Cell penetrating peptides

1. A peptide, having a primary sequence structure comprised of at least three domains, having the arrangement:

N-terminus [Domain 1]-[Domain 2]-[Domain 3] C-terminus in which:

(i) Domain 1 comprises a sequence chosen from:

RXRRBRRXR

[SEQ ID NO: 81]

RBRRXRRBR,

[SEQ ID NO: 82]

or

RXRRXR

[SEQ ID NO: 74]

(ii) Domain 2 comprises a sequence chosen from:

ILFQ,

[SEQ ID NO: 86]

or

ILIQ

[SEQ ID NO: 202]

(iii) Domain 3 comprises a sequence chosen from:

RXRBRXR

[SEQ ID NO: 159]

RBRXRBR

[SEQ ID NO: 162]

RXRRXR

[SEQ ID NO: 161]

RXRXRXR

[SEQ ID NO: 160]

RXRBRX

[SEQ ID NO: 163]

MKWHK,

[SEQ ID NO: 203]

or

WKWHK

[SEQ ID NO: 204]

wherein X=aminohexanoyl, B=betaAlanine.

2. The peptide of claim 1 , wherein Domain 2 comprises a sequence chosen from ILFQY [SEQ ID NO:88], or ILIQY [SEQ ID NO:296].

3. The peptide of claim 1 , wherein Domain 2 comprises a sequence chosen from:

Z 2 Z 3 ILFQZ 4 ,

[SEQ ID NO: 89]

or

Z 2 Z 3 ILIQZ 4

[SEQ ID NO: 297]

wherein Z 2 ═I or no amino acid, Z 3 ═K, dK, H, R or no amino acid, Z 4 ═N or Y.

4. The peptide of claim 1 , wherein Domain 3 comprises a sequence chosen from:

Z 7 Z 8 MKWHK,

[SEQ ID NO: 298]

or

Z 7 Z 8 WKWHK

[SEQ ID NO: 299]

where Z 7 ═R, dR, K or dK (wherein d=D-aminoacid)

Z 8 ═R, H or K.

5. The peptide of claim 1 , wherein Domain 3 comprises a sequence chosen from:

dRRMKWHK

[SEQ ID NO: 111]

dRHMKWHK

[SEQ ID NO: 155]

dRRWKWHK

[SEQ ID NO: 157]

dKRMKWHK,

[SEQ ID NO: 156]

or

dKHWKWHK.

[SEQ ID NO: 158]

6. The peptide of claim 1 , wherein Domain 1 comprises a sequence chosen from:

(RXR) n  where n = 2, 3 or 4,

[SEQ ID NOs: 74-76]

or

RXRRXRIdR.

[SEQ ID NO: 80]

7. The peptide of claim 1 , wherein the peptide has a maximum length of 30 residues, including natural amino acids, X and B residues.

8. The peptide of claim 1 , wherein Domain 1 has a length of from 6 to 11 residues, Domain 2 has a length of from 4 to 9 residues, and Domain 3 has a length of from 4 to 15 residues, wherein the lengths include natural amino acids, X and B residues.

9. The peptide of claim 1 , comprising, or consisting of, a sequence chosen from one of SEQ ID NOs:242-295 ( FIG. 25 ) or a sequence having at least 90% sequence identity to one of SEQ ID NOs:242-295 ( FIG. 25 ).

10. The peptide of claim 1 , comprising, or consisting of, the sequence of Domains 1 to 3 or Domains 1 to 4 of one of Pip-5e, Pip-5j or Pip-51 (SEQ ID NOs:230, 234 or 236) or a sequence having at least 90% sequence identity to the sequence of Domains 1 to 3 or Domains 1 to 4 of one of Pip-5e, Pip-5j or Pip-51 (SEQ ID NOs:230, 234 or 236).

