The Bioactivity of D-/L-Isonucleoside- and 2'-Deoxyinosine-Incorporated Aptamer AS1411s Including DNA Replication/MicroRNA Expression.
The Bioactivity of D-/L-Isonucleoside- and 2'-Deoxyinosine-Incorporated Aptamer AS1411s Including DNA Replication/MicroRNA Expression.
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DOI：
10.1016/j.omtn.2017.09.010
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发表时间：
2017-12-15
期刊：
影响因子：
--
通讯作者：
Yang Z
中科院分区：
文献类型：
--
作者：
Fan X;Sun L;Li K;Yang X;Cai B;Zhang Y;Zhu Y;Ma Y;Guan Z;Wu Y;Zhang L;Yang Z
在本研究中，对AS1411进行了2'-脱氧肌苷（2'-dI）和D-/L-异胸苷（D-/L-isoT）的化学修饰。这些修饰能够通过改变局部构象来促进核苷酸与蛋白质的相互作用。共获得了20条修饰序列，其中FCL-I和FCL-II的活性提升最为显著。它们稳定了G-四链体结构，对血清降解仍具有高度抗性且对核仁素具有特异性，进一步抑制了肿瘤细胞的生长，在影响肿瘤细胞周期不同阶段方面表现出更强的能力，诱导细胞周期停滞于S期，促进对DNA复制的抑制，并且在抑制大T抗原解旋功能方面与AS1411同样有效。基因芯片分析和TaqMan PCR结果显示，FCL-II能够上调4种乳腺癌相关且低表达的微小RNA（miRNA）的表达，并下调3种乳腺癌相关且高表达的miRNA的表达（>2.5倍）。在动物实验中，FCL-II产生的治疗效果比AS1411更显著（p < 0.01）。计算结果进一步证明，与AS1411相比，FCL-II在与靶蛋白核仁素结合方面具有更多结构优势，这表明其在抗肿瘤治疗中具有巨大潜力。
In this study, chemical modification of 2′-deoxyinosine (2′-dI) and D-/L-isothymidine (D-/L-isoT) was performed on AS1411. They could promote the nucleotide-protein interaction by changing the local conformation. Twenty modified sequences were obtained, FCL-I and FCL-II showed the most noticeable activity improvement. They stabilized the G-quadruplex, remained highly resistant to serum degradation and specificity for nucleolin, further inhibited tumor cell growth, exhibited a stronger ability to influence the different phases of the tumor cell cycle, induced S-phase arrest, promoted the inhibition of DNA replication, and suppressed the unwound function of a large T antigen as powerful as AS1411. The microarray analysis and TaqMan PCR results showed that FCL-II can upregulate the expression of four breast-cancer-related, lowly expressed miRNAs and downregulate the expression of three breast-cancer-related, highly expressed miRNAs (>2.5-fold). FCL-II resulted in enhanced treatment effects greater than AS1411 in animal experiments (p < 0.01). The computational results further proved that FCL-II exhibits more structural advantages than AS1411 for binding to the target protein nucleolin, indicating its great potential in antitumor therapy.
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影响因子：
14.9
作者：
Firnberg E;Ostermeier M
通讯作者：
Ostermeier M
DOI：
10.1073/pnas.1418718112
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作者：
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