Intracellular targeting of oligonucleotides

HK40138645APending Publication Date: 2026-10-09ENTRADA THERAPEUTICS INC
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Patent Information

Application Number
HK62026126347
Authority / Receiving Office
HK · HK
Patent Type
Applications
Current Assignee / Owner
Priority Date
2024-06-28
Filing Date
2026-07-20
Publication Date
2026-10-09
Estimated Expiration
2044-08-15

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Abstract

Compounds are provided include a. cyclic cell penetrating peptide (cCPP) and one or more linkers comprising, an amino acid component, a. polyethylene glycol component, a hydrophobic component, or a combination thereof. In embodiments, the compound includes an exocyclic peptide (EP). In embodiments, the compound does not include an exocyclic peptide.
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Description

HKP2620750 Invention Title: Intracellular Targeting of Oligonucleotides Abstract: The provided compounds comprise a cyclic cell-penetrating peptide (cCPP) and one or more linkers, said one or more linkers comprising an amino acid component, a polyethylene glycol component, a hydrophobic component, or a combination thereof. In an embodiment, the compound comprises an exocyclic peptide (EP). In an embodiment, the compound does not contain an exocyclic peptide. Abstract

Claims

CLAIMS1. An endosomal escape vehicle (EEV) comprising the structure:whereinEP is a linear exocyclic peptide; cCPP is a cyclic cell penetrating peptide;L1and L2, are, independently, a linker arm;Aindicates L- or D-stereochemistry; y' is an integer from 1 to 5; and M comprises a reactive handle.

2. The EEV of claim 1, wherein L1comprises a polyethylene glycol component (PEG)x', an amino acid component (AA)ar, , or a combination thereof, wherein a' is an integer from 0-12 and x* is an integer from 0-12.

3. The EEV of claim 1 or 2, wherein L1comprises (PEG)xrandx' is an integer from 1 to 12.

4. The EEV of claim 2, wherein x' is an integer from 0, 2, 4, 8, or 12.The EEV of any of claims 2-4, wherein x' is 0 or 2.

6. The EEV of any of claims 2-5, wherein (AA)a' comprises one or more amino acid residues selected from lysine (K), arginine (R), histidine (H), glycine (G), 0-alanine (B), phenylalanine (F), proline (P), valine (V), or combinations thereof.

7. The EEV of claim 6, wherein (AA)arcomprises at least one charged amino acid.

8. The EEV of claim 6 or 7, wherein a' is an integer from 1-12.

9. The EEV of claim 6 or 7, wherein a' is an integer from 1 -8.

10. The EEV of claim 6 or 7, wherein a' is an integer from 2-5.

11. The EEV of any of claims 1-10, wherein L2comprises one or more polyethylene glycol components (PEG)z', (PEG)z", one or more amino acid components (AA)b', (AA)b", one or more hydrophobic components (Xor), (X°"),or acombination thereof, wherein b' and b" are, independently, an integer from 0-12 and z' and z" are, independently, an integer from 0-12.

12. The EEV of claim 11, wherein L2comprises (PEG)zr, (PEG)z",or a combination thereof and z' and z" are, independently, an integer from 1 to 12.

13. The EEV of claim 11, wherein L2comprises (PEG)Z-, (PEG)Z-, or a combination thereof and z' and z" are, independently, 2, 4, 8, or 12.

14. The EEV of claim 11, wherein L2comprises (PEG)z', and z' is 2, 4, 8, or 12.

15. The EEV of claim 11, wherein L2comprises (PEG)z' and (PEG)z",and z' and z" are, independently, 2, 4, 8, or 12.

16. The EEV of any of claims 11-15, wherein (AA)b' and (AA)b" comprise one or more amino acid residues selected from lysine (K), arginine (R), histidine (H), glycine (G), P-alanine (B), phenylalanine (F), proline (P), valine (V), or combinations thereof.

17. The EEV of claim 16, wherein (AA)b' and (AA)b" comprise at least one charged amino acid.

18. The EEV of claim 16 or 17, wherein b' and b" are, independently, an integer from 1-12.

19. The EEV of claim 16 or 17, wherein b' and b" are, independently, an integer from 1-8.

20. The EEV of claim 16 or 17, wherein b' and b" are, independently, an integer from 2-5.

21. The EEV of any of claims 11-20, wherein L2comprises one or more hydrophobic components (Xor), (X°') .

22. The EEV of claim 21, wherein X0' and X°" are the same.

23. The EEV of claim 21, wherein X°' and X°" are different24. The EEV of claim 1, wherein L1, L2, cCPP or a combination thereof comprises a hydrophobic component (X).

25. The EEV of any of claims 22-24, wherein the hydrophobic components (XOf), (X°') are, independently, selected from Nal, dNal, or Bip.

26. The EEV of claim 1, comprising a structure selected from:Formula (B):Formula (BB):wherein:x' is an integer from 0 to 12; j' is 0, 1, or 2, wherein j' is 0 when x' is 0; z' is an integer from 0 to 12; j" is 0, 1 , or 2, wherein j" is 0 when z' is 0; z" is an integer from 0 to 12; j"' is 0, 1, or 2, wherein j'" is 0 when z" is 0;X°' and X°" each, individually, comprise a hydrophobic component;K#is D-lysine or L-lysine residue;(AA)b' and (AA)b" are each an amino acid (AA) component comprising at least one amino acid residue; b' is an integer from 0 to 12; and b" is an integer from 0 to 12.

