Wang Lei, Notomi Ryotaro, Sasaki Shigeki, Taniguchi Yosuke
Graduate School of Pharmaceutical Sciences, Kyushu University 3-1-1 Maidashi, Higashi-ku Fukuoka 812-8582 Japan
School of Pharmacy and Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Nantong University Nantong 226001 PR China.
RSC Med Chem. 2023 May 26;14(8):1482-1491. doi: 10.1039/d3md00139c. eCollection 2023 Aug 16.
Antigene methods are promising novel therapeutic approaches to suppress abnormal gene expression. One of these methods inhibits transcription by forming triplex DNA against duplex DNA. However, by using natural-type triplex-forming oligonucleotides (TFOs), stable triplex formation is limited to homopurine and homopyrimidine strands in targeted duplex DNA. We recently developed artificial nucleoside analogues with the ability to recognize CG and TA inversion sites. We successfully formed stable unnatural-type triplex DNA for duplex DNA containing a CG base pair and extended the target sequence using TFOs containing 2-amino-3-methylpyridinyl pseudo-dC (AP-ΨdC). Therefore, this present study investigated triplex-forming regions and synthesized antigene TFOs containing AP-ΨdC. Some of the synthesized antigene TFOs reduced transcription products and inhibited cell proliferation in several types of cultured cancer cells. The antigene effects of antigene TFOs containing artificial nucleic acids were markedly stronger than those of natural-type TFOs, and these results clearly demonstrated the usefulness of incorporating artificial nucleic acids within TFOs.
反基因方法是抑制异常基因表达的一种很有前景的新型治疗方法。其中一种方法是通过与双链DNA形成三链DNA来抑制转录。然而，使用天然型三链形成寡核苷酸（TFO）时，稳定的三链形成仅限于目标双链DNA中的同型嘌呤和同型嘧啶链。我们最近开发了具有识别CG和TA反向位点能力的人工核苷类似物。我们成功地为含有CG碱基对的双链DNA形成了稳定的非天然型三链DNA，并使用含有2-氨基-3-甲基吡啶基假-dC（AP-ΨdC）的TFO扩展了靶序列。因此，本研究调查了三链形成区域，并合成了含有AP-ΨdC的反基因TFO。一些合成的反基因TFO减少了转录产物，并抑制了几种培养癌细胞系中的细胞增殖。含人工核酸的反基因TFO的反基因作用明显强于天然型TFO，这些结果清楚地证明了在TFO中掺入人工核酸的实用性。
