Transporters comprising spaced arginine moieties

1. A composition comprising a conjugate of a biologically active compound, a transport moiety and a self-immolating linker moiety linking the biologically active compound and the transport moiety, wherein the transport moiety comprises a structure selected from the group consisting of (ZY) n Z, (ZYZ) 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, wherein the conjugate has a structure selected from

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 ;

Q 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;

Ar is a substituted or unsubstituted aryl group, wherein the methylene and oxygen substituents are either ortho or para to one another;

R 2 is hydrogen, alkyl, aryl, arylalkyl, acyl or allyl;

R 3 is the transport moiety;

R 4 is S, O, NR 6 or CR 7 R 8 ;

R 4a is S, O, NR 6 or CR 7a R 8a ;

R 5 is OH, SH, NHR 6 , or —CONH 2 ;

R 5a is H, OH, SH, NHR 6 , or —CONH 2 ;

R 6 is hydrogen, alkyl, aryl, arylalkyl, acyl or allyl;

R 7 and R 8 are independently hydrogen, alkyl or arylalkyl; and

R 7a and R 8a are independently hydrogen or alkyl; and

k and m are independently either 1 or 2; and

n1 is an integer of from 1 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 Y is a gene-encoded amino acid.

8. The composition according to claim 1 , wherein Y is an amino acid other than a gene-encoded amino acid.

9. 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.

10. A composition, comprising a conjugate of:

a biologically active compound, a transport moiety and a self-immolating linker moiety linking the biologically active compound and the transport moiety,

wherein the transport moiety comprises a structure selected from the group consisting of (ZY) n Z, (ZYZ) n Z, (ZYY) n Z, and (ZYYY) n Z,

each Z is L-arginine or D-arginine, each Y is independently glycine, γ-amino butyric acid, β-alanine or ε-amino caproic acid, and n is 6, 7 or 8, wherein the conjugate has a structure selected from

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 ;

Q 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;

Ar is a substituted or unsubstituted aryl group, wherein the methylene and oxygen substituents are either ortho or para to one another;

R 2 is hydrogen, alkyl, aryl, arylalkyl, acyl or allyl;

R 3 is the transport moiety;

R 4 is S, O, NR 6 or CR 7 R 8 ;

R 4a is S, O, NR 6 or CR 7a R 8a ;

R 5 is OH, SH, NHR 6 , or —CONH 2 ;

R 5a is H, OH, SH, NHR 6 , or —CONH 2 ;

R 6 is hydrogen, alkyl, aryl, arylalkyl, acyl or allyl;

R 7 and R 8 are independently hydrogen, alkyl or arylalkyl; and

R 7a and R 8a are independently hydrogen or alkyl; and

k and m are independently either 1 or 2; and

n1 is an integer of from 1 to 10.

11. 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.

12. 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.

13. The composition according to claim 1 , wherein the conjugate has the following structure:

14. The composition according to claim 13 , wherein each of X and Q is independently selected from the group consisting of —C(O)O—, —O—C(O)—, —C(O)NH—, —NH—C(O)—, —OC(O)NH—, —S—S—, —C(S)O—, —C(S)NH—, —NHC(O)NH—, —SO 2 NH—, —SONH—, phosphate, phosphonate and phosphinate.

15. The composition according to claim 13 , wherein each of X and Q is independently selected from the group consisting of —C(O)O—, —O—C(O)—, —C(O)NH—, —NH—C(O)—, —OC(O)NH— and —NHC(O)NH—.

16. The composition according to claim 1 , wherein the conjugate has the following structure:

17. The composition according to claim 16 wherein each of X and Q is independently selected from the group consisting of —C(O)O—, —O—C(O)—, —C(O)NH—, —NH—C(O)—, —OC(O)NH—, —S—S—, —C(S)O—, —C(S)NH—, —NHC(O)NH—, —SO 2 NH—, —SONH—, phosphate, phosphonate and phosphinate.

18. The composition according to claim 16 , wherein each of X and Q is independently selected from the group consisting of —C(O)O—, —O—C(O)—, —C(O)NH—, —NH—C(O)—, —OC(O)NH— and —NHC(O)NH—.

19. The composition according to claim 1 , wherein the conjugate has the following structure:

20. The composition according to claim 19 , wherein each of X and Q is independently selected from the group consisting of —C(O)O—, —O—C(O)—, —C(O)NH—, —NH—C(O)—, —OC(O)NH—, —S—S—, —C(S)O—, —C(S)NH—, —NHC(O)NH—, —SO 2 NH—, —SONH—, phosphate, phosphonate and phosphinate.

21. The composition according to claim 19 , wherein each of X and Q is independently selected from the group consisting of —C(O)O—, —O—C(O)—, —C(O)NH—, —NH—C(O)—, —OC(O)NH— and —NHC(O)NH—.

22. The composition according to claim 1 , wherein the conjugate has the following structure:

23. The composition according to claim 22 , wherein each of X and Q is independently selected from the group consisting of —C(O)O—, —O—C(O)—, —C(O)NH—, —NH—C(O)—, —OC(O)NH—, —S—S—, —C(S)O—, —C(S)NH—, —NHC(O)NH—, —SO 2 NH—, —SONH—, phosphate, phosphonate and phosphinate.

24. The composition according to claim 22 , wherein each of X and Q is independently selected from the group consisting of —C(O)O—, —O—C(O)—, —C(O)NH—, —NH—C(O)—, —OC(O)NH— and —NHC(O)NH—.

25. The composition according to claim 15 , wherein A is N, R 2 is benzyl, k, m and n1 are 1, and X is —OC(O)—.

26. A method for increasing the transport of a biologically active compound across a biological membrane comprising:

administering a composition comprising a conjugate of according to claim 1 .

27. The method of claim 26 , wherein the conjugate has the following structure:

28. The method of claim 26 , wherein the conjugate has the following structure:

29. The method of claim 26 , wherein the conjugate has the following structure:

30. The method of claim 26 , wherein the conjugate is of the following structure:

31. The composition of claim 1 , wherein said linker moiety covalently links the biologically active compound and the transport moiety.

32. The composition of claim 1 , wherein said linker moiety capable of self-immolation is configured so as to undergo intramolecular cleavage.

33. The composition of claim 1 , wherein said linker moiety comprises a half-life in the range of between about 10 minutes and about 24 hours in water at 37° C. and at a pH of approximately 7.4.