27. The EEV of claim 1, comprising a structure selected from:15 Formula (G):20Formula (.J):wherein: x* is an integer from 0 to 12; j' is 0, 1, or 2, wherein j' is 0 when x' is 0; z' is an integer from 0 to 12; j" is 0, 1, or 2, wherein j" is 0 when z' is 0; z" is an integer from 0 to 12; j"' is 0, 1, or 2, wherein j'" is 0 when z" is 0;X°' comprises a hydrophobic component;K#is D-lysine or L-lysine residue;(AA)a', (AA)b', and (AA)b" are each an amino acid (AA) component comprising at least one amino acid residue; a' is an integer from 0 to 12; b' is an integer from 0 to 12; and b" is an integer from 0 to 12.

28. The EEV of claim 1, comprising a structure selected from:Formula (R):20Formula (B):wherein: x' is an integer from 0 to 12; j' is 0, 1, or 2, wherein j' is 0 when x' is 0; z' is an integer from 0 to 12; j" is 0, 1, or 2, wherein j" is 0 when z' is 0; and X°' comprises a hydrophobic component.

29. The EEV any of claims 1-28, wherein EP comprises all D-amino acids; and cCPP comprises D-amino acids, achiral amino acids and AAsc, wherein AAsc is an amino acid side chain and AAsc conjugates the cCPP to the linker.

30. An EEV comprising the structure of Formula (AA):Formula (AA):(AA); wherein:Ac is an acetyl group; cCPP is a cyclic cell penetrating peptide;L2is a linker arm;Aindicates L- or D-stereochemistry y' is an integer from 1 to 5; andM is a reactive handle.

31. The EEV of claim 30, comprising a structure selected from:Formula (N):5Formula (Q):wherein: z' is an integer from 0 to 12; j" is 0, 1, or 2, wherein j" is 0 when z' is 0;X°' is a hydrophobic component;K#is D-lysine or L-lysine residue;(AA)b' is an amino acid (AA) component comprising at least one amino acid residue; and b' is an integer from 0 to 12.

32. The EEV of any of claims 1 to 31, wherein M comprises -OH,wherein y" is an integer from 1 to 4.

33. A compound comprising an EEV-cargo conjugate having the structure of Formula (A-l):wherein:EP is a linear exocyclic peptide; cCPP is a cyclic cell penetrating peptide;L1and L2, are, independently, a linker arm;Aindicates D- or L-stereochemistry; y' is an integer from 1 to 5;M' is a bonding group.

34. The compound of claim 33, wherein L1comprises a polyethylene glycol component (PEG)xz, an amino acid component (AA)az, or a combination thereof, wherein a' is an integer from 0-12 and xzis an integer from 0-12.

35. The compound of claim 33 or 34, wherein L1comprises (PEG)x' andx' is an integer from 1 to 12.

36. The compound of claim 34, wherein x' is an integer from 0, 2, 4, 8, or 12.

37. The compound of any of claims 34-36, wherein x' is 0 or 2.

38. The compound of any of claims 34-37, wherein (AA)a' comprises one or more amino acid residues selected from lysine (K), arginine (R), histidine (H), glycine (G), 0-alanine (B), phenylalanine (F), proline (P), valine (V), or combinations thereof.

39. The compound of claim 34, wherein (AA)a' comprises at least one charged amino acid.

40. The compound of claim 38 or 39, wherein a' is an integer from 1-12.

41. The compound of claim 38 or 39, wherein a' is an integer from 1-8.

42. The compound of claim 38 or 39, wherein a' is an integer from 2-5.

43. The compound of any of claims 33-42, wherein L2comprises one or more polyethylene glycol components (PEG)z', (PEG)z" , one or more amino acid components (AA)b', (AA)b", one or more hydrophobic components (XOf), (X°"), or a combination thereof, wherein b' and b" are, independently, an integer from 0-12 and z’ and z” are, independently, an integer from 0-12.

44. The compound of claim 43, wherein L2comprises (PEG)zr, (PEG)z", or a combination thereof and z' and z" are, independently, an integer from 1 to 12.

45. The compound of claim 43, wherein L2comprises (PEG)zr, (PEG)z", or a combination thereof and z' and z" are, independently, 2, 4, 8, or 12.

46. The compound of claim 43, wherein L2comprises (PEG)z', and z' is 2, 4, 8, or 12.

47. The compound of claim 43, wherein L2comprises (PEG)zrand (PEG)z" and z' and z" are, independently, 2, 4, 8, or 12.

48. The compound of any of claims 43-47, wherein (AA)brand (AA)b" comprise one or more amino acid residues selected from lysine (K), arginine (R), histidine (H), glycine (G), 0-alanine (B), phenylalanine (F), proline (P), valine (V), or combinations thereof.

49. The compound of claim 48, wherein (AA)b' and (AA)b" comprise at least one charged amino acid.

50. The compound of claim 48 or 49, wherein b' and b" are, independently, an integer from1-12.

51. The compound of claim 48 or 49, wherein b' and b" are, independently, an integer from 1-8.

52. The compound of claim 48 or 49, wherein b' and b" are, independently, an integer from 2-5.

53. The compound of any of claims 44-52, wherein L2comprises one or more hydrophobic components (Xor), (X°").

54. The compound of claim 53, wherein the hydrophobic components (X°'), (X°") are the same.

55. The compound of claim 53, wherein the hydrophobic components (XOf), (Xo,r) are different.

56. The compound of claim 33, comprising a structure selected from:Formula (B-l):Formula (C-l):Formula (E-l):10Formula (F-l):wherein: x' is an integer from 0 to 12; j' is 0, 1, or 2, wherein j' is 0 when x' is 0; z' is an integer from 0 to 12; j" is 0, 1, or 2, wherein j" is 0 when z' is 0; z" is an integer from 0 to 12; j"' is 0, 1, or 2, wherein j'" is 0 when z" is 0;X°' and X°" each, individually, comprise a hydrophobic component;K#is D-lysine or L-lysine residue;(AA)b' and (AA)b" are each an amino acid (AA) component comprising at least one amino acid residue; b' is an integer from 0 to 12; and b" is an integer from 0 to 12.

