Conjugated oligonucleotides
Provided herein are conjugated oligonucleotides that are characterized by efficient and specific tissue distribution.
1. A compound of formula (I):
wherein:
O is an oligonucleotide;
L is a linker selected from:
X c is a cholesterol, Lithocholic acid, Retinoic acid or α-tocopheryl succinate; and
Z c is a phosphodiester or phosphodiester derivative selected from
wherein X is O, S or BH 3 .
2. The compound of claim 1 , wherein O is a double-stranded nucleic acid comprising a first oligonucleotide and a second oligonucleotide, wherein:
(1) the first oligonucleotide comprises at least 16 contiguous nucleotides, a 5′ end, a 3′ end and has complementarity to a target;
(2) the second oligonucleotide comprises at least 15 contiguous nucleotides, a 5′ end, a 3′ end, and has homology with a target; and
(3) a portion of the first oligonucleotide is complementary to a portion of the second oligonucleotide.
3. The compound of claim 2 , wherein the first oligonucleotide comprises alternating 2′-methoxy-ribonucleotides and 2′-fluoro-ribonucleotides, wherein each nucleotide is a 2′-methoxy-ribonucleotide or a 2′-fluoro-ribonucleotide; and the nucleotides at positions 2 and 14 from the 5′ end of the first oligonucleotide are not 2′-methoxy-ribonucleotides.
4. The compound of claim 2 , wherein the second oligonucleotide comprises alternating 2′-methoxy-ribonucleotides and 2′-fluoro-ribonucleotides, wherein each nucleotide is a 2′-methoxy-ribonucleotide or a 2′-fluoro-ribonucleotide; and the nucleotides at positions 2 and 14 from the 5′ end of the second oligonucleotide are 2′-methoxy-ribonucleotides.
5. The compound of claim 2 , wherein the nucleotides of the first oligonucleotide are connected to adjacent nucleotides via phosphodiester or phosphorothioate linkages, wherein the nucleotides at positions 1-6 from the 3′ end, or positions 1-7 from the 3′ end are connected to adjacent nucleotides via phosphorothioate linkages.
6. The compound of claim 2 , wherein the nucleotides of the second oligonucleotide are connected to adjacent nucleotides via phosphodiester or phosphorothioate linkages, wherein the nucleotides at positions 1 and 2 from the 3′ end are connected to adjacent nucleotides via phosphorothioate linkages.
7. The compound of claim 2 , wherein the first oligonucleotide comprises a moiety X at the 5′ end, wherein X is selected from the group consisting of:
8. The compound of claim 2 , wherein the first oligonucleotide has the structure of formula (Ia):
X(—K—B—K-A) j (—S—B—S-A) r (—S—B) t —OR (Ia)
wherein:
X is selected from the group consisting of:
A, for each occurrence, independently is a 2′-methoxy-ribonucleotide;
B, for each occurrence, independently is a 2′-fluoro-ribonucleotide;
K, for each occurrence independently is a phosphodiester or phosphorothioate linker;
S is a phosphorothioate linker;
R is hydrogen, phosphate, vinylphosphonate, or a capping group;
j is 4, 5, 6 or 7;
r is 2 or 3; and
t is 0 or 1.
9. The compound of claim 2 , wherein the first oligonucleotide has the structure of formula (IIa):
C-L-B(—S-A-S—B) m′ (—P-A-P—B) n′ (—P-A-S—B) q′ (—S-A) r′ (—S—B) t′ —OR′ (IIa)
wherein:
C-L is:
A, for each occurrence, independently is a 2′-methoxy-ribonucleotide;
B, for each occurrence, independently is a 2′-fluoro-ribonucleotide;
S is a phosphorothioate linker;
P is a phosphodiester linker;
R′ is hydrogen, phosphate, vinylphosphonate, or a capping group;
m′ is 0 or 1;
n′ is 4, 5 or 6;
q′ is 0 or 1;
r′ is 0 or 1; and
t′ is 0 or 1.
10. A compound comprising a structure selected from:
11. The compound of claim 10 , wherein oligonucleotide is a double-stranded nucleic acid comprising a first oligonucleotide and a second oligonucleotide, wherein:
(1) the first oligonucleotide comprises at least 16 contiguous nucleotides, a 5′ end, a 3′ end and has complementarity to a target;
(2) the second oligonucleotide comprises at least 15 contiguous nucleotides, a 5′ end, a 3′ end, and has homology with a target; and
(3) a portion of the first oligonucleotide is complementary to a portion of the second oligonucleotide.
12. The compound of claim 11 , wherein the first oligonucleotide comprises alternating 2′-methoxy-ribonucleotides and 2′-fluoro-ribonucleotides, wherein each nucleotide is a 2′-methoxy-ribonucleotide or a 2′-fluoro-ribonucleotide; and the nucleotides at positions 2 and 14 from the 5′ end of the first oligonucleotide are not 2′-methoxy-ribonucleotides.
13. The compound of claim 11 , wherein the second oligonucleotide comprises alternating 2′-methoxy-ribonucleotides and 2′-fluoro-ribonucleotides, wherein each nucleotide is a 2′-methoxy-ribonucleotide or a 2′-fluoro-ribonucleotide; and the nucleotides at positions 2 and 14 from the 5′ end of the second oligonucleotide are 2′-methoxy-ribonucleotides.
14. The compound of claim 11 , wherein the nucleotides of the first oligonucleotide are connected to adjacent nucleotides via phosphodiester or phosphorothioate linkages, wherein the nucleotides at positions 1-6 from the 3′ end, or positions 1-7 from the 3′ end are connected to adjacent nucleotides via phosphorothioate linkages.
15. The compound of claim 11 , wherein the nucleotides of the second oligonucleotide are connected to adjacent nucleotides via phosphodiester or phosphorothioate linkages, wherein the nucleotides at positions 1 and 2 from the 3′ end are connected to adjacent nucleotides via phosphorothioate linkages.
16. The compound of claim 11 , wherein the first oligonucleotide comprises a moiety X at the 5′ end, wherein X is selected from the group consisting of:
17. The compound of claim 11 , wherein the first oligonucleotide has the structure of formula (Ia):
X(—K—B—K-A) j (—S—B—S-A) r (—S—B) t —OR (Ia)
wherein:
X is selected from the group consisting of:
A, for each occurrence, independently is a 2′-methoxy-ribonucleotide;
B, for each occurrence, independently is a 2′-fluoro-ribonucleotide;
K, for each occurrence independently is a phosphodiester or phosphorothioate linker;
S is a phosphorothioate linker;
R is hydrogen, phosphate, vinylphosphonate, or a capping group;
j is 4, 5, 6 or 7;
r is 2 or 3; and
t is 0 or 1.
18. The compound of claim 11 , wherein the first oligonucleotide has the structure of formula (IIa):
C-L-B(—S-A-S—B) m′ (—P-A-P—B) n′ (—P-A-S—B) q′ (—S-A) r′ (—S—B) t′ —OR′ (IIa)
wherein:
C-L is:
A, for each occurrence, independently is a 2′-methoxy-ribonucleotide;
B, for each occurrence, independently is a 2′-fluoro-ribonucleotide;
S is a phosphorothioate linker;
P is a phosphodiester linker;
R′ is hydrogen, phosphate, vinylphosphonate, or a capping group;
m′ is 0 or 1;
n′ is 4, 5 or 6;
q′ is 0 or 1;
r′ is 0 or 1; and
t′ is 0 or 1.