or arylalkyl; and 
 k and m are independently either 1 or 2. 
 
     
   
   
       18 . The composition according to  claim 17 , wherein each of X and Y is independently selected from the group consisting of —C(O)O—, —C(O)NH—, —OC(O)NH—, —S—S—, —C(S)O—, —C(S)NH—, —NHC(O)NH—, —SO 2 NH—, —SONH—, phosphate, phosphonate and phosphinate. 
   
   
       19 . The composition according to  claim 17 , wherein each of X and Y is independently selected from the group consisting of —C(O)O—, —C(O)NH—, —OC(O)NH— and —NHC(O)NH—. 
   
   
       20 . The composition according to  claim 7 , wherein the conjugate has the following structure: 
     
       
         
         
             
             
         
       
       wherein:
 R 1  is the biologically active compound; 
 X is a linkage between a functional group on the biologically active compound and a functional group on the linker between R 1  and R 3 ; 
 Y is a linkage between a functional group on the transport moiety and a functional group on the linker between R 1  and R 3 ; 
 R 3  is the transport moiety; 
 R 5  is H, OH, SH or NHR 6 ; 
 R 6  is hydrogen, alkyl, aryl, arylalkyl, acyl or allyl; and 
 k is 1 or 2. 
 
     
   
   
       21 . The composition according to  claim 20 , wherein each of X and Y is independently selected from the group consisting of —C(O)O—, —C(O)NH—, —OC(O)NH—, —S—S—, —C(S)O—, —C(S)NH—, —NHC(O)NH—, —SO 2 NH—, —SONH—, phosphate, phosphonate and phosphinate. 
   
   
       22 . The composition according to  claim 20 , wherein each of X and Y is independently selected from the group consisting of —C(O)O—, —C(O)NH—, —OC(O)NH— and —NHC(O)NH—. 
   
   
       23 . The composition according to  claim 7 , wherein the conjugate has the following structure: 
     
       
         
         
             
             
         
       
       wherein:
 R 1  is the biologically active compound; 
 X is a linkage between a functional group on the biologically active compound and a functional group on the linker between R 1  and R 3 ; 
 Y is a linkage between a functional group on the transport moiety and a functional group on the linker between R 1  and R 3 ; 
 Ar is a substituted or unsubstituted aryl group, wherein the methylene and oxygen substituents are either ortho or para to one another; 
 R 3  is the transport moiety; 
 R 4  is S, O, NR 6  or CR 7 R 8 ; 
 R 5  is H, OH, SH, CONHR 6  or NHR 6 ; 
 R 6  is hydrogen, alkyl, aryl, arylalkyl, acyl or allyl; 
 R 7  and R 8  are independently hydrogen or alkyl; and, 
 k and m are independently either 1 or 2. 
 
     
   
   
       24 . The composition according to  claim 23 , wherein each of X and Y is independently selected from the group consisting of —C(O)O—, —C(O)NH—, —OC(O)NH—, —S—S—, —C(S)O—, —C(S)NH—, —NHC(O)NH—, —SO 2 NH—, —SONH—, phosphate, phosphonate and phosphinate. 
   
   
       25 . The composition according to  claim 23 , wherein each of X and Y is independently selected from the group consisting of —C(O)O—, —C(O)NH—, —OC(O)NH— and —NHC(O)NH—. 
   
   
       26 . The composition according to  claim 12 , wherein A is N, R 2  is benzyl, k, m and n are 1, and X is —C(O)O—. 
   
   
       27 . The composition according to  claim 13 , wherein R 4  is S, R 5  is NHR 6 , R 6  is hydrogen, methyl, allyl, butyl or phenyl, k and m are 1 and X is —C(O)O—. 
   
   
       28 . The composition according to  claim 14 , wherein R 5  is NHR 6 , R 6  is hydrogen, methyl, allyl, butyl or phenyl, k is 2 and X is —C(O)O—. 
   