57. The compound of claim 33, comprising a structure selected from:Formula (G-l):Formula (H-1):Formula (L-l):wherein: x* is an integer from 0 to 12; j' is 0, 1, or 2, wherein j' is 0 when x' is 0; z' is an integer from 0 to 12; j" is 0, 1, or 2, wherein j" is 0 when z' is 0; z" is an integer from 0 to 12; j”' is 0, 1, or 2, wherein j"' is 0 when z" is 0;X°' comprises a hydrophobic component;K#is D-lysine or L-lysine residue;(AA)a', (AA)b', and (AA)b" are each an amino acid (AA) component comprising at least one amino acid residue; a' is an integer from 0 to 12; b' is an integer from 0 to 12; and b" is an integer from 0 to 12.

58. The compound of claim 33, comprising a structure selected from:Formula (R-l):x' is an integer from 0 to 12; j' is 0, 1, or 2, wherein j' is 0 when x' is 0; z' is an integer from 0 to 12; and j” is 0, 1, or 2, wherein j" is 0 when z' is 0.

59. A compound comprising an EEV-cargo conjugate having the structure of Formula (AA-1):wherein:Ac is an acetyl group ; cCPP is a cyclic cell penetrating peptide;L2is a linker arm;M' is a bonding group; y* is an integer from 1 to 5; and cargo is a peptide, oligonucleotide, a small molecule, or any combination thereof.

60. The compound of claim 59, comprising a structure selected from:Formula (N-l):Formula (P-1):( )Formula (Q-l):wherein: zris an integer from 0 to 12; j" is 0, 1, or 2, wherein j" is 0 when z' is 0;X°' is a hydrophobic component;K#is D-lysine or L-lysine residue;(AA)b' is an amino acid (AA) component comprising at least one amino acid residue; and b' is an integer from 0 to 12.

61. The compound of claim 59, wherein the cargo is an oligonucleotide.

62. The compound of claim 61, wherein the oligonucleotide is an antisense oligonucleotide.

63. The compound of claim 61 or 62, wherein the oligonucleotide is a phosphorodiamidate morpholino oligonucleotide (PMO).

64. The compound of any of claims 61-63, wherein M' is covalently bound to the 51end of the oligonucleotide, the 3' end of the oligonucleotide, or the backbone of the oligonucleotide.

65. The compound of any of claims 33 to 64, wherein M' comprises: -N(H), C(O), -Owherein y" is an integer from 1 to 4 and t' is 0 to 10.

66. The EEV or compound of the preceding claims, wherein the EP comprises from 2 to 10 amino acid residues, wherein at least 1 amino acid residue comprises a side chain comprising a guanidine group, a terminal amine, an imidazole, or a protonated form thereof.

67. The EEV or compound of claim 66, wherein the EP comprises from 2 to 8 amino acid residues.

68. The EEV or compound of claim 66, wherein the EP comprises from 2 to 6 amino acid residues.

69. The EEV or compound of any of claims 66 to 68, wherein the EP comprises 1, 2, 3, or 4 arginine residues.

70. The EEV or compound of any of claims 66 to 69, wherein the EP comprises 1, 2, 3, or 4 lysine residues.

71. The EEV or compound of any of claims 66 to 70, wherein the EP comprises 1 or 2 uncharged hydrophobic amino acid residues.

72. The EEV or compound of claim 71, wherein the uncharged hydrophobic amino acid residue is selected from valine, proline, b-alanine, glycine or a combination thereof.

73. The EEV or compound of claim 66, wherein the EP comprises a sequence selected from:(o) KRKIL; and(p) KFK, KRKF, or KKFRK; wherein the amino acid residues in the EP can have D- or L-stereochemistry.

74. The EEV or compound of claim 66, wherein the EP has the structure: Ac-PKKKRKV75. The EEV or compound of any of the preceding claims, wherein L2comprises one or more hydrophobic components (X°'), (X°").

76. The EEV or compound of claim 75, wherein one or more hydrophobic components (Xor), (X°") comprise one or two aromatic rings.

77. The EEV or compound of claim 75, wherein one or more hydrophobic components (Xof), (X°”) is a non-naturally occurring amino acid comprising one or more aromatic rings.

78. The EEV or compound of claim 75, wherein one or more hydrophobic components (X°'), (X°") comprise two aromatic rings.

79. The EEV or compound of claim 75, wherein one or more hydrophobic components (X°'), (X°") is, independently, selected from Nal, dNal, or Bip.

80. The EEV or compound of claim 75, wherein one or more hydrophobic components (Xor), (X°") comprise an aliphatic hydrocarbon.

81. The EEV or compound of claim 80, wherein one or more hydrophobic components (Xor), (Xo,r) comprises a C4-C8 aliphatic hydrocarbon.

82. The EEV or compound of claim 81, wherein one or more hydrophobic components (X°'), (X°") is a Ce aliphatic hydrocarbon.

83. An EEV of claim 1 comprising the structure:wherein,Ri, Rz, and R3 are each independently H or a side chain comprising an aryl or heteroaryl group; at least two of Ri, Rz, and Rs are a side chain of phenylalanine;R4, Rs, Re and R?, when present, are independently H or an amino acid side chain; q is an integer from 1-4; tn' is an integer from 0 to 3; m" is an integer from 0 to 3; and n is an integer from 1-4.

