Targeted therapeutic nucleosides and their use
Provided herein are compounds comprising one or more therapeutic nucleosides and one or more targeting groups. In certain embodiments, the compounds further comprise one or more oligonucleotides. In certain embodiments, a targeting group comprises one or more N-Acetylgalactosamine.
1. A compound consisting of a targeting group and one therapeutic nucleoside, wherein the targeting group comprises at least one cell-targeting ligand, wherein each cell-targeting ligand is N-acetylgalactosamine.
2. The compound of claim 1 , wherein the targeting group comprises 3 cell-targeting ligands.
3. The compound of claim 1 , wherein the targeting group comprises a cleavable moiety.
4. The compound of claim 1 , wherein the targeting group comprises a structure represented by formula I below:
wherein:
A is a cell-targeting ligand;
B is a tether;
C is a branching group;
D is a targeting group linker;
E is a cleavable moiety;
n is 1, 2, 3, 4, or 5; and
m is 0 or 1.
5. The compound of claim 1 , wherein the therapeutic nucleoside comprises a furanosyl ring.
6. The compound of claim 5 , wherein the furanosyl ring of the therapeutic nucleoside comprises a 2′ or 3′ substituent independently selected from hydrogen, halogen, hydroxyl, amino, alkyl, alkenyl, alkynyl, alkoxy, CF 3 , and ester, wherein if the 3′ substituent is hydroxyl, the 2′ substituent is not hydrogen or hydroxyl.
7. The compound of claim 1 , wherein the compound has the following structure:
wherein R 3 is hydroxyl or the targeting group; and
R 4 and R 5 are each independently selected from phenoxy, NHCH(CH 3 )C(O)OiPr, alkoxy, alkylamino, hydroxyl, and the targeting group;
provided that one and only one of R 3 , R 4 , and R 5 is a targeting group.
8. The compound of claim 1 , wherein the compound comprises the following structure:
wherein B is a modified or unmodified nucleobase;
X is O or CCH 2 ;
Y is S or CR 6 R 7 ; and
R 6 and R 7 are each independently selected from hydrogen, hydroxyl, O-L-valinyl ester, and the targeting group,
provided that if either of R 6 or R 7 is the targeting group, the structure is attached to a hydrogen; and provided that if neither R 6 nor R 7 is the targeting group, the structure is attached to the targeting group.
9. The compound of claim 1 , wherein the therapeutic nucleoside is an antiviral nucleoside.
10. The compound of claim 9 , wherein the antiviral nucleoside inhibits a viral polymerase.
11. The compound of claim 9 , wherein the antiviral nucleoside is selected from among an anti-HCV nucleoside and an anti-HBV nucleoside.
12. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent.
13. A method of treating an RNA-dependent virus infection comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of claim 9 .
14. The compound of claim 1 , wherein the targeting group comprises 1 N-acetylgalactosamine.
15. The compound of claim 1 , wherein the targeting group comprises 2 N-acetylgalactosamines.
16. The compound of claim 3 , wherein the cleavable moiety is a phosphodiester bond.