   
       29 . The composition according to  claim 15 , wherein Ar is an unsubstituted aryl group, R 4  is S, R 5  is NHR 6 , R 6  is hydrogen, methyl, allyl, butyl or phenyl, k and m are 1 and X is —C(O)O—. 
   
   
       30 . A method for increasing the transport of a biologically active compound across a biological membrane comprising:
 administering a composition comprising a biologically active compound and a transport moiety, wherein the transport compound comprises a structure selected from the group consisting of (ZYZ) n Z, (ZY) n Z, (ZYY) n Z and (ZYYY) n Z, wherein Z is L-arginine or D-arginine, and wherein Y is an amino acid that does not comprise an amidino or guanidino moiety, and wherein n is an integer ranging from 2 to 10,   wherein transport of the biologically active compound across the biological membrane is increased relative to transport of the biologically active compound in the absence of said transport moiety.   
   
   
       31 . The method according to  claim 20 , wherein the biologically active compound is attached to the transport moiety by a linking moiety to form a conjugate. 
   
   
       32 . The method of  claim 21 , wherein the conjugate has the following structure: 
     
       
         
         
             
             
         
       
       wherein:
 R 1  is the biologically active compound; 
 X is a linkage between a functional group on the biologically active compound and a functional group on the linker between R 1  and R 3 ; 
 Y is a linkage between a functional group on the transport moiety and a functional group on the linker between R 1  and R 3 ; 
 A is N or CH; 
 R 2  is hydrogen, alkyl, aryl, arylalkyl, acyl or allyl; 
 R 3  is a transport moiety; 
 k and m are independently either 1 or 2; and 
 n is an integer of from 1 to 10. 
 
     
   
   
       33 . The method of  claim 21 , wherein the conjugate has the following structure: 
     
       
         
         
             
             
         
       
       wherein:
 R 1  is the biologically active compound; 
 X is a linkage between a functional group on the biologically active compound and a functional group on the linker between R 1  and R 3 ; 
 Y is a linkage between a functional group on the transport moiety and a functional group on the linker between R 1  and R 3 ; 
 R 3  is a transport moiety; 
 R 4  is S, O, NR 6  or CR 7 R 8 ; 
 R 5  is OH, SH or NHR 6 ; 
 R 6  is hydrogen, alkyl, aryl, arylalkyl, acyl or allyl; 
 R 7  and R 8  are independently hydrogen, alkyl or arylalkyl; and 
 k and m are independently either 1 or 2. 
 
     
   
   
       34 . The method of  claim 21 , wherein the conjugate has the following
 structure:   
     
       
         
         
             
             
         
       
       wherein:
 R 1  is the biologically active compound; 
 X is a linkage between a functional group on the biologically active compound and a functional group on the linker between R 1  and R 3 ; 
 Y is a linkage between a functional group on the transport moiety and a functional group on the linker between R 1  and R 3 ; 
 R 3  is the transport moiety; 
 R 5  is H, OH, SH or NHR 6 ; 
 R 6  is hydrogen, alkyl, aryl, arylalkyl, acyl or allyl; and 
 k is 1 or 2. 
 
     
   
   
       35 . The method of  claim 21 , wherein the conjugate is of the following structure: 
     
       
         
         
             
             
         
       
       wherein:
 R 1  is the biologically active compound; 
 X is a linkage between a functional group on the biologically active compound and a functional group on the linker between R 1  and R 3 ; 
 Y is a linkage between a functional group on the transport moiety and a functional group on the linker between R 1  and R 3 ; 
 Ar is a substituted or unsubstituted aryl group, wherein the methylene and oxygen substituents are either ortho or para to one another; 
 R 3  is the transport moiety; 
 R 4  is S, O, NR 6  or CR 7 R 8 ; 
 R 5  is H, OH, SH, CONHR 6  or NHR 6 ; 
 R 6  is hydrogen, alkyl, aryl, arylalkyl, acyl or allyl; 
 R 7  and R 8  are independently hydrogen or alkyl; and, 
 k and m are independently either 1 or 2.