Gapped 2' modified oligonucleotides
First Claim
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1. A compound comprising a plurality of units linked by covalent linkages in a sequence that is hybridizable to a complementary nucleic acid encoding a ras gene product, wherein:
- said units are selected from nucleosides and nucleobases;
said nucleosides are selected from α
-nucleosides, β
-nucleosides, 4'"'"'-thionucleosides and carbocyclic nucleosides;
said nucleobases are selected from purin-9-yl and pyrimidin-1-yl heterocyclic bases;
said linkages are selected from charged phosphorous, neutral phosphorous or non-phosphorous linkages;
said sequence of linked units is divided into at least two segments, wherein;
a first of said segments includes nucleosides selected from;
said α
-nucleosides linked by charged and neutral 3'"'"'-5'"'"' phosphorous linkages,said α
-nucleosides linked by charged and neutral 2'"'"'-5'"'"' phosphorous linkages,said α
-nucleosides linked by non-phosphorous linkages,said 4'"'"'-thionucleosides linked by charged and neutral 3'"'"'-5'"'"' phosphorous linkages,said 4'"'"'-thionucleosides linked by charged and neutral 2'"'"'-5'"'"' phosphorous linkages,said 4'"'"'-thionucleosides linked non-phosphorous linkages,said carbocyclic nucleosides linked by charged and neutral phosphorous linkages,said carbocyclic nucleosides linked non-phosphorous linkages,said β
-nucleosides linked by charged and neutral 3'"'"'-5'"'"' linkages,said β
-nucleosides linked by charged and neutral 2'"'"'-5'"'"' linkages,said β
-nucleosides linked by non-phosphorous linkages; and
a second of said segments including said nucleobases linked by non-phosphorous linkages and nucleobases that are attached to phosphate linkages via a non-sugar tethering moiety;
said sequence of linked nucleosides has at least one of SEQ ID NOS;
1-6; and
said compound has increased binding affinity to said complementary nucleic acid, inhibits translation of said complementary nucleic acid, and promotes RNase H cleavage in vitro.
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Abstract
Oligonucleotides and other macromolecules are provided that have increased nuclease resistance, substituent groups for increasing binding affinity to complementary strand, and subsequences of 2'"'"'-deoxy-erythro-pentofuranosyl nucleotides that activate RNase H enzyme. Such oligonucleotides and macromolecules are useful for diagnostics and other research purposes, for modulating protein in organisms, and for the diagnosis, detection and treatment of other conditions susceptible to antisense therapeutics.
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Citations
19 Claims
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1. A compound comprising a plurality of units linked by covalent linkages in a sequence that is hybridizable to a complementary nucleic acid encoding a ras gene product, wherein:
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said units are selected from nucleosides and nucleobases; said nucleosides are selected from α
-nucleosides, β
-nucleosides, 4'"'"'-thionucleosides and carbocyclic nucleosides;said nucleobases are selected from purin-9-yl and pyrimidin-1-yl heterocyclic bases; said linkages are selected from charged phosphorous, neutral phosphorous or non-phosphorous linkages; said sequence of linked units is divided into at least two segments, wherein;
a first of said segments includes nucleosides selected from;said α
-nucleosides linked by charged and neutral 3'"'"'-5'"'"' phosphorous linkages,said α
-nucleosides linked by charged and neutral 2'"'"'-5'"'"' phosphorous linkages,said α
-nucleosides linked by non-phosphorous linkages,said 4'"'"'-thionucleosides linked by charged and neutral 3'"'"'-5'"'"' phosphorous linkages, said 4'"'"'-thionucleosides linked by charged and neutral 2'"'"'-5'"'"' phosphorous linkages, said 4'"'"'-thionucleosides linked non-phosphorous linkages, said carbocyclic nucleosides linked by charged and neutral phosphorous linkages, said carbocyclic nucleosides linked non-phosphorous linkages, said β
-nucleosides linked by charged and neutral 3'"'"'-5'"'"' linkages,said β
-nucleosides linked by charged and neutral 2'"'"'-5'"'"' linkages,said β
-nucleosides linked by non-phosphorous linkages; anda second of said segments including said nucleobases linked by non-phosphorous linkages and nucleobases that are attached to phosphate linkages via a non-sugar tethering moiety; said sequence of linked nucleosides has at least one of SEQ ID NOS;
1-6; and
