Conjugated antisense compounds and their use
View Patent ↗Provided herein are oligomeric compounds with conjugate groups. In certain embodiments, the oligomeric compounds are conjugated to N-Acetylgalactosamine.
1. A compound having the formula (XXVI):
wherein:
T 2 is a group comprising a conjugate linker, a cleavable moiety, and an oligomeric compound.
2. The compound of claim 1 , wherein the conjugate linker comprises an amine, an amide, an ester, an ether, a pyrrolidine, ethylene glycol, a polyamide, or a disulfide bond.
3. The compound of claim 1 , wherein the conjugate linker has the formula:
4. The compound of claim 1 , wherein T 2 has the formula:
wherein:
CM is the cleavable moiety and T 3 comprises the oligomeric compound.
5. The compound of claim 4 , wherein T 2 has the formula:
wherein:
T 3 is the oligomeric compound.
6. The compound of claim 5 , wherein the oligomeric compound is a modified oligonucleotide.
7. The compound of claim 6 , wherein the modified oligonucleotide consists of 15 to 24 linked nucleosides wherein at least one nucleoside is a modified nucleoside.
8. The compound of claim 6 , wherein the modified oligonucleotide comprises at least one modified nucleoside selected from among: a 2′-MOE nucleoside, a 2′-OMe nucleoside, a 2′-F nucleoside, a (4′-CH 2 —O-2′) bicyclic nucleoside, a (4′-(CH 2 ) 2 -O-2′) bicyclic nucleoside, a (4′-C(CH 3 )H—O-2′) bicyclic nucleoside; and a morpholino.
9. The compound of claim 8 , wherein the modified oligonucleotide has a gapmer sugar motif comprising:
a 5′-region consisting of 2-8 linked 5′-region nucleosides, wherein each 5′-region nucleoside is a modified nucleoside;
a 3′-region consisting of 2-8 linked 3′-region nucleosides, wherein each 3′-region nucleoside is a modified nucleoside; and
a central region between the 5′-region and the 3′-region consisting of 5-10 linked central region nucleosides, each independently selected from among: a modified nucleoside and an unmodified deoxynucleoside, wherein the 5′-most central region nucleoside is an unmodified deoxynucleoside and the 3′-most central region nucleoside is an unmodified deoxynucleoside.
10. The compound of claim 9 , wherein the modified oligonucleotide has a chemical motif selected from among:
MsMy(Ds) 0-1 (DsDs) (3-5) MsM
MsMy(Ds) 0-1 (DsDs) (3-5) MyMsM
MsMy(Ds) 0-1 (DsDs) (3-5) MyMyMsM
MsMy(Ds) 0-1 (DsDs) (3-5) MyMyMyMsM
MsMyMy(Ds) 0-1 (DsDs) (3-5) MsM
MsMyMy(Ds) 0-1 (DsDs) (3-5) MyMsM
MsMyMy(Ds) 0-1 (DsDs) (3-5) MyMyMsM
MsMyMy(Ds) 0-1 (DsDs) (3-5) MyMyMyMsM
MsMyMyMy(Ds) 0-1 (DsDs) (3-5) MsM
MsMyMyMy(Ds) 0-1 (DsDs) (3-5) MyMsM
MsMyMyMy(Ds) 0-1 (DsDs) (3-5) MyMyMsM
MsMyMyMy(Ds) 0-1 (DsDs) (3-5) MyMyMyMsM
MsMyMyMyMy(Ds) 0-1 (DsDs) (3-5) MsM
MsMyMyMyMy(Ds) 0-1 (DsDs) (3-5) MyMsM
MsMyMyMyMy(Ds) 0-1 (DsDs) (3-5) MyMyMsM; and
MsMyMyMyMy(Ds) 0-1 (DsDs) (3-5) MyMyMyMsM;
wherein each M is independently a modified nucleoside, each D is a deoxynucleoside; each s is a phosphorothioate internucleoside linkage, and each y is independently either a phosphodiester internucleoside linkage or a phosphorothioate internucleoside linkage, provided that at least one y is a phosphodiester internucleotide linkage.
11. The compound of claim 9 , wherein the 5′-region consists of 2-5 linked 5′-region nucleosides; the 3′-region consists of 2-5 linked 3′-region nucleosides; and the central region consists of 8-10 central region nucleosides.
12. The compound of claim 11 , wherein each internucleoside linkage of the modified oligonucleotide is either a phosphorothioate internucleoside linkage or a phosphodiester internucleoside linkage.
13. The compound of claim 11 , wherein the modified oligonucleotide is attached to the remainder of the compound at the 5′-end of the modified oligonucleotide.
14. The compound of claim 13 , wherein the modified oligonucleotide is single-stranded.
15. The compound of claim 14 , wherein the modified oligonucleotide is complementary to a target nucleic acid.
16. The compound of claim 15 , wherein the target nucleic acid is selected from among: mRNA, pre-mRNA, micro-RNA, and long non-coding RNA.
17. A compound having the formula:
wherein X is O or S;
wherein Bx is a heterocyclic base moiety;
and wherein T 4 is a nucleoside, a monomeric subunit, or an oligomeric compound.
18. The compound of claim 17 , wherein X is S.
19. The compound of claim 17 , wherein T 4 is an oligomeric compound, and wherein the oligomeric compound is a modified oligonucleotide.
20. The compound of claim 19 , wherein the modified oligonucleotide is a gapmer.
21. The compound of claim 20 , wherein the modified oligonucleotide activates RNase H when bound to a complementary target nucleic acid.
22. The compound of claim 21 , wherein the at least one modified nucleoside is a modified nucleoside selected from a 2′-F nucleoside, a 2′-OCH 3 nucleoside, a 2′-O(CH 2 ) 2 OCH 3 nucleoside, a 2′-OC(CH 3 )H-4′ nucleoside, and a 2′-OCH 2 -4′ nucleoside.
23. The compound of claim 22 , wherein the modified nucleoside is a 2′-O(CH 2 ) 2 OCH 3 nucleoside.
24. A compound having the formula:
wherein X is O or S;
wherein Bx is a heterocyclic base moiety;
wherein T 4 is a nucleoside, a monomeric subunit, or an oligomeric compound.
25. The compound of claim 24 , wherein X is S.
26. The compound of claim 24 , wherein T 4 is an oligomeric compound, and wherein the oligomeric compound is a modified oligonucleotide.
27. The compound of claim 26 , wherein the modified oligonucleotide is a gapmer.
28. The compound of claim 27 , wherein the modified oligonucleotide activates RNase H when bound to a complementary target nucleic acid.
29. The compound of claim 28 , wherein the at least one modified nucleoside is a modified nucleoside selected from a 2′-F nucleoside, a 2′-OCH 3 nucleoside, a 2′-O(CH 2 ) 2 OCH 3 nucleoside, a 2′-OC(CH 3 )H-4′ nucleoside, and a 2′-OCH 2 -4′ nucleoside.
30. The compound of claim 29 , wherein the modified nucleoside is a 2′-O(CH 2 ) 2 OCH 3 nucleoside.