Bioactivity of 2'-deoxyinosine-incorporated aptamer AS1411.
Bioactivity of 2'-deoxyinosine-incorporated aptamer AS1411.
复制标题
2'-脱氧肌苷掺入适体 AS1411 的生物活性。
DOI：
10.1038/srep25799
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发表时间：
2016-05-19
影响因子：
4.6
通讯作者：
Yang Z
中科院分区：
文献类型：
--
作者：
Fan X;Sun L;Wu Y;Zhang L;Yang Z
适配体可进行化学修饰，以增强其对核酸酶的抗性并提高与靶标的亲和力。在本研究中，我们对AS1411中的2'-脱氧肌苷进行了化学修饰。AS1411是一种具有抗增殖作用的富含鸟嘌呤的寡脱氧核苷酸适配体，能选择性结合核仁素蛋白。当2'-脱氧肌苷分别掺入AS1411的第12、13、15和24位时，其功能得到增强。此外，在第12和24位（FAN - 1224dI）、第13和24位（FAN - 1324dI）以及第15和24位（FAN - 1524dI）双掺入2'-脱氧肌苷，可促进G - 四联体的形成，抑制DNA复制和肿瘤细胞生长，并诱导细胞周期停滞在S期。在进一步的动物实验中，FAN - 1224dI、FAN - 1324dI和FAN - 1524dI比单独使用AS1411产生了更强的治疗效果。这些结果表明，AS1411中修饰取代基的位置和数量是提升适配体诊断和治疗功能的关键参数。利用分子动力学模拟对FAN - 1524dI/核仁素复合物结构进行的结构研究表明，与单独的AS1411相比，核仁素与掺入2'-dI的AS1411之间存在关键相互作用。这些发现加深了我们对2'-脱氧肌苷部分在相互结合过程中作用的理解。
Aptamers can be chemically modified to enhance nuclease resistance and increase target affinity. In this study, we performed chemical modification of 2′-deoxyinosine in AS1411, an anti-proliferative G-rich oligodeoxynucleotide aptamer, which binds selectively to the nucleolin protein. Its function was augmented when 2′-deoxyinosine was incorporated at positions 12, 13, 15, and 24 of AS1411, respectively. In addition, double incorporation of 2′-deoxyinosine at positions 12 and 24 (FAN-1224dI), 13 and 24 (FAN-1324dI), and 15 and 24 (FAN-1524dI) promoted G-quartet formation, as well as inhibition of DNA replication and tumor cell growth, and induced S-phase cell cycle arrest. In further animal experiments, FAN-1224dI, FAN-1324dI and FAN-1524dI resulted in enhanced treatment effects than AS1411 alone. These results suggested that the position and number of modification substituents in AS1411 are critical parameters to improve the diagnostic and therapeutic function of the aptamer. Structural investigations of the FAN-1524dI/nucleolin complex structure, using molecular dynamics simulation, revealed the critical interactions involving nucleolin and 2′-dI incorporated AS1411 compared with AS1411 alone. These findings augment understanding of the role of 2′-deoxyinosine moieties in interactive binding processes.