Antisense agents combining strongly bound base-modified oligonucleotide and artificial nuclease
First Claim
1. A compound comprising an oligonucleotide having from 5 to 150 nucleobases and a chelating moiety attached to the oligonucleotide, wherein at least 10% of said nucleobases are a modified nucleobase selected from the group consisting of:
- 5-mercaptocytosine, 5-mercaptouracil, 8-mercaptoguanine, 8-mercaptoadenine, 5-hydroxycytosine, 5-hydroxyuracil, 8-hydroxyadenine and 8-hydroxyguanine.
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Abstract
The present invention provides compounds having a chelating moiety and an oligonucleotide sequence wherein the oligonucleotide includes one or more modified nucleobases, such as hydroxynucleobases. The disclosed compounds are suitable for antisense therapy. The chelating moiety can be complexed to an ion of a lanthanide metal. These compounds are efficient translation inhibitors of nucleic acids and have increased binding affinity for target nucleic acids. The invention also includes compositions and methods of using these compositions as antisense therapy.
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Citations
37 Claims
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1. A compound comprising an oligonucleotide having from 5 to 150 nucleobases and a chelating moiety attached to the oligonucleotide, wherein at least 10% of said nucleobases are a modified nucleobase selected from the group consisting of:
- 5-mercaptocytosine, 5-mercaptouracil, 8-mercaptoguanine, 8-mercaptoadenine, 5-hydroxycytosine, 5-hydroxyuracil, 8-hydroxyadenine and 8-hydroxyguanine.
- View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 37)
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33. A method of making a compound to inhibit translation of a nucleic acid of an organism under physiological conditions of the organism, comprising:
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a) determining a nucleotide sequence of a target nucleic acid; b) synthesizing a compound that comprises a chelating moiety attached to an oligonucleotide that comprises a nucleotide sequence that is sufficiently complementary to at least part of the nucleotide sequence of the target nucleic acid to permit the hybridization, wherein the oligonucleotide comprises from 5 to 150 nucleobases and wherein at least 10% of the nucleobases of the oligonucleotide are a modified nucleobase selected from the group consisting of;
5-mercaptocytosine, 5-mercaptouracil, 8-mercaptoguanine, 8-mercaptoadenine, 5-hydroxycytosine, 5-hydroxyuracil, 8-hydroxyadenine and 8-hydroxyguanine; andc) mixing said compound with an ion of a metal selected from the group consisting of lanthanum, cerium, praseodymium, neodymium, promethium, samarium, europium, gadolinium, terbium, dysprosium, holmium, erbium, thulium, ytterbium, and lutetium. - View Dependent Claims (34, 35, 36)
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Specification