Compounds and methods for enhanced cellular uptake
Described herein are conjugated modified oligonucleotides that are complementary to a target RNA. The conjugate facilitates cellular uptake of the modified oligonucleotide, resulting improved potency.
1. A compound comprising the structure:
wherein each N of N m is, independently, a modified or unmodified nucleoside and m is 1, 2, or 3; at least one of X 1 and X 2 is a phosphodiester linkage; MO is a modified oligonucleotide; wherein when m is greater than 1, each modified or unmodified nucleoside of N m is connected to adjacent modified or unmodified nucleosides of N m by a phosphodiester internucleoside linkage or a phosphorothioate internucleoside linkage; and wherein the modified oligonucleotide consists of 8 to 25 linked nucleosides.
2. The compound of claim 1 , wherein each of X 1 and X 2 is a phosphodiester linkage.
3. The compound of claim 1 , wherein N m is N′ p N″, wherein each N′ is, independently, a modified or unmodified nucleoside and p is from 0 to 2; and N″ is a nucleoside comprising an unmodified sugar moiety; and wherein each pair of adjacent N′ nucleosides are connected by a phosphodiester internucleoside linkage or a phosphorothioate internucleoside linkage and N″ is connected to an adjacent N′ by a phosphodiester internucleoside linkage or a phosphorothioate internucleoside linkage.
4. The compound of claim 3 , wherein p is 0 or 1.
5. The compound of claim 4 , wherein each N of N m is linked by a phosphodiester internucleoside linkage.
6. The compound of claim 3 , wherein each N′ comprises an unmodified sugar moiety.
7. The compound of claim 3 , wherein N″ is a β-D-deoxyriboadenosine or a β-D-deoxyriboguanosine.
8. The compound of claim 1 , wherein the sugar moiety of each N of N m is independently selected from a β-D-ribose, a β-D-deoxyribose, a 2′-O-methoxy sugar, a 2′-O-methyl sugar, a 2′-fluoro sugar, and a bicyclic sugar moiety.
9. The compound of claim 1 , wherein the nucleobase sequence of the modified oligonucleotide is complementary to a target RNA.
10. The compound of claim 9 , wherein the target RNA is selected from a microRNA, a messenger RNA, a pre-messenger RNA, and a long non-coding RNA.
11. The compound of claim 9 , wherein the target RNA is a human target RNA.
12. The compound of claim 1 , wherein the nucleobase sequence of the modified oligonucleotide is at least 90% identical to the nucleobase sequence of a microRNA.
13. The compound of claim 12 , wherein the modified oligonucleotide is hybridized to a second modified oligonucleotide, wherein the nucleobase sequence of the second modified oligonucleotide is complementary to the nucleobase sequence of the modified oligonucleotide.
14. The compound of claim 12 , wherein the microRNA is a human microRNA.
15. The compound of claim 1 , wherein the modified oligonucleotide comprises at least one nucleoside with a modified sugar moiety.
16. The compound of claim 1 , wherein each nucleoside of the modified oligonucleotide comprises a modified sugar moiety.
17. The compound of claim 1 , wherein the modified oligonucleotide comprises a plurality of nucleosides with a modified sugar moiety, and a plurality of nucleosides with an unmodified sugar moiety.
18. The compound of claim 15 , wherein each modified sugar moiety is independently selected from a 2′-O-methyl sugar moiety, a 2′-O-methoxyethyl sugar moiety, a 2′-fluoro sugar moiety, and a bicyclic sugar moiety.
19. The compound of claim 18 , wherein each bicyclic sugar moiety is independently selected from a cEt sugar moiety and an LNA sugar moiety.
20. The compound of claim 1 , wherein the modified oligonucleotide comprises a plurality of non-bicyclic nucleosides and a plurality of bicyclic nucleosides.
21. The compound of claim 1 , wherein at least one linkage of the modified oligonucleotide is a modified internucleoside linkage.