NOVEL SINGLE CHEMICAL ENTITIES AND METHODS FOR DELIVERY OF OLIGONUCLEOTIDES
In an embodiment the instant invention discloses a modular composition comprising 1) an oligonucleotide; 2) one or more linkers, which may be the same or different, selected from Table 1, wherein the linkers are attached to the oligonucleotide at the 2′-position of the ribose rings and/or the terminal 3′- and/or 5′-positions of the oligonucleotide; 3) optionally, one or more peptides, which may be the same or different, selected from SEQ ID NOs: 1-59, wherein the peptides are attached to the linkers; and optionally one or more lipids, solubilizing groups and/or targeting ligands attached to the oligonucleotide.
1 . A modular composition comprising 1) an oligonucleotide; 2) one or more linkers, which may be the same or different, wherein the linkers are attached to the oligonucleotide at the 2′-position of the ribose rings and/or the terminal 3′- and/or 5′-positions of the oligonucleotide; and 3) one or more peptides, which may be the same or different, selected from SEQ ID NOs: 1-59, wherein the peptides are attached to the linkers at one or more of positions 3, 5, 8, 10, 13, 17, 18, and 19 from the 5′-end of the oligonucleotide.
2 . The modular composition of claim 1 , wherein the oligonucleotide is an siRNA.
3 . The modular composition of claim 2 , wherein the linkers are attached to the guide strand of the siRNA at the 2′-position of the ribose rings excluding the terminal 3′- and/or 5′-positions of the guide strand.
4 . The modular composition of claim 2 , wherein the linkers are attached to the passenger strand of the siRNA at the 2′-position of the ribose rings excluding the terminal 3′- and/or 5′-positions of the passenger strand.
5 . The modular composition of claim 1 , wherein one or more of the linkers are selected from the group consisting of:
wherein
R is H, Boc (tert-butyloxycarbonyl), Cbz (Carboxybenzyl), Ac (acetyl), PEG, a lipid, a targeting ligand, another linker, and/or a peptide; and
n is 0 to 750 in each occurrence.
6 . The modular composition of claim 1 , wherein the peptides are attached via the linkers to position 3 from the 5′-end of the oligonucleotide.
7 . The modular composition of claim 1 , wherein the peptides are attached via the linkers to positions 3 and 13 from the 5′-end of the oligonucleotide.
8 . The modular composition of claim 1 , wherein the peptides are attached via the linkers to positions 3 and 19 from the 5′-end of the oligonucleotide.
9 . The modular composition of claim 1 , wherein the peptides are attached via the linkers to positions 17 and 19 from the 5′-end of the oligonucleotide.
10 . The modular composition of claim 1 , wherein the peptides are attached via the linkers to positions 3, 8, and 13 from the 5′-end of the oligonucleotide.
11 . The modular composition of claim 1 , wherein the peptides are attached via the linkers to positions 3, 8, and 19 from the 5′-end of the oligonucleotide.
12 . The modular composition of claim 1 , wherein the peptides are attached via the linkers to positions 3, 13, and 19 from the 5′-end of the oligonucleotide.
13 . The modular composition of claim 1 , wherein the peptides are attached via the linkers to positions 3, 8, 13, and 18 from the 5′-end of the oligonucleotide.
14 . The modular composition of claim 1 , wherein the peptides are attached via the linkers to positions 3, 8, 13, and 19 from the 5′-end of the oligonucleotide.
15 . The modular composition of claim 1 , wherein two or more peptides are attached to the same position on the oligonucleotide.
16 . The modular composition of claim 1 , wherein three or more peptides are attached to the same position on the oligonucleotide.
17 . The modular composition of claim 1 , wherein the oligonucleotide is a double-stranded oligonucleotide, and two or more peptides are attached via the linkers to the same strand.
18 . The modular composition of claim 1 , wherein the oligonucleotide is a double-stranded oligonucleotide, and two or more peptides are attached via the linkers to different strands.
19 . The modular composition of claim 1 , wherein one or more targeting ligands are attached to the oligonucleotide via one or more linkers at the 2′-position of the ribose rings and/or the terminal 3′- and/or 5′-positions of the oligonucleotide.
20 . The modular composition of claim 19 , wherein the targeting ligand is an RGD peptide, RGD peptide mimic, D-galactose, N-acetyl-D-galactosamine (GalNAc), GalNAc2, GalNAc3, cholesterol, or folate.
21 . The modular composition of claim 19 , wherein the oligonucleotide is a double-stranded oligonucleotide, and the peptide(s) and the targeting ligand(s) are attached via the linkers to the same strand.
22 . The modular composition of claim 19 , wherein the oligonucleotide is a double-stranded oligonucleotide, and the peptide(s) and the targeting ligand(s) are attached via the linkers to different strands.