84. The EEV of claim 83, wherein the linker has a structure of Formula (B'), (BBr), (C'), (O'), (E') or (F'):Formula (B):15Formula (BB):wherein:x' is an integer from 0 to 12; j' is 0, 1, or 2, wherein j' is 0 when x' is 0; z' is an integer from 0 to 12; j" is 0, 1 , or 2, wherein j" is 0 when z' is 0; z" is an integer from 0 to 12; j"' is 0, 1, or 2, wherein j'" is 0 when z" is 0;X°' and X°" each, individually, comprise a hydrophobic component;K#is D-lysine or L-lysine residue;(AA)b' and (AA)b" are each an amino acid (AA) component comprising at least one amino acid residue; b' is an integer from 0 to 12; and b" is an integer from 0 to 12.

85. The EEV of claim 83, wherein the linker has a structure selected from Formula (O'), (Hr), (I), (13, (in (K3, (L3, or (M'):Formula (G):Formula (I):Formula (J):Formula (JJ):wherein: x' is an integer from 0 to 12; j' is 0, 1, or 2, wherein j' is 0 when x' is 0; z' is an integer from 0 to 12; j" is 0, 1, or 2, wherein j" is 0 when z' is 0; z" is an integer from 0 to 12; j"' is 0, 1, or 2, wherein j'" is 0 when z" is 0;X°' comprises a hydrophobic component;K#is D-lysine or L-lysine residue;(AA)a', (AA)b', and (AA)b" are each an amino acid (AA) component comprising at least one amino acid residue; a' is an integer from 0 to 12; b' is an integer from 0 to 12; and b" is an integer from 0 to 12.

86. An EEV of claim 30, comprising the structure:wherein,Ri, Rz, and R3 are each independently H or a side drain comprising an aryl or heteroaryl group; at least two of Ri, Rz, and Rj are a side chain of phenylalanine;Rt, Rs, Rs and R?, when present, are independently H or an amino acid side chain; q is 1, 2, 3 or 4; m' is an integer from 0 to 3; m" is an integer from 0 to 3; and n is an integer from 1-4.

87. The EEV of claim 86, wherein the linker is selected from:Formula (N):Formula (O)’ :wherein: z' is an integer from 0 to 12; j" is 0, 1, or 2, wherein j" is 0 when z' is 0;X°' is a hydrophobic component;K#is D-lysine or L-lysine residue;(AA)b' is an amino acid (AA) component comprising at least one amino acid residue; and b' is an integer from 0 to 12.

88. The EEV of claim 83, wherein the linker comprises Formula (R / ):Formula (R):wherein: x' is an integer from 0 to 12; j' is 0, 1 , or 2, wherein j' is 0 when x' is 0; z' is an integer from 0 to 12; and j" is 0, 1, or 2, wherein j" is 0 when z' is 0.

89. The EEV of any of claims 83-88, wherein: one of Ri, Rz, and Rs is H; and two of Ri, Rz, and Rs are a side chain of phenylalanine.

90. The EEV of any of claims 83-88, wherein: Ri, Rz, and Rs are a side chain of phenylalanine.

91. The EEV of any of claims 83-88, wherein:Ri, Rz, and Rs are each independently a side chain comprising an aryl or heteroaryl group; and at least two of Ri, Rz, and Rs are a side chain of phenylalanine.

92. The EEV of any of claims 83-91, wherein R4 and Re are H or an amino acid side chain of arginine, serine, histidine or citrulline.

93. The EEV of any of claims 83-92, wherein R» and Re are H or an amino acid side chain of arginine.

94. The EEV of any of claims 83-93, wherein R» and Re are H.

95. The EEV of any of claims 83-94, wherein Rs and Re are arginine.

96. The EEV or compound of any of claims 1 to 88, wherein the cyclic cell penetrating peptide is selected from Ff-Nal-GrGrQ; FfFGRGRQ; FGFGRGRQ; GfFGrGrQ; FGFGRRRQ; and FGFRRRRQ.

97. The EEV or compound of any of claims 1 to 88, wherein the cyclic cell penetrating peptide is FAFARARQ.

98. The EEV or compound of claims 1 to 88, wherein the cyclic cell penetrating peptide is Ff-Nal-GrGrQ.

99. The EEV or compound of claims 1 to 88, wherein the cyclic cell penetrating peptide is selected from FfFGRGRQ, FfFRRRRQ, FfFRrRrQ, fffrrrrQ or FfFRrRrQ.

100. The EEV or compound of claims 1 to 88, wherein the cyclic cell penetrating peptide is FG-Nal-GRGRQ.

101. The EEV or compound of claims 1 to 88, wherein the cyclic cell penetrating peptide is selected from FGFGRGRQ, fGfGrGrQ, fGfGrGrQ, FGFGRGRQ, FGFGRQ, fGfrrrrQ, FGFRRRRQ, or FGFRRRRQ102. The EEV or compound of any of claims 1 to 88, wherein the cyclic cell penetrating peptide is FGWRGRQ.

103. The EEV or compound of any of claims 1-88, wherein the cyclic peptide is selected from FfFGRGRQ, FGFGRGRQ, and FfFGRGRQ.

