Enhanced Immunostimulatory Activity of Covalent DNA Dendrons
Enhanced Immunostimulatory Activity of Covalent DNA Dendrons
复制标题
DOI：
10.1002/cbic.202100583
复制
发表时间：
2021-12-23
期刊：
影响因子：
3.2
通讯作者：
Takakura，Yoshinobu
中科院分区：
文献类型：
--
作者：
Kawamoto，Yusuke;Liu，Wen;Takakura，Yoshinobu
本研究的重点是设计和合成的共价DNA树突携带多价胞嘧啶-磷酸-鸟嘌呤寡脱氧核苷酸（CpG ODN），可以通过激活TLR 9刺激免疫系统。使用含有三个相同保护基团的支化三重亚磷酰胺合成这些树枝状分子，所述保护基团使得能够在单个分子上同时合成多条链。与线性ODN相比，发现共价DNA树突对核酸酶降解更具抗性，并且更有效地被巨噬细胞样RAW 264.7细胞摄取。细胞摄取由巨噬细胞清道夫受体介导。由多价免疫刺激分支组成的共价DNA树突增强了RAW264.7细胞分泌促炎细胞因子TNF-α和IL-6，9分支DNA树突表现出最高的增强作用。鉴于其增强的功效，我们期望共价DNA树突是寡核苷酸药物的有用结构。
The present study focused on the design and synthesis of covalent DNA dendrons bearing multivalent cytosine‐phosphate‐guanine oligodeoxynucleotides (CpG ODNs) that can stimulate the immune system through the activation of TLR9. These dendrons were synthesized using branching trebler phosphoramidite containing three identical protecting groups that enabled the simultaneous synthesis of multiple strands on a single molecule. Compared with linear ODNs, covalent DNA dendrons were found to be more resistant to nuclease degradation and were more efficiently taken up by macrophage‐like RAW264.7 cells. Cellular uptake was suggested to be mediated by macrophage scavenger receptors. The covalent DNA dendrons composed of multivalent immunostimulatory branches enhanced the secretion of proinflammatory cytokines TNF‐α and IL‐6 from RAW264.7 cells, and 9‐branched DNA dendrons showed the highest enhancement. Given their enhanced efficacy, we expect covalent DNA dendrons to be useful structures of oligonucleotide medicines.