11. The peptide of claim 1 , comprising, or consisting of, a sequence chosen from one of:

Z 1 Z 2 Z 3 ILFQZ 4 Z 5 RMKWHK

[SEQ ID NO: 113]

Z 1 Z 2 Z 3 ILFQZ 4 Z 5 HMKWHK

[SEQ ID NO: 183]

Z 1 Z 2 Z 3 ILFQZ 4 Z 5 RWKWHK

[SEQ ID NO: 184]

Z 1 Z 2 Z 3 ILFQZ 4 Z 5 HWKWHK

[SEQ ID NO: 185]

Z 1 Z 2 Z 3 ILFQZ 4 RXRBRXR

[SEQ ID NO: 186]

Z 1 Z 2 Z 3 ILFQZ 4 RXRXRXR

[SEQ ID NO: 187]

Z 1 Z 2 Z 3 ILFQZ 4 RXRRXR

[SEQ ID NO: 188]

Z 1 Z 2 Z 3 ILFQZ 4 RBRXRBR

[SEQ ID NO: 189]

Z 1 Z 2 Z 3 ILFQZ 4 RXRBRXR

[SEQ ID NO: 190]

Z 1 Z 2 Z 3 ILFQZ 4 RXRBRX

[SEQ ID NO: 191]

Z 1 Z 2 Z 3 ILIQZ 4 Z 5 RMKWHK

[SEQ ID NO: 192]

Z 1 Z 2 Z 3 ILIQZ 4 Z 5 HMKWHK

[SEQ ID NO: 193]

Z 1 Z 2 Z 3 ILIQZ 4 Z 5 RWKWHK

[SEQ ID NO: 194]

Z 1 Z 2 Z 3 ILIQZ 4 Z 5 HWKWHK

[SEQ ID NO: 195]

Z 1 Z 2 Z 3 ILIQZ 4 RXRBRXR

[SEQ ID NO: 196]

Z 1 Z 2 Z 3 ILIQZ 4 RXRXRXR

[SEQ ID NO: 197]

Z 1 Z 2 Z 3 ILIQZ 4 RXRRXR

[SEQ ID NO: 198]

Z 1 Z 2 Z 3 ILIQZ 4 RBRXRBR

[SEQ ID NO: 199]

Z 1 Z 2 Z 3 ILIQZ 4 RXRBRXR

[SEQ ID NO: 200]

Z 1 Z 2 Z 3 ILIQZ 4 RXRBRX

[SEQ ID NO: 201]

wherein:

Z 1 ═(RXR) n where n=2, 3, or 4; (RBR) n where n=2, 3, or 4; (R) m where m=5, 6, 7 or 8; RXRRXRIdR [SEQ ID NO:80]; RXRRBRRXR [SEQ ID NO:81]; or RBRRXRRBR [SEQ ID NO:82];

Z 2 ═I or no amino acid

Z 3 ═K, dK, H, R or no amino acid

Z 4 ═N, Y

Z 5 ═R or dR, K or dK

wherein d=D-aminoacid.

12. The peptide of claim 1 , comprising, or consisting of, a sequence chosen from one of SEQ ID NOs:34-73 ( FIG. 16 ), or a sequence having at least 90% sequence identity to one of SEQ ID NOs:34-73 ( FIG. 16 ).

13. The peptide of claim 1 , wherein the peptide further comprises a linker sequence at the C-terminus.

14. The peptide of claim 13 , wherein the linker sequence is chosen from BCys, XCys, Cys, GGCys, BBCys, BXCys, XBCys, BX, or XB.

15. The peptide of claim 1 , wherein the peptide is chemically conjugated to a cargo molecule.

16. The peptide of claim 15 , wherein the conjugation is at the C-terminus of the peptide.

17. The peptide of claim 1 , wherein the peptide is chemically conjugated to a cargo molecule, wherein the cargo molecule is chosen from a nucleic acid, peptide nucleic acid (PNA), phosphorodiamidate morpholino oligonucleotide (PMO), locked nucleic acid (LNA), antisense oligonucleotide, short interfering RNA (siRNA), peptide, cyclic peptide, protein, or drug.

18. The peptide of claim 15 , wherein the cargo molecule has a molecular weight less than 5,000Da.

19. The peptide of claim 1 , wherein the peptide is chemically conjugated to a cargo molecule, wherein the cargo molecule is PNADMD [SEQ ID NO:115] or PMODMD [SEQ ID NO:206] or a molecule having at least 90% sequence identity to one of PNADMD [SEQ ID NO:115] or PMODMD [SEQ ID NO:206].

20. A pharmaceutical composition or medicament comprising a peptide according to claim 1 .

21. The pharmaceutical composition or medicament of claim 20 further comprising a pharmaceutically acceptable diluent, adjuvant or carrier.