Aminopyridinyl-pseudodeoxycytidine derivatives selectively stabilize antiparalleltriplex DNA with multiple CG inversion sites
Aminopyridinyl-pseudodeoxycytidine derivatives selectively stabilize antiparalleltriplex DNA with multiple CG inversion sites
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氨基吡啶基-假脱氧胞苷衍生物选择性稳定具有多个 CG 倒位位点的反平行三链体 DNA
DOI：
10.1002/ange.201606136
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发表时间：
2016
期刊：
影响因子：
--
通讯作者：
Sasaki Shigeki
中科院分区：
文献类型：
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作者：
Okamura Hidenori;Taniguchi Yosuke;Sasaki Shigeki
三链DNA的序列特异性形成为基因组靶向技术提供了潜在的基础。在反平行三链DNA中，序列特异性是通过在形成三链的寡核苷酸和双链DNA之间形成特定的碱基三联体(G−GC、A−AT和T−AT)来建立的。然而，没有天然的核苷可以选择性地识别倒置的CG和TA碱基对。因此，识别CG和TA的转位位点以形成稳定的三链DNA一直是三链形成技术的长期目标。我们现在描述了用于选择性识别CG碱基对以扩展三链形成序列的伪脱氧胞苷(ΨDC)衍生物的设计和合成。含氨基吡啶的ΨDC衍生物在所有邻近的碱基环境中对CG碱基对表现出高的选择性和亲和力。值得注意的是，3-甲基-2-氨基吡啶−ΨDC(−ΨDC)与含有4个CG反转位点的hTERT基因启动子序列形成了稳定的三链，并有效地抑制了其在人癌细胞中的转录。因此，MEAP−ΨDC有望成为广泛的基因组靶向应用中形成三链寡核苷酸的新起点。
The sequence‐specific formation of triplex DNA offers a potential basis for genome‐targeting technologies. In an antiparallel triplex DNA, the sequence‐specificity is established by the formation of specific base triplets (G−GC, A−AT, and T−AT) between a triplex‐forming oligonucleotide (TFO) and a duplex DNA. However, there are no natural nucleosides that can selectively recognize the inverted CG and TA base pairs. Therefore, the recognition of the CG and TA inversion sites to form a stable triplex DNA has been a long‐standing goal for the triplex‐forming technology. We now describe the design and synthesis of pseudo‐deoxycytidine (ΨdC) derivatives for selective recognition of the CG base pair to expand the triplex‐forming sequence. The aminopyridine‐bearing ΨdC derivatives showed high selectivity and affinity toward the CG base pair in all neighboring base contexts. Remarkably, 3‐methyl‐2‐aminopyridinyl−ΨdC (MeAP−ΨdC) formed a stable triplex with the promoter sequence of the hTERT gene containing four CG inversion sites, and effectively inhibited its transcription in human cancer cells. Thus,MeAP−ΨdC is expected to serve as a new starting point of triplex‐forming oligonucleotides for a wide variety of genome‐targeting applications.