Cell-penetrating peptide conjugates and methods of their use
Disclosed are conjugates of an oligonucleotide and a peptide covalently bonded or linked via a linker to the oligonucleotide, the peptide including at least one cationic domain comprising at least 4 amino acid residues and at least one hydrophobic domain comprising at least 3 amino acid residues, provided that the peptide includes a total of 7 to 40 amino acid residues and does not include any artificial amino acid residues; and the oligonucleotide including a total of 12 to 40 contiguous nucleobases, where at least 12 contiguous nucleobases are complementary to a target sequence in a human dystrophin gene.
1 . A conjugate, or a pharmaceutically acceptable salt thereof, is of the following structure having a glutamic acid residue:
wherein the peptide consists of the sequence RBRRBRFQILYBRBR (SEQ ID NO: 35) and is covalently linked to the glutamic acid residue at the C-terminus of the peptide, wherein the peptide is acetylated at its N-terminus; and
wherein the oligonucleotide is a PMO and consists of the sequence 5′-CTCCAACATCAAGGAAGATGGCATTTCTAG-3′ (SEQ ID NO: 195), wherein the oligonucleotide is linked by its 3′-terminus to the glutamic acid residue and has the following group at its 5′ terminus:
2 . A pharmaceutical composition comprising
a conjugate, or a pharmaceutically acceptable salt thereof, is of the following structure having a glutamic acid residue:
wherein the peptide consists of the sequence RBRRBRFQILYBRBR (SEQ ID NO: 35) and is covalently linked to the glutamic acid residue at the C-terminus of the peptide, wherein the peptide is acetylated at its N-terminus; and
wherein the oligonucleotide is a PMO and consists of the sequence 5′-CTCCAACATCAAGGAAGATGGCATTTCTAG-3′ (SEQ ID NO: 195), wherein the oligonucleotide is linked by its 3′-terminus to the glutamic acid residue and has the following group at its 5′ terminus:
and
a pharmaceutically acceptable carrier.
3 . A pharmaceutically acceptable salt of
a conjugate of the following structure having a glutamic acid residue:
wherein the peptide consists of the sequence RBRRBRFQILYBRBR (SEQ ID NO: 35) and is covalently linked to the glutamic acid residue at the C-terminus of the peptide, wherein the peptide is acetylated at its N-terminus; and
wherein the oligonucleotide is a PMO and consists of the sequence 5′-CTCCAACATCAAGGAAGATGGCATTTCTAG-3′ (SEQ ID NO: 195), wherein the oligonucleotide is linked by its 3′-terminus to the glutamic acid residue and has the following group at its 5′ terminus:
4 . A pharmaceutical composition comprising
a pharmaceutically acceptable salt of a conjugate of the following structure having a glutamic acid residue:
wherein the peptide consists of the sequence RBRRBRFQILYBRBR (SEQ ID NO: 35) and is covalently linked to the glutamic acid residue at the C-terminus of the peptide, wherein the peptide is acetylated at its N-terminus; and
wherein the oligonucleotide is a PMO and consists of the sequence 5′-CTCCAACATCAAGGAAGATGGCATTTCTAG-3′ (SEQ ID NO: 195), wherein the oligonucleotide is linked by its 3′-terminus to the glutamic acid residue and has the following group at its 5′ terminus:
and
a pharmaceutically acceptable carrier.