104. The EEV or compound of any of claims 1-88, wherein the cyclic peptide is RGRGRGRQ.

105. The EEV or compound of any of claims 1-88, wherein the cyclic peptide is FFFGRGRQ.

106. The EEV on compound of any of claims 1-88, wherein the cyclic peptide is FGFRRRRQ.

107. The EEV on compound of any of claims 1-88, wherein the cyclic peptide is FGFRGRGQ.

108. The EEV on compound of any of claims 1-88, wherein the cyclic peptide is FRGRGRGQ.

109. The EEV on compound of any of claims 1-88, wherein the cyclic peptide is FRFGRGRQ.

110. The EEV on compound of any of claims 1-88, wherein the cyclic peptide is FRFRFRFQ.

111. The EEV on compound of any of claims 1-88, wherein the cyclic peptide is FGFLRLRQ.

112. The EEV on compound of any of claims 1-88, wherein the cyclic peptide is FGFVRVRQ.

113. The EEV of claim 26, comprising Formula (B):Formula (B):wherein: x' is an integer from 0 to 12; j' is 0, 1, or 2, wherein j' is 0 when x' is 0;117. The EEV of claim 113, comprising: Ac-rbrrbr-PEG2-K(cyclo[fGfX3rGrQ)]-PEG12-Nal-OH.

118. The EEV of claim 113, comprising: Ac-pkkkrkv-PEG2-k(cyclo[fGfrrrrQ])-PEGi2-Nal-OH.

119. The EEV of claim 113, wherein X°' is dNal.

120. The EEV of claim 119, selected from:

121. The EEV of claim 119, comprising:

122. The EEV of claim 113, wherein X0' is Bip.

123. The EEV of claim 122, comprising:Ac-PKKKRKV-PEG2-K(cyclo[FGFGRGRQ])-PEGi2-Bip-OH.

124. The EEV of claim 113, wherein X°' is a C4-C8 an aliphatic hydrocarbon.

125. The EEV of claim 124, comprising: Ac-PKKKRKV-PEG2-K(cyclo[FGFGRGRQ])-PEGi2-C6-OH.

126. The EEV of claim 113, wherein X°' is a hydrophobic amino acid.

127. The EEV of claim 126, wherein the hydrophobic amino acid is selected from phenylalanine, tryptophan, tyrosine, valine, isoleucine, leucine, and histidine or a combination thereof.

128. The EEV of claim 127, wherein:(a) z' is 12 and the EEV is selected from:Ac-PKKKRKV-PEG2-K(cyc / o[FGFGRGRQ])-PEGi2-F-OH;Ac-PKKKRKV-PEG2-K(cyc / o[FGFGRGRQ])-PEGi2-W-OH;Ac-PKKKRKV-PEG2-K(cyc / o[FGFGRGRQ])-PEGi2-Y-OH;Ac-PKKKRKV-PEG2-K(cyc / o[FGFGRGRQ])-PEGi2-V-OH;Ac-PKKKRKV-PEG2-K(cyc / o[FGFGRGRQ])-PEGi2-I-OH;Ac-PKKKRKV-PEG2-K(cyc / o[FGFGRGRQ])-PEGi2-L-OH;Ac-PKKKRKV-PEG2-K(cyclo[FGFGRGRQ])-PEGi2-H-0H; or(a) z' is 0 and the EEV is Ac-PKKKRKV-PEG2-K(cyclo[FGFGRGRQ])-G-OH.

129. The EEV of claim 26, comprising Formula (C):Formula (C):wherein: x' is an integer from 0 to 12; j' is 0, 1, or 2, wherein j' is 0 when x' is 0; z' is an integer from 0 to 12; j” is 0, 1, or 2, wherein j" is 0 when z' is 0;X°' comprises a hydrophobic component;(AA)b' and (AA)b" each comprise an amino acid (AA) component comprising at least one amino acid residue; b' is an integer from 0 to 12; and b" is an integer from 0 to 12.

130. The EEV of claim 129, wherein b' is an integer from 2 to 5 and b" is an integer from 1 to8.

131. The EEV of claim 129, wherein b' is an integer from 1-8.

132. The EEV of claim 129, wherein b" is an integer from 1-8.

133. The EEV of any one of claims 129, wherein b' is 2-5 and b" is 2-5.

134. The EEV of claim 129, wherein x' is 2, z' is 12, b' is 2 and b" is 2.

135. The EEV of any one of claims 130-133, wherein x' is 2.

136. The EEV of any one of claims 130-133, wherein z' is 12.

137. The EEV of any of claims 130-136, wherein the amino acid of (AA)brcomprises arginine, histidine, lysine, or a combination thereof.

138. The EEV of any one of claimsl30 to 137, wherein the amino acids are D amino acids.

139. The EEV of any one of claims 130 to 137, wherein the amino acids are L amino acids.

140. The EEV of any one of claims 130 to 137, wherein X°' is Nal, dNal, or Bip.

141. The EEV of claim 130 wherein X is Bip.

142. The EEV of claim 141, wherein the (AA)brcomprises charged amino acids comprising histidine, asparagine, arginine, or combinations thereof.

143. The EEV of claim 141, comprising:

144. The EEV of claim 26, comprising Formula (D):Formula (D):wherein: x' is an integer from 0 to 12; j' is 0, 1, or 2, wherein j' is 0 when x' is 0; z' is an integer from 0 to 12; j" is 0, 1, or 2, wherein j" is 0 when z' is 0;X°' comprises a hydrophobic component;(AA)b' comprises an amino acid (AA) component comprising at least one amino acid residue; and b' is an integer from 0 to 12.

145. The EEV of claim 144, wherein b' is an integer from 2 to 5.

146. The EEV of claim 144 or 145, wherein (AA)b' comprises charged amino acids comprising arginine, histidine, lysine, or combinations thereof.

