TLR9 agonists
The present application provides novel oligonucleotides and therapeutic use thereof. The oligonucleotides of the present invention can be used for the activation or modulation of immunity in the subject.
1 . A single strand oligonucleotide comprising a nucleotide sequence motif 5′-tcgcaacgttt-n-cgacg-n-cg-nn-cg-3′ (SEQ ID NO:2), wherein n denotes any base, and wherein the total base number of the single strand oligonucleotide is 24 or 25.
2 . The oligonucleotide according to claim 1 , wherein the oligonucleotide comprises a sequence motif selected from the group consisting of:
(SEQ ID NO: 54)
5′-tcgcaacgtttgcgacgtcggtcga;
(SEQ ID NO: 55)
5′-tcgcaacgtttgcgacggcgctcga;
(SEQ ID NO: 56)
5′-tcgcaacgtttgcgacgtcgttcga;
(SEQ ID NO: 57)
5′-tcgcaacgtttgcgacggcgttcga;
(SEQ ID NO: 58)
5′-tcgcaacgtttgcgacgtcgttcg;
(SEQ ID NO: 59)
5′-tcgcaacgtttgcgacgtcgttcgg;
(SEQ ID NO: 60)
5′-tcgcaacgtttacgacgtcggtcga;
(SEQ ID NO: 61)
5′-tcgcaacgtttacgacggcgctcga;
(SEQ ID NO: 62)
5′-tcgcaacgtttacgacgtcgttcga; and
(SEQ ID NO: 63)
5′-tcgcaacgtttacgacggcgttcga.
3 . The oligonucleotide according to claim 1 , wherein the internucleotide linkage(s) of the oligonucleotide is partially or fully chemically modified.
4 . The oligonucleotide according to claim 3 , wherein the chemically-modified internucleotide linkage is phosphorothioated.
5 . The oligonucleotide according to claim 1 , wherein the oligonucleotide comprises a partially phosphorothioated oligonucleotide stretch selected from the group consisting of:
(SEQ ID NO: 16)
5′-tCgcaacgtttgcgacgtcgttcgA-3′;
(SEQ ID NO: 17)
5′-tCgcaaCgtttgcgacgtcgttcgA-3′;
(SEQ ID NO: 18)
5′-tCgCaaCgtttgcgacgtcgttcgA-3′;
(SEQ ID NO: 19)
5′-tCgCaacgtttgCgaCgtcgttcgA-3′;
(SEQ ID NO: 20)
5′-tCgCaacgtttgCgaCgtcgttCgA-3′;
(SEQ ID NO: 21)
5′-tCgCaaCgtttgcgacgtCgttCgA-3′;
(SEQ ID NO: 22)
5′-tCgCaaCgtttgCgaCgtCgttCgA-3′;
(SEQ ID NO: 23)
5′-tCgCaaCgtttgcgacgtCggtCgA-3′;
(SEQ ID NO: 24)
5′-tCgCaaCgtttgcgacggCgctCgA-3′;
(SEQ ID NO: 26)
5′-tCgCaaCgtttgcgacggCgttCgA-3′;
(SEQ ID NO: 27)
5′-tCgCaaCgtttgcgacgcCgttCgA-3′;
(SEQ ID NO: 28)
5′-tCgCaaCgtttgcgacggCgtaCgA-3′;
(SEQ ID NO: 29)
5′-tCgCaaCgtttgcgacggCgtgCgA-3′;
(SEQ ID NO: 30)
5′-tCgCaaCgtttacgacgtCggtCgA-3′;
(SEQ ID NO: 31)
5′-tCgCaaCgtttacgacggCgctCgA-3′;
(SEQ ID NO: 32)
5′-tCgCaaCgtttacgacgtCgttCgA-3′;
(SEQ ID NO: 33)
5′-tCgCaaCgtttGcgacgtCggtCgA-3′;
(SEQ ID NO: 34)
5′-tCgCaaCgtttAcgacgtCggtCgA-3′;
(SEQ ID NO: 35)
5′-tCgCaaCgtttGcgacggCgctCgA-3′;
(SEQ ID NO: 36)
5′-tCgCaaCgtttAcgacggCgctCgA-3′;
(SEQ ID NO: 37)
5′-tCgCaaCgtttGcgacgtCgttCgA-3′;
(SEQ ID NO: 38)
5′-tCgCaaCgtttAcgacgtCgttCgA-3′;
(SEQ ID NO: 39)
5′-tCgCaaCgtttGcgacgtCggtCgG-3′;
(SEQ ID NO: 40)
5′-tCgCaaCgtttAcgacgtCggtCgG-3′;
(SEQ ID NO: 41)
5′-tCgCaaCgtttGcgacggCgctCgG-3′;
(SEQ ID NO: 42)
5′-tCgCaaCgtttAcgacggCgctCgG-3′;
(SEQ ID NO: 43)
5′-tCgCaaCgtttGcgacgtCgttCgG-3′; and
(SEQ ID NO: 44)
5′-tCgCanCgittAcgacgtCgttCgG-3′;
wherein the capital letter denotes a nucleoside with no modified internucleotide linkage at 3′, and the small letter denotes a nucleoside with an internucleotide linkage with phosphorothioation at 3′.
6 . The oligonucleotide according to claim 1 , wherein the oligonucleotide comprises a partially phosphorothioated oligonucleotide stretch selected from the group consisting of:
(SEQ ID NO: 33)
5′-tCgCaaCgtttGcgacgtCggtCgA-3′;
(SEQ ID NO: 34)
5′-tCgCaaCgtttAcgacgtCggtCgA-3′;
(SEQ ID NO: 35)
5′-tCgCaaCgtttGcgacggCgctCgA-3′; and
(SEQ ID NO: 36)
5′-tCgCaaCgtttAcgacggCgctCgA-3′,
wherein the capital letter denotes a nucleoside with no modified internucleotide linkage at 3′, and the small letter denotes a nucleoside with an internucleotide linkage with phosphorothioation at 3′.
7 . A pharmaceutical composition, comprising (i) a therapeutically effective amount of the oligonucleotide according to claim 1 or a double-strand oligonucleotide comprising the oligonucleotide according to claim 1 , and (ii) a pharmaceutical acceptable carrier.