基于单体G-四链体的CpG寡聚脱氧核苷酸作为有效的Toll-like受体9激动剂。,Biomacromolecules

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基于单体G-四链体的CpG寡聚脱氧核苷酸作为有效的Toll-like受体9激动剂。
Biomacromolecules ( IF 5.5 ) Pub Date : 2020-08-28 , DOI: 10.1021/acs.biomac.0c00679
Anh Thi Tram Tu _{1,

2} , Kazuaki Hoshi ₂ , Kazunori Ikebukuro ₃ , Nobutaka Hanagata _{1,

4} , Tomohiko Yamazaki _{1,

2}

Affiliation

含有未甲基化的胞嘧啶-磷酸-鸟嘌呤（CpG）基序的合成寡脱氧核苷酸（ODN）通过刺激内体Toll样受体（TLR）9触发免疫反应。天然线性ODN易受核酸酶降解的影响，从而限制了其临床应用。在这里，我们设计了基于单体G-四链体的CpG ODN（G4 CpG ODN），该CpG ODN在G4结构的中央环区域中包含CpG基序。单体G4 CpG ODN在血清中比线性ODN更稳定。包含两个或三个CpG基序的单体G4 CpG ODN诱导了小鼠巨噬细胞样RAW264细胞中免疫刺激细胞因子白介素（IL）-6，IL-12和干扰素（IFN）-β的产生。我们还表明，CpG基序的数量以及CpG基序和G序列之间的核苷酸数量定义了G4 CpG ODN在激活TLR9方面的功效。将人外周血单核细胞与G4 CpG ODN一起孵育可促进IL-6和IFN-γ的产生，从而证实它们对人免疫细胞的刺激作用。与线性ODN注射相比，腹膜内注射G4 CpG ODN的小鼠产生更高的血浆IL-6。这些发现为控制G4 CpG ODN的免疫刺激活性的参数提供了进一步的了解，从而为疫苗佐剂的高效G4 CpG ODN的合理设计提供了见识。证实它们对人体免疫细胞有刺激作用。与线性ODN注射相比，腹膜内注射G4 CpG ODN的小鼠产生更高的血浆IL-6。这些发现为控制G4 CpG ODN的免疫刺激活性的参数提供了进一步的了解，从而为疫苗佐剂的高效G4 CpG ODN的合理设计提供了见识。证实它们对人体免疫细胞有刺激作用。与线性ODN注射相比，腹膜内注射G4 CpG ODN的小鼠产生更高的血浆IL-6。这些发现为控制G4 CpG ODN的免疫刺激活性的参数提供了进一步的了解，从而为疫苗佐剂的高效G4 CpG ODN的合理设计提供了见识。

"点击查看英文标题和摘要"

Monomeric G-Quadruplex-Based CpG Oligodeoxynucleotides as Potent Toll-Like Receptor 9 Agonists.

Synthetic oligodeoxynucleotides (ODNs) containing unmethylated cytosine–phosphate–guanine (CpG) motifs trigger the immune response by stimulating endosomal Toll-like receptor (TLR) 9. Natural linear ODNs are susceptible to nuclease degradation, thereby limiting their clinical applications. Here, we designed monomeric G-quadruplex-based CpG ODNs (G4 CpG ODNs) containing CpG motifs in the central loop region of the G4 structure. The monomeric G4 CpG ODNs were more stable in serum than the linear ODNs. The monomeric G4 CpG ODNs containing two or three CpG motifs induced the production of immunostimulatory cytokines interleukin (IL)-6, IL-12, and interferon (IFN)-β in mouse macrophage-like RAW264 cells. We also showed that the number of CpG motifs and the number of nucleotides between the CpG motif and G-tracts define the efficacy of the G4 CpG ODNs in activating TLR9. Incubating human peripheral blood mononuclear cells with G4 CpG ODNs promoted IL-6 and IFN-γ production, confirming their stimulatory effects on human immune cells. Mice given intraperitoneal injections of G4 CpG ODNs produced higher plasma IL-6 compared with injections of linear ODNs. These findings provide further understanding of the parameters governing the immunostimulatory activity of G4 CpG ODNs, thereby providing insights into the rational design of highly potent G4 CpG ODNs for vaccine adjuvants.

更新日期：2020-09-14

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