Syntheses of Pyrimidine-Modified Seleno-DNAs as Stable Antisense Molecules.
Syntheses of Pyrimidine-Modified Seleno-DNAs as Stable Antisense Molecules.
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作为稳定反义分子的嘧啶修饰硒代 DNA 的合成。
DOI：
10.1101/2023.05.02.539140
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Huang,Zhen
中科院分区：
文献类型：
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作者：
Fang,Ziyuan;Dantsu,Yuliya;Chen,Cen;Zhang,Wen;Huang,Zhen
化学修饰的反义寡核苷酸(ASO)目前在临床前和临床实验中主要集中在2‘位衍生化，以提高稳定性和靶向亲和力。考虑到2‘-修饰可能与RNaseH的刺激和活性不相容，我们假设核碱基上的原子特异性修饰可以保留RNaseH的复杂结构和RNaseH的活性，同时增强ASO与核酸酶的结合亲和力、特异性和稳定性。在这里，我们报告了一种新的策略来探索我们的假设，通过合成胸苷5位硒修饰的脱氧核苷亚磷酰胺构筑块，以及它的硒寡核苷酸。通过X-射线晶体结构研究发现，Se修饰位于核酸双链的主槽中，不会引起热扰动和结构扰动。令人惊讶的是，我们的核苷酸碱基修饰的Se-DNA特别抵抗核酸酶的消化，同时与RNaseH活性兼容。这为以硒反义寡核苷酸(Se-ASO)的形式进行潜在的反义修饰提供了一条新的途径。
Chemically modified antisense oligonucleotides (ASO) currently in pre-clinical and clinical experiments mainly focus on the 2’-position derivatizations to enhance stability and targeting affinity. Considering the possible incompatibility of 2’-modifications with RNase H stimulation and activity, we have hypothesized that the atom specific modifications on nucleobases can retain the complex structure and RNase H activity, while enhancing ASO’s binding affinity, specificity, and stability against nucleases. Herein we report a novel strategy to explore our hypothesis by synthesizing the deoxynucleoside phosphoramidite building block with the seleno-modification at 5-position of thymidine, as well as its Se-oligonucleotides. Via X-ray crystal structural study, we found that the Se-modification was located in the major groove of nucleic acid duplex and didn’t cause the thermal and structural perturbations. Surprisingly, our nucleobase-modified Se-DNAs were exceptionally resistant to nuclease digestion, while compatible with RNase H activity. This affords a novel avenue for potential antisense modification in the form of Se-antisense oligonucleotides (Se-ASO).