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首页> 外文期刊>BMC Biotechnology >Nuclease-resistant immunostimulatory phosphodiester CpG oligodeoxynucleotides as human Toll-like receptor 9 agonists
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Nuclease-resistant immunostimulatory phosphodiester CpG oligodeoxynucleotides as human Toll-like receptor 9 agonists

机译：抗核酸酶的免疫刺激性磷酸二酯CpG寡脱氧核苷酸作为人类Toll样受体9激动剂

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Background Unmethylated cytosine-guanine ( CpG ) motif-containing oligodeoxynucleotides (ODNs) have been well characterized as agonists of Toll -like receptor 9 ( TLR9 ). ODNs with a phosphorothioate (PTO) backbone have been studied as TLR9 agonists since natural ODNs with a phosphodiester (PD) backbone are easily degraded by a serum nuclease, which makes them problematic for therapeutic applications. However, ODNs with a PTO backbone have been shown to have undesirable side effects. Thus, our goal was to develop nuclease-resistant, PD ODNs that are effective as human TLR9 (hTLR9) agonists. Results The sequence of ODN2006, a CpG ODN that acts as an hTLR9 agonist, was used as the basic CpG ODN material. The 3'-end modification of ODN2006 with a PD backbone (PD-ODN2006) improved its potential as an hTLR9 agonist because of increased resistance to nucleolytic degradation. Moreover, 3'-end modification with oligonucleotides showed higher induction than modification with biotin, FITC , and amino groups. Further, enhancement of hTLR9 activity was found to be dependent on the number of CpG core motifs (GTCGTT) in the PD ODN containing the 3'-end oligonucleotides. In particular, ODN sequences consisting of two to three linked ODN2006 sequences with a PD backbone (e.g., PD-ODN2006-2006 and PD-ODN2006-2006-2006) acted as effective agonists of hTLR9 even at lower concentrations. Conclusions This study showed that PD-ODN2006-2006 and PD-ODN-2006-2006-2006 can be used as potentially safe agonists for hTLR9 activation instead of CpG ODNs with a PTO backbone. We propose these CpG ODNs consisting of only a PD backbone as a novel class of CpG ODN.
机译：背景技术含有未甲基化的胞嘧啶-鸟嘌呤（CpG）基序的寡脱氧核苷酸（ODN）已被很好地表征为Toll样受体9（TLR9）的激动剂。已经研究了具有硫代磷酸酯（PTO）骨架的ODN作为TLR9激动剂，因为具有磷酸二酯（PD）骨架的天然ODN容易被血清核酸酶降解，这使其成为治疗应用中的难题。但是，具有PTO主干的ODN已显示出不良副作用。因此，我们的目标是开发能有效作为人TLR9（hTLR9）激动剂的抗核酸酶的PD ODN。结果将作为hTLR9激动剂的CpG ODN ODN2006序列用作基础CpG ODN材料。具有PD骨架的ODN2006的3'末端修饰（PD-ODN2006）提高了其作为hTLR9激动剂的潜力，因为它增加了对核酸降解的抗性。此外，用寡核苷酸进行的3'末端修饰显示出比用生物素，FITC和氨基进行修饰更高的诱导作用。此外，发现hTLR9活性的增强取决于包含3'端寡核苷酸的PD ODN中CpG核心基序（GTCGTT）的数量。特别地，即使是在较低浓度下，由具有PD主链的两个至三个连接的ODN2006序列组成的ODN序列（例如，PD-ODN2006-2006和PD-ODN2006-2006-2006）也可以作为hTLR9的有效激动剂。结论这项研究表明，PD-ODN2006-2006和PD-ODN-2006-2006-2006可以用作hTLR9激活的潜在安全激动剂，而不是具有PTO主链的CpG ODN。我们提出这些仅由PD主干组成的CpG ODN，作为一类新颖的CpG ODN。

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