Oligoribonucleotides for cleaving RNA
First Claim
1. A synthetic oligomeric compound which is specifically hybridizable with a preselected RNA target and comprises;
- a first segment having at least one ribofuranosyl nucleoside subunit which is modified to improve the binding affinity of said compound to the preselected RNA target when compared to the binding affinity of an unmodified oligoribonucleotide to the RNA target; and
a second segment comprising at least four consecutive ribofuranosyl nucleoside subunits having 2'"'"'-hydroxyl moieties thereon;
said nucleoside subunits of said oligomeric compound being connected by internucleoside linkages which are modified to stabilize said linkages from degradation as compared to phosphodiester linkages.
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Accused Products
Abstract
Oligomeric compounds including oligoribonucleotides and oligoribonucleosides are provided that have subsequences of 2-pentoribofuranosyl nucleosides that activate dsRNase. The oligoribonucleotides and oligoribonucleosides can include substituent groups for increasing binding affinity to complementary nucleic acid strand as well as substituent groups for increasing nuclease resistance. The oligomeric compounds are useful for diagnostics and other research purposes, for modulating the expression of a protein in organisms, and for the diagnosis, detection and treatment of other conditions susceptible to oligonucleotide therapeutics.
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Citations
66 Claims
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1. A synthetic oligomeric compound which is specifically hybridizable with a preselected RNA target and comprises;
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a first segment having at least one ribofuranosyl nucleoside subunit which is modified to improve the binding affinity of said compound to the preselected RNA target when compared to the binding affinity of an unmodified oligoribonucleotide to the RNA target; and a second segment comprising at least four consecutive ribofuranosyl nucleoside subunits having 2'"'"'-hydroxyl moieties thereon; said nucleoside subunits of said oligomeric compound being connected by internucleoside linkages which are modified to stabilize said linkages from degradation as compared to phosphodiester linkages. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 43, 44, 45, 46, 47)
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10. A synthetic oligomeric compound which is specifically hybridizable with a preselected RNA target and comprises;
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a first segment having at least one ribofuranosyl nucleoside subunit that is modified to improve at least one of;
pharmacokinetic binding, absorption, distribution or clearance properties of the compound;
affinity or specificity of said compound to said target RNA;
or modification of the charge of said compound as compared to unmodified compound; anda second segment comprising at least four consecutive ribofuranosyl nucleoside subunits having 2'"'"'-hydroxyl moieties thereon; said nucleoside subunits of said oligomeric compound being connected by internucleoside linkages which are modified to stabilize said linkages from degradation as compared to phosphodiester linkages. - View Dependent Claims (11, 12, 13, 14, 15, 16, 17, 18)
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19. A synthetic oligomeric compound which is specifically hybridizable with a preselected RNA target comprising;
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a first segment having at least one 2'"'"'-O-C1-20 alkyl, 2'"'"'-O-substituted C1-20 alkyl or 2'"'"'-fluoro modified ribofuranosyl nucleoside subunit where the substitution on said alkyl is amino, hydroxy or C1-10 alkyl ether modification; a second segment comprising at least four consecutive ribofuranosyl nucleoside subunits having 2'"'"'-hydroxyl moieties thereon; and said nucleoside subunits of said oligomeric compound being connected by internucleoside linkages that are stable to degradation as compared to phosphodiester bonds. - View Dependent Claims (20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37)
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38. A synthetic oligomeric compound which is specifically hybridizable with a preselected RNA comprising at least twelve ribofuranosyl nucleosides in a sequence;
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said nucleoside subunits being joined by internucleoside bonds which are more stable to degradation as compared to phosphodiester bonds; the compound having two wing portions interspaced by a gap portion; the wing portions each comprising at least one modified nucleoside subunit, which modified nucleoside subunit is modified to improve at least one of;
pharmacokinetic binding, absorption, distribution or clearance properties of the compound;
affinity or specificity of said compound to said target RNA;
or modification of the charge of said compound as compared to unmodified compound;the gap portion having at least four consecutive ribonucleoside subunits. - View Dependent Claims (39)
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40. A synthetic oligomeric compound comprising, in sequence;
