Towards improved anticancer properties of the G-quadruplex-forming T40231 aptamer through increased flexibility of nucleoside residues.

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.