Phosphorous-linked oligomeric compounds and their use in gene modulation
Oligonucleotide compositions comprising first and second oligonucleotides are provided wherein at least a portion of the first oligonucleotide is capable of hybridizing with at least a portion of the second oligonucleotide, at least a portion of the first oligonucleotide is complementary to and capable of hybridizing to a selected target nucleic acid, and at least one of the first or second oligonucleotides includes at least one nucleotide having a modified phosphorous-containing internucleoside linkage. Oligonucleotide/protein compositions are also provided comprising an oligonucleotide 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 nucleotide of the oligonucleotide has a modified phosphorous-containing internucleoside linkage.
1. A composition comprising a first oligomer and a second oligomer, wherein:
each of said first and second oligomers, independently, has from 12 to 30 nucleobases;
at least a portion of said first oligomer is capable of hybridizing with at least a portion of said second oligomer,
at least a portion of said first oligomer is complementary to and capable of hybridizing to a selected target nucleic acid, and
at least one of said first or said second oligomers includes at least one 2′-5′ internucleoside linkage, located between the 5′-terminal nucleoside and the adjacent nucleoside of said first or said second oligomers, having the formula:
wherein Y is O or S; and
a 5′-modified phosphate group.
2. The composition of claim 1 wherein said 5′-terminal nucleoside has one of the following formulas:
wherein:
Y is O or S;
T 3 is said 5′-modified phosphate group;
R 1 is H, OH, or OCH 3 ;
R 2 is O—CH 2 —CH 2 —NH—C(NH)NH 2 or O—CH 2 —CH 2 —N(CH 3 ) 2 ; and
B is adenine, guanine, cytosine, uracil, 5-methyl uracil, or 5-methyl cytosine.
3. The composition of claim 1 wherein said 2′-5′ internucleoside linkage is located on said first oligomer.
4. The composition of claim 1 wherein said 2′-5′ internucleoside linkage is located on said second oligomer.
5. The composition of claim 1 wherein said first or second oligomer comprises a 5′-modified phosphate group.
6. The composition of claim 1 wherein said first and second oligomers are a complementary pair of siRNA oligomers.
7. The composition of claim 1 wherein said first and second oligomers each comprise at least one 2′-5′ internucleoside linkage.
8. A composition comprising an oligomer complementary to and capable of hybridizing to a selected target nucleic acid, wherein:
said oligomer has from 12 to 30 nucleobases;
said oligomer includes at least one 2′-5′ internucleoside linkage, located between the 5′-terminal nucleoside and the adjacent nucleoside, having the formula:
wherein Y is O or S; and
wherein said oligomer includes a 5′-modified phosphate group.
9. The composition of claim 8 wherein said 2′-5′ internucleoside linkage is a 2′-5′ adenosine linkage, 2′-5′ adenosine phosphorothioate linkage, or a 2′-5′ xyloadenosine linkage.
10. The composition of claim 8 wherein said 5′-terminal nucleoside has of one of the following formulas:
wherein:
Y is O or S;
R 1 is H, OH, or OCH 3 ;
R 2 is O—CH 2 —CH 2 —NH—C(NH)NH 2 or O—CH 2 —CH 2 —N(CH 3 ) 2 ;
B is adenine, guanine, cytosine, uracil, 5-methyl uracil, or 5-methyl cytosine; and
T 3 is said modified phosphate group.
11. A method of modulating the expression of a target nucleic acid in a cell comprising contacting said cell with a composition of claim 1 .
12. A method of modulating the expression of a target nucleic acid in a cell comprising contacting said cell with a composition of claim 8 .