Agonists of Toll-like receptor 9 containing synthetic dinucleotide motifs.
Oligodeoxynucleotides (ODNs) containing unmethylated CpG motifs activate Toll-like receptor 9 (TLR9). Our previous studies have shown that ODNs containing two 5'-ends are more immunostimulatory than those with one 5'-end. In the present study, to understand the role of functional groups in TLR9 recognition and subsequent immune response, we substituted C or G of a CpG dinucleotide with 5-OH-dC, 5-propyne-dC, furano-dT, 1-(2'-deoxy-beta- d-ribofuranosyl)-2-oxo-7-deaza-8-methyl-purine, dF, 4-thio-dU, N(3)-Me-dC, N (4)-Et-dC, Psi-iso-dC, and arabinoC or 7-deaza-dG, 7-deaza-8-aza-dG, 9-deaza-dG, N(1)-Me-dG, N(2)-Me-dG, 6-Thio-dG, dI, 8-OMe-dG, 8-O-allyl-dG, and arabinoG in ODN containing two 5'-ends. Agonists of TLR9 containing cytosine or guanine modification showed activity in HEK293 cells expressing TLR9, mouse spleen, and human cell-based assays and in vivo in mice. The results presented here provide insight into which specific chemical modifications at C or G of the CpG motif are recognized by TLR9 and the ability to modulate immune responses substituting natural C or G in immune modulatory oligonucleotides.
Yu
Dong
D
Idera Pharmaceuticals, Inc., 167 Sidney Street, Cambridge, Massachusetts 02139, USA.
Putta
Mallikarjuna R
MR
Bhagat
Lakshmi
L
Li
Yukui
Y
Zhu
Fugang
F
Wang
Daqing
D
Tang
Jimmy X
JX
Kandimalla
Ekambar R
ER
Agrawal
Sudhir
S
D000276:Adjuvants, Immunologic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D018899:CpG Islands; D016207:Cytokines / Q000378:metabolism; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology; D009841:Oligonucleotides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013154:Spleen / Q000166:cytology; D013329:Structure-Activity Relationship; D051217:Toll-Like Receptor 9 / Q000819:agonists* / Q000235:genetics
D000276:Adjuvants, Immunologic; D016207:Cytokines; D009841:Oligonucleotides; C495371:TLR9 protein, human; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9