Antiviral anticancer poly-substituted phenyl derivatized oligoribonucleotides and methods for their use
First Claim
1. An oligoribonucleotide complementary to a sequence of nucleotides found in a virus or a cell, said oligoribonucleotide comprising at least one 2′
- -O position conjugated with a compound of the following general structure;
wherein R1, R2, R3, R4, and R5 are independently, H, NO2, halide, linear or branched alkyl, linear or branched acyl, linear or branched alkylene, linear or branched O-alkyl, linear or branched amido, linear or branched S-alkyl, mono or disubstituted amine, linear or branched thioamido, phosphothionate, or phosphothioate.
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Accused Products
Abstract
In accordance with the present invention, antisense oligonucleotides are provided with enhanced membrane permeability and stability. This is accomplished in accordance with the invention through conjugating oligoribonucleotides with a hydrophobic carrier agent at the 2′-O position of the oligonucleotides. The hydrophobic carrier agent comprises a compound of the following general structure:
wherein R1, R2, R3, R4, and R5 are independently H, NO2, halide, linear or branched alkyl, linear or branched acyl, linear or branched alkylene, linear or branched O-alkyl, linear or branched amido, linear or branched S-alkyl, mono or disubstituted amine, linear or branched thioamido, phosphothionate, or phosphothioate. In a preferred embodiment, R1 and R3 are NO2. In such embodiment, it will be appreciated that when R2, R4, and R5 are H, the compound is DNP and when R4 is F, the compound is FDNP. In another preferred embodiment, the antisense oligoribonucleotide comprises a sequence complementary to a cellular or viral gene, and application of the derivatized antisense oligoribonucleotide inhibits the expression of said gene.
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Citations
48 Claims
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1. An oligoribonucleotide complementary to a sequence of nucleotides found in a virus or a cell, said oligoribonucleotide comprising at least one 2′
- -O position conjugated with a compound of the following general structure;
wherein R1, R2, R3, R4, and R5 are independently, H, NO2, halide, linear or branched alkyl, linear or branched acyl, linear or branched alkylene, linear or branched O-alkyl, linear or branched amido, linear or branched S-alkyl, mono or disubstituted amine, linear or branched thioamido, phosphothionate, or phosphothioate. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22)
wherein R1, R2, R3, R4, and R5 are independently H, NO2, halide, linear or branched alkyl, linear or branched acyl, linear or branched alkylene, linear or branched O-alkyl, linear or branched amido, linear or branched S-alkyl, mono or disubstituted amine, linear or branched thioamido, phosphothionate, or phosphothioate.
- -O position conjugated with a compound of the following general structure;
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8. The oligoribonucleotide of claim 7, wherein R1 and R3 are NO2.
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9. The oligoribonucleotide of claim 8, wherein R2, R4, and R5 are H.
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10. The oligoribonucleotide of claim 1, wherein said oligoribonucleotide is complementary to a gene from the human immunodeficiency virus (HIV).
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11. The oligoribonucleotide of claim 1, wherein said oligoribonucleotide is complementary to a gene from the hepatitis B virus.
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12. The oligoribonucleotide of claim 1, wherein said oligoribonucleotide is complementary to a gene found in a leukemia cell.
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13. A multifunctional inhibitor made by a method to decrease the entropy associated with cellular uptake, said method comprising:
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(1) selecting at least 2 oligoribonucleotide sequences which separately are at least partially effective at inhibiting gene expression;
(2) combining said sequences into a combined oligoribonucleotide of between 10 and 50 nucleotides in length; and
(3) derivatizing said combined oligoribonucleotide at at least one 2′
-O position with a poly substituted phenyl compound according the compound in claim 1.
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14. The multifunctional inhibitor of claim 13, wherein at least one gene is a gene of a cancer cell.
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15. The multifunctional inhibitor of claim 14, wherein said cancer cell is selected from the group consisting of a leukemia cell and a breast cancer cell.
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16. The multifunctional inhibitor of claim 15, wherein said gene is selected from the group consisting of bcr-abl, erb-B2 and RIα
- /PKA.
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17. The multifunctional inhibitor of claim 13, wherein at least one gene is a viral gene.
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18. The multifunctional inhibitor of claim 17, wherein said viral gene is selected from the group consisting of a hepatitis B virus gene and a human immunodeficiency virus gene.
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19. The multifunctional inhibitor of claim 17, wherein said viral gene is a human immunodeficiency virus gene selected from the group consisting of tat and gag.
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20. The multifunctional inhibitor of claim 13, wherein said different oligoribonucleotide sequences are selected from the same gene.
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21. The multifunctional inhibitor of claim 13, wherein at least one of said oligoribonucleotide sequences is an antisense nucleotide sequence.
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22. The oligoribonucleotide of claim 1 that is an antisense oligoribonucleotide.
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23. A poly substituted phenyl derivatized oligoribonucleotide having a sequence selected from the group consisting of SEQ ID NO:
- 3, SEQ ID NO;
5, SEQ ID NO;
8, SEQ ID NO;
9, SEQ ID NO;
10, SEQ ID NO;
13, SEQ ID NO;
14, SEQ ID NO;
15, SEQ ID NO;
16, SEQ ID NO;
19, SEQ ID NO;
20, SEQ ID NO;
21, SEQ ID NO;
23, SEQ ID NO;
24, SEQ ID NO;
25 and SEQ ID NO;
26.
- 3, SEQ ID NO;
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24. A poly substituted phenyl derivatized oligoribonucleotide which hybridizes with the complement of at least one sequence selected from the group consisting of SEQ ID NO:
- 3, SEQ ID NO;
5, SEQ ID NO;
8, SEQ ID NO;
9, SEQ ID NO;
10, SEQ ID NO;
13, SEQ ID NO;
14, SEQ ID NO;
15, SEQ ID NO;
16, SEQ ID NO;
19, SEQ ID NO;
20, SEQ ID NO;
21, SEQ ID NO;
23, SEQ ID NO;
24, SEQ ID NO;
25 and SEQ ID NO;
26 under stringent hybridization conditions.
- 3, SEQ ID NO;
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25. A method of delivering an oligoribonucleotide to a cell, comprising the steps of:
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selecting an oligoribonucleotide complementary to a nucleotide sequence found in a virus or a cell, said oligoribonucleotide being derivatized at a plurality of the 2′
-O positions with a compound of the following structure;
wherein R1, R2, R3, R4, and R5 are independently H, NO2, halide, linear or branched alkyl, linear or branched acyl, linear or branched alkylene, linear or branched O-alkyl, linear or branched amido, linear or branched S-alkyl, mono or disubstituted amine, linear or branched thioamido, phosphothionate, or phosphothioate; and
administering said derivatized oligoribonucleotide to at least one of said virus and said cell. - View Dependent Claims (26, 27, 28, 29, 30, 31)
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32. A method for increasing the effectiveness of an oligoribonucleotide targeted to a gene associated with a disease or condition in an animal, comprising:
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selecting a non-derivatized oligoribonucleotide comprising a plurality of 2′
-O positions wherein said oligoribonucleotide is at least partially effective in reducing the symptoms of said disease;
derivatizing said oligoribonucleotide at said plurality of 2′
-O positions with a substituted phenyl moiety therby making a derivatized oligoribonucleotide; and
administering said derivatized oligoribonucleotide to said animal, and wherein said derivatized oligoribonucleotide is more effective at decreasing symptoms of disease than is said non-derivatized oligoribonucleotide. - View Dependent Claims (33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48)
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Specification