Structure-activity relationship of a guanine-free oligodeoxynucleotide as immunopotent inhibitor.
Excessive innate immune response could contribute to the pathogenesis of inflammatory and autoimmune diseases. It is required to develop agents to inhibit the overwhelming innate immune response. SAT05f, an inhibitory ODN with CCT repeat sequence found in human microsatellite DNA, has been demonstrated to down-regulate TLR7/9-mediated innate immune response, protect mice from D-GalN/CpG ODN induced lethal shock, and reduce anti-ssDNA antibody level in the lupus-prone mice induced by chronic graft versus host disease (cGVHD). In this article, to explore the structure-activity relationship of SAT05f, we designed and synthesized a series of ODNs based on the sequence of SAT05f by changing repeat number of the CCT unit, substituting CCT unit with AAG at 3' end or 5' end or in the middle and by forming hairpin at 5' or 3' end, and tested their inhibitory effect on the CpG ODN induced proliferation and TNF-α production in murine immune cells. The results indicated that 1) at least 8 CCT units were required for a CCT repeat ODN to display its inhibitory activity; 2) CCT unit at 3' end of SAT05f was necessary for its full inhibitory activity; and 3) 5' end of SAT05f could be modified to design a more potent SAT05f derived inhibitory ODN. The data provided here would be helpful for finding a potent inhibitory ODN as a candidate medicament for the treatment of diseases associated with over-activated innate immune response.
Department of Molecular Biology, Norman Bethune College of Medicine, Jilin University, Changchun 130021, China.
Yong-Sheng
YS
Zhang
Xiu-Li
XL
Wu
Ying
Y
Wang
Ran
R
Sun
Yong-Li
YL
Yu
Li-Ying
LY
Wang
D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D006147:Guanine / Q000737:chemistry; D006801:Humans; D055029:Inverted Repeat Sequences / Q000235:genetics; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D018895:Microsatellite Repeats / Q000235:genetics; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D051199:Toll-Like Receptor 7 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
C423449:CpG ODN 1826; D009838:Oligodeoxyribonucleotides; C561797:SAT05f; D051199:Toll-Like Receptor 7; D014409:Tumor Necrosis Factor-alpha; D006147:Guanine