将糖改性核酸引入含有CpG的反感性寡核酸中,可以抑制TLR9的激活
Tokuyuki Yoshida1,2, Tomoko Hagihara3, Yasunori Uchida1
1Division of Molecular Target and Gene Therapy Products, National Institute of Health Sciences, 3-25-26 Tonomachi, Kawasaki-ku, Kawasaki, Kanagawa, 210-9501, Japan.
反感性寡核酸 (ASO) 可以通过CpG动机触发免疫反应. 在ASO治疗中糖的修改显著降低了这种类似收费9 (TLR9) 受体的刺激活性,有助于更安全的药物设计.
科学领域:
- 生物化学 生物化学
- 免疫学 免疫学 免疫学
- 药用化学 医学化学
背景情况:
- 反感性寡核酸 (ASO) 是通过沃森-克里克基配对与RNA结合的治疗剂.
- 在ASO中的非甲基化CpG基因可以通过收费类受体9 (TLR9) 激活先天免疫力.
- 治疗性ASO的关键结构特征,包括长度,链接和糖修饰,需要对TLR9刺激进行彻底的研究.
研究的目的:
- 调查结构元素对短期ASO的TLR9刺激性质的影响.
- 确定CpG基因的必要性和糖修饰对ASO疗法中TLR9激活的影响.
- 为设计更安全的ASO基药物提供洞察力,其免疫性降低.
主要方法:
- 确立了一种具有TLR9刺激活性的18核酸酸寡氧核酸 (SY-ODN18).
- 证明了5'-近端非甲基化CpG基因对TLR9激活的重要作用.
- 系统地生成模型ASO,具有不同的糖修饰 (间隙器,混合器,完全修饰) 以模仿治疗结构.
主要成果:
- 在ASO的5'-end附近的非甲基化CpG基因对TLR9激活至关重要.
- 在gapmer,mixmer和完全修改的ASO设计中引入糖改性核酸,大大降低了TLR9刺激活性.
- 在糖修饰存在时,即使没有CpG基因甲基化,也观察到减少TLR9刺激.
结论:
- 对于ASO介导的TLR9激活来说,CpG基因的位置和存在至关重要.
- 糖的修改对于ASO治疗发展至关重要,显著减弱TLR9的刺激作用.
- 这些发现指导了ASO疗法的合理设计,以尽量减少不必要的先天免疫反应.
更多相关视频
09:04Sequence-specific and Selective Recognition of Double-stranded RNAs over Single-stranded RNAs by Chemically Modified Peptide Nucleic Acids
Published on: September 21, 2017
12:47Using RNA-interference to Investigate the Innate Immune Response in Mouse Macrophages
Published on: November 3, 2014
相关概念视频
Experimental RNAi
Types of RNA
Three main types of RNA are involved in protein synthesis: messenger RNA (mRNA), transfer RNA (tRNA), and ribosomal RNA (rRNA). These RNAs perform diverse functions and can be broadly classified as protein-coding or non-coding RNA. Non-coding RNAs play important roles in the regulation of gene expression in response to developmental and environmental changes. Non-coding RNAs in prokaryotes can be manipulated to develop more effective antibacterial drugs for human or animal use.
RNA...
siRNA - Small Interfering RNAs
In the cytoplasm, siRNA is processed from a double-stranded RNA, which comes from either endogenous DNA transcription or exogenous sources like a virus. This double-stranded RNA is then cleaved by the...
RNA Interference
This process occurs naturally in cells, often through the activity of genomically-encoded microRNAs. Researchers can take advantage of this mechanism by introducing synthetic RNAs to deactivate specific genes for research or therapeutic purposes. For example, RNAi could be used...
Transcription Attenuation in Prokaryotes
There are several different mechanisms used to attenuate transcription. In ribosome mediated...
Eukaryotic Transcription Inhibitors
Eukaryotic transcription inhibitors usually contain two distinct domains, a...
