Oligonucleotides bearing free, uncapped 5′ phosphate group(s) are recognized by RIG-I, leading to the induction of type I IFN, IL-18 and IL-1β production. Bacterial RNA also induces type I IFN production. 5′ phosphate oligonucleotides and bacterial RNA can be used for inducing an anti-viral response
Oligonucleotides bearing free, uncapped 5′ phosphate group(s) are recognized by RIG-I, leading to the induction of type I IFN, IL-18 and IL-1β production. Bacterial RNA also induces type I IFN production. 5′ phosphate oligonucleotides and bacterial RNA can be used for inducing an anti-viral response or an anti-bacterial response, in particular, type I IFN and/or IL-18 and/or IL-1β production, in vitro and in vivo and for treating various disorders and diseases such as viral infections, bacterial infections, parasitic infections, tumors, allergies, autoimmune diseases, immunodeficiencies and immunosuppression. Single-stranded 5′ triphosphate RNA can be used for inducing an anti-viral response, an anti-bacterial response, or an anti-tumor response, in particular, type I IFN and/or IL-18 and/or IL-1β production, in a target cell-specific manner.
대표청구항▼
1. A modified double-stranded oligonucleotide wherein the oligonucleotide is 19 to 57 nucleotides in length and wherein each strand of the double-stranded oligonucleotide comprises a 5′ end and a 3′ end, the 5′ end comprising a 5′ triphosphate, and at least 1 ribonucleotide, wherein the ribonucleoti
1. A modified double-stranded oligonucleotide wherein the oligonucleotide is 19 to 57 nucleotides in length and wherein each strand of the double-stranded oligonucleotide comprises a 5′ end and a 3′ end, the 5′ end comprising a 5′ triphosphate, and at least 1 ribonucleotide, wherein the ribonucleotide at the 5′ end is selected from the group of ribonucleotides consisting of adenine and guanine, wherein the double-stranded oligonucleotide has no overhangs or has a one- or two-nucleotide overhang at the 3′ end of one strand. 2. The oligonucleotide of claim 1, wherein the oligonucleotide comprises a 2′-O-methylribonucleoside, a 2′-O-methoxyethylribonucleoside, 2′-O-allylribonucleoside, 2′-O-propargylribonucleoside or an oxymethylene bridge to the 4′ carbon of the same ribose sugar. 3. The oligonucleotide of claim 1, wherein the oligonucleotide comprises an internucleoside linkage selected from phosphodiester, phosphorothioate, phosphorodithioate, and boranophosphate. 4. The oligonucleotide of claim 1, wherein the oligonucleotide comprises at the 3′ end of at least one strand a 3′ cationic group, or a 3′ C5-aminoalkyl dT. 5. The oligonucleotide of claim 1, wherein oligonucleotide comprises a 2′-deoxyribonucleotide region. 6. The oligonucleotide of claim 1, wherein the oligonucleotide is covalently linked to one or more lipophilic group. 7. The oligonucleotide of claim 6, wherein the lipophilic group is selected from an sterol, cholic acid, deoxycholic acid, dehydrocholic acid, cortisone, digoxigenin, testosterone, cholesterol, cholesteryl (6-hydroxyhexyl) carbamate, saturated fatty acids, unsaturated fatty acids, waxes, a C10 terpene, a C15 sesquiterpene, a C20 diterpene, a C30 triterpene, a C40 tetraterpene. 8. The oligonucleotide of claim 6, wherein the lipophilic group is attached via a phosphodiester group. 9. The oligonucleotide of claim 6, wherein the lipophilic group is linked to the 3′ end of at least one strand of the oligonucleotide. 10. The oligonucleotide of claim 1, wherein the oligonucleotide comprises a 2′-modified ribose, in which the hydroxyl group at the 2′ position is replaced by an oxymethylene bridge to the 4′ carbon of the same ribose sugar, or an amino, fluoro, methoxy, or allyloxy group. 11. The oligonucleotide of claim 1, herein the oligonucleotide is covalently linked to at least one antigen. 12. The oligonucleotide of claim 1, wherein said oligonucleotide is formulated with a pharmaceutically acceptable carrier or diluent. 13. The oligonucleotide of claim 12, further comprising one or more of a complexation agent, an antiviral agent, an anti-tumor agent, an immunostimulatory agent, type I IFN, and an antigen. 14. A modified double-stranded oligonucleotide wherein the oligonucleotide is 19 to 0.57 nucleotides in length and wherein each strand of the oligonucleotide comprises a 5′ end and a 3′ end, the 5′ end comprising a 5′ triphosphate and at least 1 ribonucleotide at the 5′ end, wherein the first ribonucleotide at the 5′ end is selected from the group of ribonucleotides consisting of adenine and guanine; and wherein the oligonucleotide comprises nucleosides selected from the group consisting of adenine, cytosine, guanine, thymidine, and uracil, and wherein the double-stranded oligonucleotide has no overhangs or has a one- or two-nucleotide overhang at the 3′ end of one strand and wherein the backbone of the oligonucleotide is modified. 15. The oligonucleotide of claim 14, wherein the oligonucleotide is covalently linked to at least one antigen. 16. The oligonucleotide of claim 14, wherein the oligonucleotide is formulated with a pharmaceutically acceptable carrier or diluent. 17. The oligonucleotide of claim 16, further comprising one or more of a complexation agent, an antiviral agent, an anti-tumor agent, an immunostimulatory agent, type I IFN, and an antigen. 