Kotkowiak Weronika, Bartyś Natalia, Pasternak Anna
Department of Nucleic Acids Bioengineering, Institute of Bioorganic Chemistry, Polish Academy of Sciences, Noskowskiego 12/14, 61-704, Poznan, Poland.
Sci Rep. 2025 Jul 11;15(1):25159. doi: 10.1038/s41598-025-09934-8.
In this article, the T40231 aptamer, an anticancer agent, originally known for its ability to inhibit STAT3, was altered with UNAs to enhance its flexibility in the loops or G-tetrads. The experimental results indicate formation of an intramolecular, parallel G-quadruplex unit with the ability to form dimers. The stability of the G-quadruplex structure is reduced by enhanced flexibility of the sugar residue. Increased flexibility mostly had also a negative impact on the aptamers ability to inhibit cancer cell growth. Nevertheless, two altered variants were found to be more potent in suppressing the viability of HeLa cancer cells with no effect on non-cancerous cells. The analysis of gene transcripts showed that these variants affect the expression of the VEGF gene, but do not suppress the CDC25A gene transcription. The data show that the mechanism of action of the G-rich aptamer is an intricate combination of factors that impact its overall anticancer abilities. It further indicates that the suppression of STAT3 is influenced by the chemical characteristics of particular nucleotide residues. The results might greatly contribute to the broadening of general knowledge about modified G-quadruplexes and their structure-activity relationship but also to the development of novel T40231 derivatives with superior anticancer potential.
在本文中，T40231适配体作为一种抗癌剂，最初因其抑制信号转导和转录激活因子3（STAT3）的能力而闻名，通过非天然核酸（UNA）进行了改造，以增强其在环或G-四联体中的灵活性。实验结果表明形成了一种具有形成二聚体能力的分子内平行G-四链体单元。糖残基灵活性的增强降低了G-四链体结构的稳定性。灵活性的增加大多也对适配体抑制癌细胞生长的能力产生了负面影响。然而，发现两个改造后的变体在抑制HeLa癌细胞活力方面更有效，对非癌细胞没有影响。基因转录本分析表明，这些变体影响血管内皮生长因子（VEGF）基因的表达，但不抑制细胞周期蛋白磷酸酶25A（CDC25A）基因的转录。数据表明，富含G的适配体的作用机制是影响其整体抗癌能力的多种因素的复杂组合。这进一步表明STAT3的抑制受特定核苷酸残基化学特性的影响。这些结果可能极大地有助于拓宽关于修饰G-四链体及其构效关系的一般知识，也有助于开发具有卓越抗癌潜力的新型T40231衍生物。