147. The EEV of any one of claims 144-146, wherein the amino acids comprising (AA)b' are D amino acids.

148. The EEV of any one of claims 144-147, wherein the amino acids comprising (AA)brare L amino acids.

149. The EEV of any one of claims 144-148, wherein X°' is Nal, dNal or Bip.

150. The EEV of claim 149, wherein X0' is Nal.

151. The EEV of claim 150, wherein (AA)b' comprises one or more R, K, or a combination thereof.

152. The EEV of claim 150, selected from: -KKKRK-PEG12-Nal-OH.

153. The EEV of claim 26, comprising Formula (E):Formula (E):wherein: x' is an integer from 0 to 12; j' is 0, 1, or 2, wherein j' is 0 when x' is 0; z' is an integer from 0 to 12; j" is 0, 1, or 2, wherein j" is 0 when z' is 0;X°' comprises a hydrophobic component; and K#is D-lysine or L-lysine residue.

154. The EEV of claim 153, wherein X°' comprises Nal, dNal, or Bip.

155. The EEV of claim 154, selected from:

156. The EEV of claim 153, wherein Xoris a hydrophobic amino acid.

157. The EEV of claim 156, wherein the hydrophobic amino acid is tryptophan, tyrosine, isoleucine, leucine, histidine, phenylalanine, or a combination thereof.

158. The EEV of claim 156, selected from:

159. The EEV of claim 26, comprising Formula (F):Formula (F):( ) wherein: x' is an integer from 0 to 12; j' is 0, 1, or 2, wherein j' is 0 when x' is 0; z' is an integer from 0 to 12;j" is 0, 1, or 2, wherein j" is 0 when z' is 0;X°' comprises a hydrophobic component;(AA)b' comprises an amino acid (AA) component comprising at least one amino acid residue; and b' is an integer from 0 to 12.

160. The EEV of claim 159, wherein Xorcomprises Bip.

161. The EEV of claim 160, selected from:

162. The EEV of claim 27, comprising Formula (G):Formula (G):wherein: x' is an integer from 0 to 12; j' is 0, 1, or 2, wherein j' is 0 when x' is 0; z' is an integer from 0 to 12; j" is 0, 1, or 2, wherein j" is 0 when z' is 0; z" is an integer from 0 to 12; j"' is 0, 1, or 2, wherein j"' is 0 when z" is 0;(AA)b' comprises an amino acid (AA) component comprising at least one amino acid residue; and b' is an integer from 0 to 12.

163. The EEV of claim 162, wherein x' is 2.

164. The EEV of claim 162 or 163, wherein z' is 2, 4, or 8.

165. The EEV of any of claims 162-164, wherein z" is 2, 4 or 8.

166. The EEV of claim 162, wherein z' is 2 and z" is 2.

167. The EEV of claim 162, comprising:

168. The EEV of claim 162, wherein z' is 2.

169. The EEV of claim 162, wherein z" is 4.

170. The EEV of claim 162, selected from:

171. The EEV of claim 162, comprising: Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RF-PEG4-K(N3)-NH2.

172. The EEV of claim 162, wherein z' is 4 and z" is 4.

173. The EEV of claim 162, selected from:

174. The EEV of claim 162, wherein z' is 8 and z" is 4.

175. The EEV of claim 162, selected from:

176. The EEV of claim 162, selected from:

177. The EEV of claim 162, selected from:

178. The EEV of claim 162, selected from:

179. The EEV of claim 162, selected from:

180. The EEV of claim 162, selected from:

181. The EEV of claim 162, selected from:

182. The EEV of claim 27, comprising Formula (H):Formula (H):wherein: x' is an integer from 0 to 12; j' is 0, 1, or 2, wherein j' is 0 when x' is 0; z' is an integer from 0 to 12; j” is 0, 1, or 2, wherein j" is 0 when z' is 0;z" is an integer from 0 to 12; j"' is 0, 1, or 2, wherein j'" is 0 when z" is 0;X°' comprises a hydrophobic component;(AA)b' and (AA)b" are each an amino acid (AA) component comprising at least one amino acid residue; b' is an integer from 0 to 12; and b" is an integer from 0 to 12.

183. The EEV of claim 182, wherein x' is 2.

184. The EEV of claim 182 or 183, wherein z' is 2, 4, or 8.

185. The EEV of any one of claims 182-184, wherein z" is 2, 4, or 8.

186. The EEV of claim 182, wherein z' is 2, z" is 2, and Xoris Bip.

187. The EEV of claim 186, comprising:

188. The EEV of claim 186, wherein z' is 2, z" is 4 and X°' is Bip.

189. The EEV of claim 186, selected from:

190. The EEV of claim 186, wherein z’ is 2, z” is 0, j” is 0 and X°' is Bip.

191. The EEV of claim 186, comprising: Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG8-R-Bip-OH.

192. The EEV of claim 27, comprising Formula (I):Formula (I):(i); wherein: x' is an integer from 0 to 12; j' is 0, 1, or 2, wherein j' is 0 when x' is 0; z' is an integer from 0 to 12; j" is 0, 1 , or 2, wherein j" is 0 when z' is 0; z" is an integer from 0 to 12; j"' is 0, 1, or 2, wherein j'" is 0 when z" is 0;(AA)b' and (AA)b" are each an amino acid (AA) component comprising at least one amino acid residue; b' is an integer from 0 to 12; and b" is an integer from 0 to 12.