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a first segment having a plurality of 2'"'"'-O-alkyl nucleoside subunits; a second segment having at least four consecutive 2'"'"'-hydroxyl ribonucleoside subunits; and a third segment having a plurality of 2'"'"'-O-alkyl nucleoside subunits; and the nucleoside subunits of the oligomer being joined by phosphorothioate internucleoside linkages. - View Dependent Claims (41, 42)
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48. A synthetic oligomeric compound which is specifically hybridizable with a preselected RNA target comprising;
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a first segment including at least one surrogate nucleoside subunit; a second segment comprising at least four ribofuranosyl nucleoside subunits located in a consecutive sequence and having 2'"'"'-hydroxyl moieties thereon; and said nucleoside subunits of said oligomeric compound being connected by internucleoside linkages that are stable to degradation as compared to phosphodiester bonds. - View Dependent Claims (49, 50, 51, 52)
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53. A synthetic oligomeric compound which is specifically hybridizable with a preselected RNA target comprising;
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a first segment including at least two nucleoside subunits; said nucleoside subunits of said first segment being connected by non-phosphorus internucleoside linkages; a second segment comprising at least four consecutive ribofuranosyl nucleoside subunits having 2'"'"'-hydroxyl moieties thereon; and said nucleoside subunits of said second segment being connected by internucleoside linkages that are stable to degradation as compared to phosphodiester bonds. - View Dependent Claims (54, 55, 56)
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57. A synthetic oligomeric compound which is specifically hybridizable with a preselected RNA target comprising;
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a first segment including at least three nucleoside subunits; said nucleoside subunits of said first segment being connected by alternating phosphorus, non-phosphorus internucleoside linkages; a second segment comprising at least four consecutive ribofuranosyl nucleoside subunits having 2'"'"'-hydroxyl moieties thereon; and said nucleoside subunits of said second segment being connected by internucleoside linkages that are more stable to degradation as compared to phosphodiester bonds. - View Dependent Claims (58, 59, 60)
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61. A synthetic oligomeric compound which is specifically hybridizable with a preselected RNA target comprising;
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a first segment including at least two nucleoside subunits; said nucleoside subunits of said first segment being connected by 3'"'"'-deoxy-3'"'"'-thio-phosphorothioate, 5'"'"'-deoxy-5'"'"'-thio-phosphorothioate, phosphorodithioate, phosphoroselenate, 3'"'"'-deoxy phosphinate, 5'"'"'-deoxy phosphinate, borano phosphate, 3'"'"'-deoxy-3'"'"'-amino phosphoramidate, 5'"'"'-deoxy-5'"'"'-amino phosphoramidate, hydrogen phosphonate, borano phosphate ester, phosphoramidate, alkyl phosphonate, aryl phosphonate or phosphotriester phosphate linkages; and a second segment comprising at least four consecutive ribofuranosyl nucleoside subunits having 2'"'"'-hydroxyl moieties thereon; and said nucleoside subunits of said second segment being connected by internucleoside linkages that are more stable to degradation as compared to phosphodiester bonds. - View Dependent Claims (62, 63)
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64. A synthetic oligomeric compound which is specifically hybridizable with a preselected RNA target and comprises;
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a first segment having at least one ribofuranosyl nucleoside subunit that is not a DNA or RNA major building block nucleoside; a second segment comprising at least four consecutive ribofuranosyl nucleoside subunits having 2'"'"'-hydroxyl moieties thereon; said nucleoside subunits of said oligomeric compound being connected by internucleoside linkages which are modified to stabilize said linkages from degradation as compared to phosphodiester linkages. - View Dependent Claims (65)
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66. A synthetic oligomeric compound which is specifically hybridizable with a preselected RNA target and comprises;
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a first segment having at least one ribofuranosyl nucleoside subunit excluding the nucleoside group consisting of adenosine, 2'"'"'-deoxyadenosine, guanosine, 2'"'"'-deoxyguanosine, cytidine, 2'"'"'-deoxycytidine, uridine and 2'"'"'-deoxythymidine; a second segment comprising at least four consecutive ribofuranosyl nucleoside subunits having 2'"'"'-hydroxyl moieties thereon; said nucleoside subunits of said oligomeric compound being connected by internucleoside linkages which are modified to stabilize said linkages from degradation as compared to phosphodiester linkages.
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Specification