said compound has increased binding affinity to said complementary nucleic acid, inhibits translation of said complementary nucleic acid, and promotes RNase H cleavage in vitro. - View Dependent Claims (2, 3, 4, 5)
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6. A compound comprising a plurality of nucleosides linked by covalent linkages in a sequence that is hybridizable to a complementary nucleic acid encoding a ras gene product, wherein:
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said nucleosides are selected from α
-nucleosides, β
-nucleosides, 4'"'"'-thionucleosides and carbocyclic nucleosides;said linkages are selected from charged phosphorous linkages, neutral phosphorous linkages or non-phosphorous linkages; said sequence of linked nucleosides contains at least two nucleoside segments, wherein;
a first of said segments includes nucleosides selected from;said α
-nucleosides linked by charged and neutral 3'"'"'-5'"'"' phosphorous linkages,said α
-nucleosides linked by charged and neutral 2'"'"'-5'"'"' phosphorous linkages,said α
-nucleosides linked by non-phosphorous linkages,said 4'"'"'-thionucleosides linked by charged and neutral 3'"'"'-5'"'"' phosphorous linkages, said 4'"'"'-thionucleosides linked by charged and neutral 2'"'"'-5'"'"' phosphorous linkages, said 4'"'"'-thionucleosides linked non-phosphorous linkages, said carbocyclic nucleosides linked by charged and neutral 3'"'"'-5'"'"' phosphorous linkages, said carbocyclic nucleosides linked by charged and neutral 2'"'"'-5'"'"' phosphorous linkages, said carbocyclic nucleosides linked non-phosphorous linkages, said β
-nucleosides linked by charged and neutral 2'"'"'-5'"'"' linkages, andsaid β
-nucleosides linked by non-phosphorous linkages;a second of said segments consists of 2'"'"'-deoxy-erythro-pentofuranosyl β
nucleosides linked by charged 3'"'"'-5'"'"' phosphorous linkages having a negative charge at physiological pH;said sequence of linked nucleosides has at least one of SEQ ID NOS;
1-6; and
said compound has increased binding affinity to said complementary nucleic acid, inhibits translation of said complementary nucleic acid, and promotes RNase H cleavage in vitro. - View Dependent Claims (7, 8, 9, 10, 11, 12, 13)
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14. A compound comprising a plurality of units linked by covalent linkages in a sequence that is hybridizable to a complementary nucleic acid encoding a ras gene product, wherein:
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said units are selected from nucleosides and nucleobases; said nucleosides are selected from α
-nucleosides, β
-nucleosides, 4'"'"'-thionucleosides and carbocyclic nucleosides;said nucleobases are selected from purin-9-yl and pyrimidin-1-yl heterocyclic bases; said linkages are selected from charged 3'"'"'-5'"'"' phosphorous, neutral 3'"'"'-5'"'"' phosphorous, charged 2'"'"'-5'"'"' phosphorous neutral 2'"'"'-5'"'"' phosphorous or non-phosphorous linkages; said sequence of linked units is divided into at least two segments, wherein; a first of said segments includes linked moieties selected from; said nucleobases linked by non-phosphorous linkages, said nucleobases linked to phosphate linkages via non-sugar tethering groups, said α
-nucleosides linked by charged and neutral 3'"'"'-5'"'"' phosphorous linkages,said α
-nucleosides linked by charged and neutral 2'"'"'-5'"'"' phosphorous linkages,said α
-nucleosides linked by non-phosphorous linkages,said 4'"'"'-thionucleosides linked by charged and neutral 3'"'"'-5'"'"' phosphorous linkages, said 4'"'"'-thionucleosides linked by charged and neutral 2'"'"'-5'"'"' phosphorous linkages, said 4'"'"'-thionucleosides linked non-phosphorous linkages, said carbocyclic nucleosides linked by charged and neutral 3'"'"'-5'"'"' phosphorous linkages, said carbocyclic nucleosides linked by charged and neutral 2'"'"'-5'"'"' phosphorous linkages, said carbocyclic nucleosides linked non-phosphorous linkages, said β
-nucleosides linked by charged and neutral 2'"'"'-5'"'"' linkages, andsaid β
-nucleosides linked by non-phosphorous linkages;a second of said segments includes 2'"'"'-deoxy-erythro-pentofuranosyl β
nucleosides linked by charged 3'"'"'-5'"'"' phosphorous linkages having a negative charge at physiological pH;said sequence of linked nucleosides has at least one of SEQ ID NOS;
1-6; and
said compound has increased binding affinity to said complementary nucleic acid, inhibits translation of said complementary nucleic acid, and promotes RNase H cleavage in vitro. - View Dependent Claims (15, 16, 17, 18, 19)
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Specification