18. A composition comprising a viral vector encoding the oligonucleotide of claim 14, and a pharmaceutically acceptable carrier or diluent. 19. The composition of claim 18, further comprising one or more of a complexation agent, an antiviral agent, an anti-tumor agent, an immunostimulatory agent, type I IFN, and an antigen. 20. A method of preventing or treating a tumor in a vertebrate animal comprising administering an effective amount of the oligonucleotide of claim 1 to the vertebrate animal in need thereof, thereby preventing or treating a tumor in the vertebrate animal. 21. A method of preventing or treating a tumor in a vertebrate animal comprising administering an effective amount of the oligonucleotide of claim 14 to the vertebrate animal in need thereof, thereby preventing or treating a tumor in the vertebrate animal. 22. A method of preventing or treating a tumor in a vertebrate animal comprising administering an effective amount of the composition of claim 18 to the vertebrate animal in need thereof, thereby preventing or treating a tumor in the vertebrate animal. 23. A method for inducing apoptosis of a tumor cell, comprising contacting a tumor cell with the oligonucleotide of claim 1 to thereby induce apoptosis of the tumor cell. 24. A method for inducing apoptosis of a tumor cell, comprising contacting a tumor cell with the oligonucleotide of claim 14 to thereby induce apoptosis of the tumor cell. 25. A method for inducing apoptosis of a tumor cell, comprising contacting a tumor cell with the composition of claim 18 to thereby induce apoptosis of the tumor cell. 26. A combined preparation comprising the oligonucleotide of claim 1 and an agent selected from an anti-viral agent and an anti-tumor agent, wherein the oligonucleotide or the precursor thereof and the agent are for simultaneous, separate or sequential administration. 27. A combined preparation comprising the oligonucleotide of claim 14 and an agent selected from an anti-viral agent and an anti-tumor agent, wherein the oligonucleotide or the precursor thereof and the agent are for simultaneous, separate or sequential administration. 28. The modified oligonucleotide of claim 1, wherein one or more of the components of the oligonucleotide is different from that which occurs in nature. 29. The modified oligonucleotide of claim 14, wherein the oligonucleotide comprises a phosphorothioate internucleoside linkage.
연구과제 타임라인
LOADING...
LOADING...
LOADING...
LOADING...
LOADING...
이 특허에 인용된 특허 (36)
Ecker David J. (Carlsbad CA), Antisense inhibitors of the human immunodeficiency virus phosphorothioate oligonucleotides.
Wilfried Seifert, Compositions and methods for inhibiting cox-2 expression and treating cox-2 associated disorders by using cox-2 antisense oligonucleotides.
Agrawal Sudhir (Shrewsbury MA) Leiter Josef M. E. (Brooklyn NY) Palese Peter (Leonia NJ) Zamecnik Paul C. (Shrewsbury MA), Inhibition of influenza virus replication by oligonucleotide phosphorothioates.
Harel Bellan,Annick; Ait Si Ali,Slimane; Cabon Georget,Florence; Chauchereau,Anne; Dautry,Francois, Inhibitor oligonucleotides and their use for specific repression of a gene.
Cohen Jack S. (Bethesda MD) Neckers Len (Bethesda MD) Stein Cy (Gaithersburg MD) Loke She L. (Wheaton MD) Shinozuka Kazuo (Kazo JPX), Inhibitors for replication of retroviruses and for the expression of oncogene products.
Stec Wojciech J. (Lodz PLX) Grajkowski Andrzej (Lodz PLX) Uznanski Bogdan (Lodz PLX), Method of making oligonucleotides and oligonucleotide analogs using phospholanes and enantiomerically resolved phosphola.
Pederson Thoru (Worcester MA) Agrawal Sudhir (Shrewsbury MA) Mayrand Sandra (Shrewsbury MA) Zamecnik Paul C. (Shrewsbury MA), Method of site-specific alteration of RNA and production of encoded polypeptides.
Pederson Thoru (Worcester MA) Agrawal Sudhir (Shrewsbury MA) Mayrand Sandra (Shrewsbury MA) Zamecnik Paul C. (Shrewsbury MA), Method of site-specific alteration of RNA and production of encoded polypeptides.
Stec Wojciech J. (Lodz PLX) Uznanski Bogdan (Lodz CA PLX) Bergot B. John (Redwood City CA) Hirschbein Bernard L. (San Francisco CA) Fearson Karen L. (Union City CA), Method of synthesizing sulfurized oligonucleotide analogs.
Beigelman Leonid ; Burgin Alex ; Beaudry Amber ; Karpeisky Alexander ; Matulic-Adamic Jasenka ; Sweedler David, Nucleoside triphosphates and their incorporation into oligonucleotides.
Cook, Phillip D.; Wang, Guangyi; Bruice, Thomas W.; Boyle, Nicholas A.; Leeds, Janet M.; Brooks, Jennifer L.; Prhavc, Marija; Ariza, Maria Eugenia; Fagan, Patrick C.; Jin, Yi; Rajwanshi, Vivek K.; Tucker, Kathleen D., Nucleotide mimics and their prodrugs.
Cook, Phillip D.; Wang, Guangyi; Bruice, Thomas W.; Boyle, Nicholas A.; Leeds, Janet M.; Brooks, Jennifer L.; Prhavc, Marija; Ariza, Maria Eugenia; Fagan, Patrick C.; Jin, Yi; Rajwanshi, Vivek K.; Tucker, Kathleen D., Nucleotide mimics and their prodrugs.
Eppstein Deborah A. (Los Altos CA) Fraser-Smith Elizabeth B. (Los Altos CA) Matthews Thomas R. (Los Gatos CA), Serial injection of muramyldipeptides and liposomes enhances the anti-infective activity of muramyldipeptides.
※ AI-Helper는 부적절한 답변을 할 수 있습니다.