OLIGONUCLEOTIDE-BASED COMPOUNDS AS INHIBITORS OF TOLL-LIKE RECEPTORS
First Claim
Patent Images
1. An oligonucleotide-based TLR antagonist containing a modified immune stimulatory motif comprising one or more modified immune stimulatory motifs, wherein CG is the modified immune stimulatory motif, wherein C is cytosine, or a pyrimidine nucleotide derivative selected from 5-methyl-dC, 2′
- -O-substituted-C, 2′
-O-methyl-C, 2′
-O-methoxyethoxy-C, 2′
-O-methoxyethyl-5-methyl-C, and 2′
-O-methyl-5-methyl-C, and G is guanosine or a purine nucleotide derivative selected from 2′
-O-substituted-G, 2′
-O-methyl-G, and 2′
-O-methoxyethoxy-G;
provided that at least one C and/or G of the modified immune stimulatory motif is a specified nucleotide derivative;
wherein the modified immune stimulatory motif would be immune stimulatory but for the nucleotide derivative.
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Abstract
The invention provides novel oligonucleotide-based TLR antagonists containing a modified immune stimulatory motif and the use of such compounds in the prevention and treatment of TLR-medicated diseases. These oligonucleotide-based TLR antagonists containing a modified immune stimulatory motif have one or more chemical modifications in the immune stimulatory motif, which would be immune stimulatory but for the modification.
41 Citations
17 Claims
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1. An oligonucleotide-based TLR antagonist containing a modified immune stimulatory motif comprising one or more modified immune stimulatory motifs, wherein CG is the modified immune stimulatory motif, wherein C is cytosine, or a pyrimidine nucleotide derivative selected from 5-methyl-dC, 2′
- -O-substituted-C, 2′
-O-methyl-C, 2′
-O-methoxyethoxy-C, 2′
-O-methoxyethyl-5-methyl-C, and 2′
-O-methyl-5-methyl-C, and G is guanosine or a purine nucleotide derivative selected from 2′
-O-substituted-G, 2′
-O-methyl-G, and 2′
-O-methoxyethoxy-G;
provided that at least one C and/or G of the modified immune stimulatory motif is a specified nucleotide derivative;
wherein the modified immune stimulatory motif would be immune stimulatory but for the nucleotide derivative. - View Dependent Claims (2, 3, 4, 5, 6, 9, 10, 11, 12, 13, 14, 15, 16, 17)
- -O-substituted-C, 2′
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7. A method for modifying a TLR-stimulating oligonucleotide comprising an immune stimulatory motif, the method comprising incorporating chemical modifications into the immune stimulatory motif, wherein CG is the immune stimulatory motif and the chemical modification is selected from 5-methyl-dC, 2′
- -O-substituted-C, 2′
-O-methyl-C, 2′
-O-methoxyethoxy-C, 2′
-O-methoxyethyl-5-methyl-C, 2′
-O-methyl-5-methyl-C, 2′
-O-substituted-G, 2′
-O-methyl-G, and 2′
-O-methoxyethoxy-G.
- -O-substituted-C, 2′
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8. A method for modifying a TLR-stimulating oligonucleotide comprising an immune stimulatory motif, the method comprising incorporating chemical modifications into the immune stimulatory motif and/or to a sequence flanking the immune stimulatory motif, wherein CG is the immune stimulatory motif and the chemical modification is selected from 5-methyl-dC, 2′
- -O-substituted-C, 2′
-O-methyl-C, 2′
-O-methoxyethoxy-C, 2′
-O-methoxyethyl-5-methyl-C, 2′
-O-methyl-5-methyl-C, 2′
-O-substituted-G, 2′
-O-methyl-G, and/or 2′
-O-methoxyethoxy-G.
- -O-substituted-C, 2′
Specification