Peptide oligonucleotide conjugates
First Claim
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1. A conjugate comprising:
- (a) a carrier peptide comprising amino acid subunits, the carrier peptide comprising a proline amino acid at the carboxy terminus of the carrier peptide; and
(b) a phosphorodiamidate morpholino oligonucleotide comprising a substantially uncharged backbone and a targeting base sequence for sequence-specific binding to a target nucleic acid; and
(c) a covalent attachment between the nucleic acid analog and the carrier peptide, the covalent attachment comprising the carboxy-terminal proline and an optional linker group;
wherein;
two or more of the amino acid subunits are positively charged amino acids, no more than seven contiguous amino acid subunits are arginine, and the carrier peptide is covalently attached to the nucleic acid analogue, the covalent attachment between the nucleic acid analog and the carrier peptide is not 6-aminohexanoic acid or β
-alanine.
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Abstract
Oligonucleotide analogs 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
20 Claims
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1. A conjugate comprising:
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(a) a carrier peptide comprising amino acid subunits, the carrier peptide comprising a proline amino acid at the carboxy terminus of the carrier peptide; and (b) a phosphorodiamidate morpholino oligonucleotide comprising a substantially uncharged backbone and a targeting base sequence for sequence-specific binding to a target nucleic acid; and (c) a covalent attachment between the nucleic acid analog and the carrier peptide, the covalent attachment comprising the carboxy-terminal proline and an optional linker group; wherein; two or more of the amino acid subunits are positively charged amino acids, no more than seven contiguous amino acid subunits are arginine, and the carrier peptide is covalently attached to the nucleic acid analogue, the covalent attachment between the nucleic acid analog and the carrier peptide is not 6-aminohexanoic acid or β
-alanine.- View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20)
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12. The conjugate of claim 11, wherein at least one of the morpholino ring structures has the following structure (i):
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13. The conjugate of claim 11, wherein each linkage is linkage (A) and X is —
- N(CH3)2.
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14. The conjugate of claim 11, wherein W and Y are each O at each occurrence.
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15. The conjugate of claim 11, wherein the nucleic acid analogue has the following structure (XVII):
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16. The conjugate of claim 15, wherein R18 is the carrier peptide.
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17. The conjugate of claim 15, wherein R19 is the carrier peptide.
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18. The conjugate of claim 15, wherein R19 is
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19. The conjugate of claim 15, wherein L1 has the following structure (XXIX):
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20. The conjugate of claim 15, 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.
Specification