193. The EEV of claim 192, wherein x' is 2.

194. The EEV of claim 192 or 193 wherein z' is 2, 4, or 8.

195. The EEV of any one of claims 191-193, wherein z" is 2, 4 or 8.

196. The EEV of claim 192, comprising:

197. The EEV of claim 192, comprising:

198. The EEV of claim 192, comprising:

199. The EEV of claim 192, comprising:

200. The EEV of claim 192, comprising:

201. The EEV of claim 27, comprising Formula (J) or Formula (JJ):Formula (J):10Fwherein: x* is an integer from 0 to 12; j' is 0, 1, or 2, wherein j' is 0 when x' is 0; z' is an integer from 0 to 12;211. The EEV of claim 27, comprising Formula (K):Formula (K):wherein:(AA)a’ is an amino acid linker comprising at least one amino acid; x' is an integer from 0 to 12; j' is 0, 1, or 2, wherein j' is 0 when x' is 0; z' is an integer from 0 to 12; j" is 0, 1 , or 2, wherein j" is 0 when z' is 0;(AA)b' comprises an amino acid (AA) component comprising at least one amino acid residue; and b' is an integer from 0 to 12.

212. The EEV of claim 211, wherein b' is an integer from 1-8.

213. The EEV of claim 211-212, wherein the amino acid in (AA)brcomprises G, F, B, R or combinations thereof.

214. The EEV of any of claims 211-213, wherein x' is 2.

215. The EEV of any of claims 211-214, wherein z' is 4.

216. The EEV of claim 211, wherein b' is 2, x' is 2 and z' is 4.

217. The EEV of claim 211, selected from:

218. The EEV of claim 211, wherein a’ is 3, x’ is 2 and z’ is 4.

219. The EEV of claim 211 selected from:

220. The EEV of claim 27, comprising formula (L):Formula (L):wherein: x' is an integer from 0 to 12; j' is 0, 1, or 2, wherein j' is 0 when x' is 0; z' is an integer from 0 to 12; j” is 0, 1, or 2, wherein j" is 0 when z' is 0;(AA)b' comprises an amino acid (AA) component comprising at least one amino acid residue; andb' is an integer from 0 to 12.

221. The EEV of claim 220, wherein b' is an integer from 1-8.

222. The EEV of claim 220 or 221, wherein (AA)b' comprises a charged amino acid selected from G, E, R or a combination thereof.

223. The EEV of any one of claims 220-222, wherein x' is 2.

224. The EEV of any one of claims 220-223, wherein z' is 0, 2 or 8.

225. The EEV of claim 220, wherein x' is 2, z' is 0, j" is 0 and b' is 3.

226. The EEV of claim 220, selected from:

229. The EEV of claim 220, wherein x' is 2, z' is 0, j" is 0, and b' is an integer from 2-8.

230. The EEV of claim 220, comprising:Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-GGRRGRRG-OH.

231. The EEV of claim 220, wherein (AA)brcomprises a charged amino acid selected from R and F.

232. The EEV of claim 227, wherein x' is 2, z' is 2, and b' is an integer from 8-12.

233. The EEV of claim 220, comprising:Ac-PKKKRKV-PEG2-K(cyclo[F£FGRGRQ])-PEG2-RFQILYBRBRB-OH.

234. The EEV of claim 220, wherein x' is 2, z' is 8, and b' is 2.

235. The EEV of claim 220, comprising: Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG8-RF-OH.

236. The EEV of claim 27, comprising Formula (M):wherein: x' is an integer from 0 to 12; j' is 0, 1, or 2, wherein j' is 0 when x' is 0; z' is an integer from 0 to 12; j" is 0, 1 , or 2, wherein j" is 0 when z' is 0;X°' comprises a hydrophobic component;(AA)b' comprises an amino acid (AA) component comprising at least one amino acid residue; a' is an integer from 0 to 12; b' is an integer from 0 to 12; andb" is an integer from 0 to 12.

237. The EEV of claim 236, wherein X°' is Nal, dNal, or Bip.

238. The EEV of claim 236, wherein X°' is Bip.

239. The EEV of claim 236, selected from:

240. The EEV of claim 236, wherein the amino acid in of (AA)b' comprises histidine, asparagine, arginine, or combinations thereof.

241. The EEV of claim 236, selected from:

244. The EEV of claim 236, wherein Xoris Nal.

245. The EEV of claim 244, selected from:

246. The EEV of claim 236, wherein Xoris dNal.

247. The EEV of claim 246, selected from:

248. The EEV of claim 31, comprising Formula (N):Formula (N):wherein: z' is an integer from 0 to 12; j" is 0, 1 , or 2, wherein j" is 0 when z' is 0;X°' is a hydrophobic component;K#is D-lysine or L-lysine residue;(AA)b' is an amino acid (AA) component comprising at least one amino acid residue; and b' is an integer from 0 to 12.

249. The EEV of claim 248, wherein z' is 2, 4, 8, or 12.

250. The EEV of claim 248 or 249, wherein z' is 12.

251. The EEV of any of claims 248 to 250, wherein b' is an integer from 2-5.

252. The EEV of claim 248, selected from:Ac-K(cycZo[FGFGRGRQ])-PEGi2-KKKR-K(Ac-Nal)-OH;Ac-K(qvc / o[FGFGRGRQ])-PEGi2-KKR-K(Ac-Nal)-OH; and Ac-K(cyclo[FGFGRGRQ])-PEGi2-KR-K(Ac-Nal)-OH.

253. The EEV of claim 248, selected fromAc-K(cyc / o[FGFGRGRQ])-PEGi2-KKKR-K(Ac-dNal)-OH;Ac-K(cyc / o[FGFGRGRQ])-PEGi2-KKR-K(Ac-dNal)-OH; and Ac-K(cyclo[FGFGRGRQ])-PEGi2-KR-K(Ac-dNal)-OH.

