Bimodular Antiparallel G-Quadruplex Nanoconstruct with Antiproliferative Activity

Abstract

Oligonucleotides with an antiproliferative activity for human cancer cells have attracted attention over the past decades; many of them have a G-quadruplex structure (GQ), and a cryptic target. In particular, DNA oligonucleotide HD1, a minimal GQ, could inhibit proliferation of some cancer cell lines. The HD1 is a 15-nucleotide DNA oligonucleotide that folds into a minimal chair-like monomolecular antiparallel GQ structure. In this study, for eight human cancer cell lines, we have analyzed the antiproliferative activities of minimal bimodular DNA oligonucleotide, biHD1, which has two HD1 modules covalently linked via single T-nucleotide residue. Oligonucleotide biHD1 exhibits a dose-dependent antiproliferative activity for lung cancer cell line RL-67 and cell line of central nervous system cancer U87 by MTT-test and Ki-67 immunoassay. The study of derivatives of biHD1 for the RL-67 and U87 cell lines revealed a structure-activity correlation of GQ folding and antiproliferative activity. Therefore, a covalent joining of two putative GQ modules within biHD1 molecule provides the antiproliferative activity of initial HD1, opening a possibility to design further GQ multimodular nanoconstructs with antiproliferative activity—either as themselves or as carriers.

Tuning the Polymorphism of the Anti-VEGF G-rich V7t1 Aptamer by Covalent Dimeric Constructs

“…These are not the unique literature examples of aptamer optimization obtained by dimerization of known aptamer sequences. Indeed, in the last decade a number of works described improved aptamers realized by engineering bivalent or multivalent analogues of the selected oligonucleotide, not only for VEGF, but also for thrombin [19,[22][23][24][25][26][27], mIgM (B-cell receptor) [28,29], and other biologically relevant targets [30][31][32], so that this strategy can be considered among those of choice to increase the overall efficacy of selected aptamers [33][34][35].…”

Covalent Bi-Modular Parallel and Antiparallel G-Quadruplex DNA Nanocostructs Reduce Viability of Patient Glioma Primary Cell Cultures

“…On the contrary, it was shown that just the single stranded oligonucleotide extensions at both the 3′- and 5′-ends of GQ of HD1 could affect the GQ properties [ 19 ]. Indeed, for the simplest case, bi-HD1, it seems that the two GQ modules are not equal, being covalently conjugated via single T ([ 14 ], and refs therein). Indeed, the molar ellipticity of CD spectrum at 295 nm of bi-HD1 is not exactly twice as for HD1, but just 1.5 times ( Figure 2 A).…”

“…Originally, 15-mer DNA GQ HD1 ( Figure 1 ) was discovered in 1991 as a thrombin binding aptamer via selection by conventional SELEX [ 13 ]. As HD1 has a typical GQ structure, it exhibits anti-proliferative activity like some other GQs [ 1 , 14 , 15 ].…”

“…Certainly, a simple covalent joining of two single GQ modules does not necessarily yield a perfect “twin” molecule with a double anti-proliferative activity, because extensions at both the 3′- and 5′-ends could affect the GQ stability and functioning [ 19 ]. For instance, HD1 could be covalently conjugated via a single T nucleotide; yielding bi-HD1 ( Figure 1 ), which retains anti-proliferative activity [ 14 ].…”

Anti‐VEGF DNA‐based aptamers in cancer therapeutics and diagnostics

“…Figure was redrawn from Kimoto et al 203 [Color figure can be viewed at wileyonlinelibrary.com] strategy. [206][207][208] Several examples are reported, not only for VEGF, but also for thrombin, 185,205,[209][210][211][212][213][214] (B-cell receptor), 215,216 and other biologically relevant targets. [217][218][219] Notably, multimerization can be very easily achieved with nucleic acid-based aptamers through ad hoc synthetic modifications in their oligonucleotide backbones.…”