Modulation of oligonucleotide CpG-mediated immune stimulation by positional modification of nucleosides
View Patent ↗The invention provides compounds having increased or reduced immunostimulatory effect, said compounds comprising a CpG dinucleotide and an immunomodulatory moiety wherein the increased or reduced immunomodulatory effect is relative to a similar compound lacking the immunomodulatorv moiety.
1. A compound having increased or reduced immunostimulatory effect, the compound comprising a 5′-CpG-3′ dinucleotide, wherein C is cytosine and G is guanosine or a substituted guanosine, and an immunomodulatory moiety, wherein the immunomodulatory moiety is selected from the group consisting of abasic nucleoside, 1,3-propanediol linker, nitropyrrole, nitroindole, deoxyuridine, inosine, isoguanosine, 2-aminopurine, nebularine, 7-deazaguanosine, 4-thiodeoxyuridine, 4-thiothymidine, d-isoguanosine, d-iso-5-methylcytosine, P-base, and 3′-3′ linkage, wherein the compound is 12 to 35 nucleotides in length, wherein the compound does not have antisense activity, and wherein the increased or reduced immunomodulatory effect is relative to a similar compound lacking the immunomodulatory moiety.
2. The compound according to claim 1 , wherein the compound has the structure
5′-Yn . . . Y6-Y5-Y4-Y3-Y2-Y1-CG-X1-X2-X3-X4-X5-X6-X7-X8-X9 . . . Xm-3′, wherein C is cytosine, G is guanosine or a substituted guanosine, and each X and Y is independently a nucleoside or an immunomodulatory moiety, and n is a number from −6 to +20, and m is a number from −9 to +20.
3. The compound according to claim 2 , wherein the substituted guanosine is inosine.
4. The compound according to claim 2 , wherein the substituted guanosine is 7-deazaguanosine.