Multitasking Water‐Soluble Synthetic G‐Quartets: From Preferential RNA–Quadruplex Interaction to Biocatalytic Activity

Abstract

Natural G-quartets, a cyclic and coplanar array of four guanine residues held together through a Watson-Crick/Hoogsteen hydrogen-bond network, have received recently much attention due to their involvement in G-quadruplex DNA, an alternative higher-order DNA structure strongly suspected to play important roles in key cellular events. Besides this, synthetic G-quartets (SQ), which artificially mimic native G-quartets, have also been widely studied for their involvement in nanotechnological applications (i.e., nanowires, artificial ion channels, etc.). In contrast, intramolecular synthetic G-quartets (iSQ), also named template-assembled synthetic G-quartets (TASQ), have been more sparingly investigated, despite a technological potential just as interesting. Herein, we report on a particular iSQ named (PNA) DOTASQ, which demonstrates very interesting properties in terms of DNA and RNA interaction (notably its selective recognition of quadruplexes according to a bioinspired process) and catalytic activities, through its ability to perform peroxidase-like hemin-mediated oxidations either in an autonomous fashion (i.e., as pre-catalyst for TASQzyme reactions) or in conjunction with quadruplex DNA (i.e., as enhancing agents for DNAzyme processes). These results provide a solid scientific basis for TASQ to be used as multitasking tools for bionanotechnological applications.

Selective Luminescent Labeling of DNA and RNA Quadruplexes by π‐Extended Ruthenium Light‐Up Probes

“…This multi‐site recognition usually insures a high quadruplex‐versus‐duplex specificity for the ligand/DNA association. Other anchor sites, such as the nature of the ribose, are currently studied to reach another level of selectivity, that is, the selectivity for DNA‐ versus RNA‐quadruplexes ,. Recent results acquired with Ru II ‐polypyridyl complexes show that their octahedral geometry makes them prone to interact with quadruplexes in between quartets and loops .…”

Native and Synthetic G-quartet-based DNAzyme Systems – Artificial Enzymes for Biotechnological Applications

“…These templateassembled synthetic G-quartets, able to form an intramolecular G-quartet, proved that a small synthetic molecule can selectively interact with hemin to catalyze peroxidase-mimicking reactions. Interestingly, all the TASQ highlighted here (DOTASQ, [14,205] PNA DOTASQ, [15,206] or RAFT-G 4 ) [13,197]) offer different activities, and the best edifice is definitely PNA DOTASQ, which is closer to the efficiency of G-quadruplex-based DNAzymes, even if a decrease by a factor of 10, approximately, is observed. However, the use of synthetic molecules instead of natural structures (i.e., enzymes or DNA) is an undeniable advantage, in particular because these TASQ are easily synthesized in four straightforward steps from commercially available products, with good yields.…”

“…For the sake of comparison, experiments with the same range of concentration were carried out with DO-TASQ-C 5 (i.e., the most efficient DOTASQ) and also with 22AG at 2 µM as a reference. [206] Interestingly, the results showed the far better catalytic ability of PNA DOTASQ compared to the DOTASQ. Indeed, the initial rates were evaluated at 1.25 µM.min -1 and 0.05 µM.min -1 at 50 µM, respectively, corresponding to an average increase of efficiency of 2600 %.…”

“…Schematic representation of the peroxidase-like activity promoted by the use of a TASQ. [205,206] The catalytic activity was therefore evaluated by UV-Vis absorbance, in 1-mL-quartz cuvettes, measuring the formation of ABTS ⋅+ (also proposed as ABTS ⋅-in the scientific literature), the oxidized product of ABTS which absorbs at 420 nm. [80,81] All the results were compared to a control experiment, strictly composed of all the same reagents, except the lack of the precatalyst (i.e., the hemin is alone with ABTS and hydrogen peroxide, and not catalyzed by Gquadruplexes or TASQs).…”

Cellular Detection of G‐Quadruplexes by Optical Imaging Methods

“…This quadruplex/ligand interaction is thus driven by a G‐quartet association reminiscent of what was initially surmised by Sen and Gilbert. The study of TASQ ligands, which is ongoing since 2011, allows us to sequentially develop a series of prototypes: the first biomimetic ligands (i.e., synthetic G‐quartets that interact with native G‐quartets according to a bioinspired association; Stefan et al., ; Xu et al., ), the first smart quadruplex ligands (i.e., synthetic G‐quartets that actively assemble in the presence of their native G‐quartet targets only; Haudecoeur, Stefan, & Monchaud, ; Haudecoeur, Stefan, Denat, & Monchaud, ; Laguerre et al., ), and the first twice‐as‐smart quadruplex ligands (i.e., a synthetic G‐quartet that is both a smart quadruplex ligand and a smart fluorescent probe; Laguerre et al., ; Zhou et al., ). Of particular interest are the twice‐as‐smart quadruplex ligands, whose design was intended to meet the aforementioned challenges (i.e., the direct detection of quadruplexes across multiple techniques, facilities, and imaging conditions with the use of a single ligand).…”