254. The EEV of claim 252 or 253, wherein (AA)b' comprises A”^16.

255. The EEV of claim 31, comprising Formula (O):Formula (O):wherein: z' is an integer from 0 to 12; j" is 0, 1, or 2, wherein j" is 0 when z' is 0;(AA)b' is an amino acid (AA) component comprising at least one amino acid residue; and b' is an integer from 0 to 12.

256. The EEV of claim 255, wherein z' is 2, 4, 8, or 12.

257. The EEV of claim 255 or 256, wherein z' is 12.

258. The EEV of any of claims 255-257, wherein b' is 2, 3, or 4.

259. The EEV of claim 255, selected from:Ac-K(cycZo[FGFGRGRQ])-PEGi2-KKKR-k(N3)-NH2Ac-K(qvc / o[FGFGRGRQ])-PEGi2-KKR-k(N3)-NH2; andAc-K(cyclo[FGFGRGRQ])-PEG12-KR- k(N3)-NH2260. The EEV of claim 255, selected from:Ac-K(cyc / o[FGFGRGRQ])-PEGi2-KKKR-OHAc-K(cyc / o[FGFGRGRQ])-PEGi2-KKR-OH; and Ac-K(cyclo[FGFGRGRQ])-PEGl 2-KR-OH.

261. The EEV of claims 259 or 260, wherein (AA)brcomprises V**6.

262. The EEV of claim 31, comprising Formula (P):Formula (P):wherein: z' is an integer from 0 to 12; j" is 0, 1, or 2, wherein j" is 0 when z' is 0;X°' is a hydrophobic component;(AA)b' is an amino acid (AA) component comprising at least one amino acid residue; and b' is an integer from 0 to 12.

263. The EEV of claim 262, wherein z' is 2, 4, 8, or 12.

264. The EEV of claim 262 or 263, wherein z' is 12.

265. The EEV of any of claims 262-264, wherein b' is 2-8.

266. The EEV of any of claims 262-265, wherein X°' is Nal or dNal.

267. The EEV of claim 262, selected from:

268. The EEV of claim 267, wherein (AA),- comprises ZV*14®.

269. The EEV of claim 31, comprising Formula (Q):Formula (Q):wherein: z' is an integer from 0 to 12; j" is 0, 1, or 2, wherein j" is 0 when z' is 0;X°' is a hydrophobic component;(AA)b' is an amino acid (AA) component comprising at least one amino acid residue; andb' is an integer from 0 to 12.

270. The EEV of claim 265 comprising: Ac-K(cyclo[FGFGRGRQ])-KKKRK-PEGi2-Nal-OH.

271. The EEV of claim 28, comprising Formula (R):wherein: x' is an integer from 0 to 12; j' is 0, 1, or 2, wherein j' is 0 when x' is 0; z' is an integer from 0 to 12; and j" is 0, 1 , or 2, wherein j" is 0 when z' is 0.

272. The EEV claim 271, wherein x' is 2.

273. The EEV of claim 271 or 272, wherein z' is 2, 4, 8 or 12.

274. The EEV of any one of claims 271-273, wherein x' is 2 and z' is 12.

275. The EEV of claim 271, selected from:Ac-pkkkrkv-PEG2-k(cyclo[fGfGrGrQ])-PEG12-OH; andAc-pkkkrkv-PEG2-k(cyclo[fGfGrGrQ])-PEGi2-K(N3)-NH2.

276. The EEV of any of claims 1 to 32 or 66 to 271, conjugated to a cargo to form an EEV- cargo conjugate.

277. The EEV of claim 276, wherein cargo is a peptide, oligonucleotide, a small molecule, ora combination thereof.

278. The EEV of claim 277, wherein cargo is an oligonucleotide.

279. The EEV of claim 278, wherein oligonucleotide is an antisense oligonucleotide.

280. The EEV of 278 or279, wherein oligonucleotide is a phosphorodiamidate morpholino oligonucleotide (PMO).

281. The EEV of any of claims 278-280, wherein M is covalently bound to the 5' end of the oligonucleotide, the 3’ end of the oligonucleotide, or the backbone of the oligonucleotide.

282. A pharmaceutical composition comprising the compound of claims 33-82 and a pharmaceutically acceptable carrier.

283. A method of treating a disease in a subject in need thereof comprising administering to the subject an effective amount of the pharmaceutical composition of claim 282.

284. The method of claim 283, wherein administering comprises parenteral administration.

285. The method of claim 284, wherein parenteral administration is selected from: subcutaneous, intradermal, intravenous, intramuscular, intraperitoneal, intrastemal, intrathecal and intracerebroventricular administration286. The EEV of claim 26, comprising a structure selected from:Formula (BB):wherein: x' is an integer from 0 to 12; j' is 0, 1, or 2, wherein j' is 0 when x' is 0; z' is an integer from 0 to 12; j" is 0, 1, or 2, wherein j" is 0 when z' is 0; z" is an integer from 0 to 12; j"' is 0, 1, or 2, wherein j'" is 0 when z" is 0;X°' and X°' each, independently, comprise a hydrophobic component; b' is an integer from 0 to 12; and b" is an integer from 0 to 12.

287. The EEV of claim 286, wherein x' is 2, z' is 12, z" is 2, and X°' and X°' are each, independently Nal.

288. The EEV of claim 287, comprising: Ac-PKKKRKV-PEG2-K(cyclo[FGFGRGRQ])-PEGi2-Nal-PEG2-Nal-OH.