2′-Fluoro substituted oligomeric compounds and compositions for use in gene modulations
Compositions comprising first and second oligomers are provided wherein at least a portion of the first oligomer is capable of hybridizing with at least a portion of the second oligomer, at least a portion of the first oligomer is complementary to and capable of hybridizing to a selected target nucleic acid, and at least one of the first or second oligomers includes a modified sugar and/or backbone modification. In some embodiments the modification is a 2′-F substituent group on a sugar moiety. Oligomer/protein compositions are also provided comprising an oligomer complementary to and capable of hybridizing to a selected target nucleic acid and at least one protein comprising at least a portion of an RNA-induced silencing complex (RISC), wherein at least one nucleoside of the oligomer has a modified sugar and/or backbone modification.
1. A composition comprising first and second chemically synthesized oligomeric compounds, wherein:
the first and second chemically synthesized oligomeric compounds are not covalently linked to each other;
each of the first and second oligomeric compounds consists of 20 to 24 linked nucleosides;
the first oligomeric compound is 100% complementary to the second oligomeric compound and to a selected target messenger RNA;
the first oligomeric compound has the formula:
(Z 1 ) n —X 1 —Y 1 —X 2 —Y 2 —X 3 —Y 3 —X 4 —Y 4 —(Z 2 ) m
wherein:
each Z 1 is, independently, a natural or modified nucleoside;
X 1 is a region of two 2′-F modified nucleosides;
Y 1 is a region of one 2′-O-methyl modified nucleoside;
X 2 is a region of two 2′-F modified nucleosides;
Y 2 is a region of two 2′-O-methyl modified nucleosides;
X 3 is a region of five 2′-F modified nucleosides;
Y 3 is a region of three 2′-O-methyl modified nucleosides;
X 4 is a region of three 2′-F modified nucleosides;
Y 4 is a region of two 2′-O-methyl modified nucleosides;
each Z 2 is, independently, a natural or modified nucleoside; and
n and m are each, independently, 0, 1, or 2; and
the second oligomeric comprises a plurality of ribose nucleoside subunits.
2. The composition of claim 1 comprising a conjugate.
3. The composition of claim 2 , wherein the conjugate is attached to either the 5′ or 3′ terminal nucleoside of either the first or the second oligomeric compound.
4. The composition of claim 1 , wherein the target messenger RNA is a mammalian messenger RNA.
5. The composition of claim 4 , wherein the target messenger RNA is a human messenger RNA.
6. The composition of claim 1 wherein Z 1 is deoxythymidine.
7. The composition of claim 1 wherein Z 2 is deoxythymidine.
8. The composition of claim 1 wherein Z 1 and Z 2 are each deoxythymidine.
9. The composition of claim 1 wherein n and m are each 0.
10. The composition of claim 1 wherein n and m are each 1.
11. The composition of claim 1 wherein n and m are each 2.
12. The composition of claim 1 wherein n is 0 and m is 1.
13. The composition of claim 1 wherein n is 0 and m is 2.
14. The composition of claim 1 wherein n is 1 and m is 0.
15. The composition of claim 1 wherein n is 1 and m is 2.
16. The composition of claim 1 wherein n is 2 and m is 0.
17. The composition of claim 1 wherein n is 2 and m is 1.
18. A composition comprising first and second chemically synthesized oligomeric compounds, wherein:
the first and second chemically synthesized oligomeric compounds are not covalently linked to each other;
each of the first and second oligomeric compounds consists of 20 linked nucleosides;
the first oligomeric compound is 100% complementary to the second oligomeric compound and to a selected target messenger RNA;
the first oligomeric compound has the formula:
X 1 —Y 1 —X 2 —Y 2 —X 3 —Y 3 —X 4 —Y 4
wherein:
X 1 is a region of two 2′-F modified nucleosides;
Y 1 is a region of one 2′-O-methyl modified nucleoside;
X 2 is a region of two 2′-F modified nucleosides;
Y 2 is a region of two 2′-O-methyl modified nucleosides;
X 3 is a region of five 2′-F modified nucleosides;
Y 3 is a region of three 2′-O-methyl modified nucleosides;
X 4 is a region of three 2′-F modified nucleosides; and
Y 4 is a region of two 2′-O-methyl modified nucleosides; and
the second oligomeric comprises a plurality of ribose nucleoside subunits.
19. The composition of claim 18 comprising a conjugate.
20. The composition of claim 19 , wherein the conjugate is attached to either the 5′ or 3′ terminal nucleoside of either the first or the second oligomeric compound.
21. The composition of claim 18 , wherein the target messenger RNA is a mammalian messenger RNA.
22. The composition of claim 21 , wherein the target messenger RNA is a human messenger RNA.