Toll-like receptor 9 antagonist and methods of use thereof
AssigneeIdera Pharmaceuticals, Inc.
InventorsSudhir Agrawal, Daqing Wang, Fu-Gang Zhu
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Abstract
The invention provides antagonist of TLR9 and methods of use thereof. These compounds inhibit or suppress TLR9-mediated signaling. The methods may have use in the prevention and treatment of diseases or disorders mediated by TLR9.
Claims22
A method for inhibiting a TLR-mediated immune response in a mammal, the method comprising administering an effective amount of a compound to inhibit the TLR-mediated immune response, wherein the compound comprises the sequence 5′-GxTC*G*(N1)mCC*G*CAGx(N2)p-3′, wherein N1 2′-deoxyguanosine or 2′-deoxyguanosine methylphosphonate and N2 is 2′-deoxycytosine, wherein m is 10 and p is 0 or 1, and wherein C* is a nucleotide comprising a nitrogenous base selected from the group consisting of cytosine, 5-methyl-2′-deoxycytosine and 2′-O-methylcytosine and G* is a nucleotide comprising a nitrogenous base selected from the group consisting of guanine, 5-methyl-2′-deoxyguanosine and 2′-O-methylguanine, provided that at least one of the nucleotides C or G comprises a methylated nitrogenous base;
- and provided that at each instance that N1 comprises a CG dinucleotide C is a nucleotide comprising a nitrogenous base selected from the group consisting of cytosine, 5-methyl-2′-deoxycytosine and 2′-O-methylcytosine and G is a nucleotide comprising a nitrogenous base selected from the group consisting of guanine, 5-methyl-2′-deoxyguanosine and 2′-O-methylguanine, provided that at least one of the nucleotides C or G comprises a methylated nitrogenous base;
- or the complementary sequence thereto.
A method for inhibiting the activity of a TLR agonist comprising administering an effective amount of a compound to inhibit the activity of a TLR agonist, wherein the compound comprises the sequence 5′-GxTC*G*(N1)mCC*G*CAGx(N2)p-3′, wherein N1 2′-deoxyguanosine or 2′-deoxyguanosine methylphosphonate and N2 is 2′-deoxycytosine, wherein m is 10 and p is 0 or 1, and wherein C* is a nucleotide comprising a nitrogenous base selected from the group consisting of cytosine, 5-methyl-2′-deoxycytosine and 2′-O-methylcytosine and G* is a nucleotide comprising a nitrogenous base selected from the group consisting of guanine, 5-methyl-2′-deoxyguanosine and 2′-O-methylguanine, provided that at least one of the nucleotides C or G comprises a methylated nitrogenous base;
- and provided that at each instance that N1 comprises a CG dinucleotide C is a nucleotide comprising a nitrogenous base selected from the group consisting of cytosine, 5-methyl-2′-deoxycytosine and 2′-O-methylcytosine and G is a nucleotide comprising a nitrogenous base selected from the group consisting of guanine, 5-methyl-2′-deoxyguanosine and 2′-O-methylguanine, provided that at least one of the nucleotides C or G comprises a methylated nitrogenous base;
- or the complementary sequence thereto.
A method for therapeutically treating a mammal, such method comprising administering an effective amount of a compound comprising the sequence 5′-GxTC*G*(N1)mCC*G*CAGx(N2)p-3′, wherein N1 2′-deoxyguanosine or 2′-deoxyguanosine methylphosphonate and N2 is 2′-deoxycytosine, wherein m is 10 and p is 0 or 1, and wherein C* is a nucleotide comprising a nitrogenous base selected from the group consisting of cytosine, 5-methyl-2′-deoxycytosine and 2′-O-methylcytosine and G* is a nucleotide comprising a nitrogenous base selected from the group consisting of guanine, 5-methyl-2′-deoxyguanosine and 2′-O-methylguanine, provided that at least one of the nucleotides C or G comprises a methylated nitrogenous base;
- and provided that at each instance that N1 comprises a CG dinucleotide C is a nucleotide comprising a nitrogenous base selected from the group consisting of cytosine, 5-methyl-2′-deoxycytosine and 2′-O-methylcytosine and G is a nucleotide comprising a nitrogenous base selected from the group consisting of guanine, 5-methyl-2′-deoxyguanosine and 2′-O-methylguanine, provided that at least one of the nucleotides C or G comprises a methylated nitrogenous base;
- or the complementary sequence thereto;
- and wherein the compound inhibits a TLR-mediated immune response.
A method for preventing disease, such method comprising administering to a mammal a compound comprising the sequence 5′-GxTC*G*(N1)mCC*G*CAGx(N2)p-3′, wherein N1 2′-deoxyguanosine or 2′-deoxyguanosine methylphosphonate and N2 is 2′-deoxycytosine, wherein m is 10 and p is 0 or 1, and wherein C* is a nucleotide comprising a nitrogenous base selected from the group consisting of cytosine, 5-methyl-2′-deoxycytosine and 2′-O-methylcytosine and G* is a nucleotide comprising a nitrogenous base selected from the group consisting of guanine, 5-methyl-2′-deoxyguanosine and 2′-O-methylguanine, provided that at least one of the nucleotides C or G comprises a methylated nitrogenous base;
- and provided that at each instance that N1 comprises a CG dinucleotide C is a nucleotide comprising a nitrogenous base selected from the group consisting of cytosine, 5-methyl-2′-deoxycytosine and 2′-O-methylcytosine and G is a nucleotide comprising a nitrogenous base selected from the group consisting of guanine, 5-methyl-2′-deoxyguanosine and 2′-O-methylguanine, provided that at least one of the nucleotides C or G comprises a methylated nitrogenous base;
- or the complementary sequence thereto, and wherein the compound inhibits a TLR-mediated immune response.
Dependencies are inferred from the claim text.