PEPTIDE OLIGONUCLEOTIDE CONJUGATES
First Claim
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1. A conjugate comprising:
- (a) a carrier peptide comprising amino acid subunits; and
(b) a nucleic acid analogue comprising a substantially uncharged backbone and a targeting base sequence for sequence-specific binding to a target nucleic acid;
wherein;
two or more of the amino acid subunits are positively charged amino acids, the carrier peptide comprises a glycine (G) or proline (P) amino acid subunit at a carboxy terminus of the carrier peptide, no more than seven contiguous amino acid subunits are arginine, and the carrier peptide is covalently attached to the nucleic acid analogue.
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Abstract
Oligonucleotide analogues conjugated to carrier peptides are provided. The disclosed compounds are useful for the treatment of various diseases, for example diseases where inhibition of protein expression or correction of aberrant mRNA splice products produces beneficial therapeutic effects.
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Citations
65 Claims
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1. A conjugate comprising:
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(a) a carrier peptide comprising amino acid subunits; and (b) a nucleic acid analogue comprising a substantially uncharged backbone and a targeting base sequence for sequence-specific binding to a target nucleic acid; wherein; two or more of the amino acid subunits are positively charged amino acids, the carrier peptide comprises a glycine (G) or proline (P) amino acid subunit at a carboxy terminus of the carrier peptide, no more than seven contiguous amino acid subunits are arginine, and the carrier peptide is covalently attached to the nucleic acid analogue. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65)
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36. The conjugate of claim 35, wherein at least one of the morpholino ring structures has the following structure (i):
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37. The conjugate of claim 35, wherein at least one of the intersubunit linkages is linkage (A).
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38. The conjugate of claim 35, wherein each of the intersubunit linkages is linkage (A).
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39. The conjugate of claim 35, wherein each linkage (A) has the same structure at each occurrence.
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40. The conjugate of claim 35, wherein for at least one occurrence of linkage (A), X is —
- N(CH3)2.
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41. The conjugate of claim 35, wherein X is —
- N(CH3)2 at each occurrence of linkage (A).
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42. The conjugate of claim 35, wherein each linkage is linkage (A) and X is —
- N(CH3)2.
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43. The conjugate of claim 35, wherein for at least one occurrence of linkage (A), X has the following structure:
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44. The conjugate of claim 35, wherein for at least one occurrence of linkage (B), X has the following structure:
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45. The conjugate of claim 35, wherein for at least one occurrence of linkage (B), X has the following structure:
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46. The conjugate of claim 35, wherein W and Y are each O at each occurrence.
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47. The conjugate of claim 35, wherein at least 5% of the intersubunit linkages are linkage (B).
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48. The conjugate of claim 35, wherein each linkage (B) has the same structure at each occurrence.
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49. The conjugate of claim 35, wherein the nucleic acid analogue has the following structure (XVII):
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50. The conjugate of claim 49, wherein R18 is the carrier peptide.
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51. The conjugate of claim 49, wherein R19 is the carrier peptide.
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52. The conjugate of claim 49, wherein at least one of R18 or R19 is R20.
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53. The conjugate of claim 49, wherein R19 is —
- C(═
O)OR21.
- C(═
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54. The conjugate of claim 53, wherein R19 is
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55. The conjugate of claim 49, wherein L1 comprises phosphorodiamidate and piperazine bonds.
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56. The conjugate of claim 55, wherein L1 has the following structure (XXIX):
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57. The conjugate of claim 56, wherein R24 is absent.
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58. The conjugate of claim 49, wherein R18 is the carrier peptide, L2 is a direct bond, and the carrier peptide forms a bond between the carboxy terminus of the carrier peptide and the 3′
- terminal nitrogen of the nucleic acid analogue.
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59. A composition comprising the conjugate of claim 1 and a pharmaceutically acceptable vehicle.
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60. A method of treating a disease in a subject, the method comprising administering a therapeutically effective amount of the conjugate of claim 1 to the subject.
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61. The method of claim 60, wherein the disease is a viral infection, a neuromuscular disease, a bacterial infection, inflammation or polycystic kidney disease.
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62. The method of claim 61, wherein the viral infection is influenza.
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63. The method of claim 61, wherein the neuromuscular disease is Duchenne muscular dystrophy.
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64. A method for enhancing the transport of a nucleic acid analogue into a cell, the method comprising conjugating the carrier peptide of claim 1 to a nucleic acid analogue, and wherein the transport of the nucleic acid analogue into the cell is enhanced relative to the nucleic acid analogue in unconjugated form.
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65. The method of claim 64, wherein the nucleic acid analogue is a morpholino oligomer.
Specification