Aptamer-Modified Homogeneous Catalysts, Heterogenous Nanoparticle Catalysts, and Photocatalysts: Functional "Nucleoapzymes", "Aptananozymes", and "Photoaptazymes".

Conjugation of aptamers to homogeneous catalysts ("nucleoapzymes"), heterogeneous nanoparticle catalysts ("aptananozymes"), and photocatalysts ("photoaptazymes") yields superior catalytic/photocatalytic hybrid nanostructures emulating functions of native enzymes and photosystems. The concentration of the substrate in proximity to the catalytic sites ("molarity effect") or spatial concentration of electron-acceptor units in spatial proximity to the photosensitizers, by aptamer-ligand complexes, leads to enhanced catalytic/photocatalytic efficacies of the hybrid nanostructures. This is exemplified by sets of "nucleoapzymes" composed of aptamers conjugated to the hemin/G-quadruplex DNAzymes or metal-ligand complexes as catalysts, catalyzing the oxidation of dopamine to aminochrome, oxygen-insertion into the Ar─H moiety of tyrosinamide and the subsequent oxidation of the catechol product into aminochrome, or the hydrolysis of esters or ATP. Also, aptananozymes consisting of aptamers conjugated to Cu2+ - or Ce4+ -ion-modified C-dots or polyadenine-stabilized Au nanoparticles acting as catalysts oxidizing dopamine or operating bioreactor biocatalytic cascades, are demonstrated. In addition, aptamers conjugated to the Ru(II)-tris-bipyridine photosensitizer or the Zn(II) protoporphyrin IX photosensitizer provide supramolecular photoaptazyme assemblies emulating native photosynthetic reaction centers. Effective photoinduced electron transfer followed by the catalyzed synthesis of NADPH or the evolution of H2 is demonstrated by the photosystems. Structure-function relationships dictate the catalytic and photocatalytic efficacies of the systems.

Dynamic Fusion of Nucleic Acid Functionalized Nano-/Micro-Cell-Like Containments: From Basic Concepts to Applications.

Membrane fusion processes play key roles in biological transformations, such as endocytosis/exocytosis, signal transduction, neurotransmission, or viral infections, and substantial research efforts have been directed to emulate these functions by artificial means. The recognition and dynamic reconfiguration properties of nucleic acids provide a versatile means to induce membrane fusion. Here we address recent advances in the functionalization of liposomes or membranes with structurally engineered lipidated nucleic acids guiding the fusion of cell-like containments, and the biophysical and chemical parameters controlling the fusion of the liposomes will be discussed. Intermembrane bridging by duplex or triplex nucleic acids and light-induced activation of membrane-associated nucleic acid constituents provide the means for spatiotemporal fusion of liposomes or nucleic acid modified liposome fusion with native cell membranes. The membrane fusion processes lead to exchange of loads in the fused containments and are a means to integrate functional assemblies. This is exemplified with the operation of biocatalytic cascades and dynamic DNA polymerization/nicking or transcription machineries in fused protocell systems. Membrane fusion processes of protocell assemblies are found to have important drug-delivery, therapeutic, sensing, and biocatalytic applications. The future challenges and perspectives of DNA-guided fused containments and membranes are addressed.

Photocleavable Ortho-Nitrobenzyl-Protected DNA Architectures and Their Applications.

This review article introduces mechanistic aspects and applications of photochemically deprotected ortho-nitrobenzyl (ONB)-functionalized nucleic acids and their impact on diverse research fields including DNA nanotechnology and materials chemistry, biological chemistry, and systems chemistry. Specific topics addressed include the synthesis of the ONB-modified nucleic acids, the mechanisms involved in the photochemical deprotection of the ONB units, and the photophysical and chemical means to tune the irradiation wavelength required for the photodeprotection process. Principles to activate ONB-caged nanostructures, ONB-protected DNAzymes and aptamer frameworks are introduced. Specifically, the use of ONB-protected nucleic acids for the phototriggered spatiotemporal amplified sensing and imaging of intracellular mRNAs at the single-cell level are addressed, and control over transcription machineries, protein translation and spatiotemporal silencing of gene expression by ONB-deprotected nucleic acids are demonstrated. In addition, photodeprotection of ONB-modified nucleic acids finds important applications in controlling material properties and functions. These are introduced by the phototriggered fusion of ONB nucleic acid functionalized liposomes as models for cell-cell fusion, the light-stimulated fusion of ONB nucleic acid functionalized drug-loaded liposomes with cells for therapeutic applications, and the photolithographic patterning of ONB nucleic acid-modified interfaces. Particularly, the photolithographic control of the stiffness of membrane-like interfaces for the guided patterned growth of cells is realized. Moreover, ONB-functionalized microcapsules act as light-responsive carriers for the controlled release of drugs, and ONB-modified DNA origami frameworks act as mechanical devices or stimuli-responsive containments for the operation of DNA machineries such as the CRISPR-Cas9 system. The future challenges and potential applications of photoprotected DNA structures are discussed.

Functional catalytic nanoparticles (nanozymes) for sensing.

Nanoparticles exhibiting diverse shapes, high porosity and chemical stability reveal, upon appropriate chemical engineering, enzyme-like catalytic activities, "nanozymes", providing a plethora of nanomaterials for diverse applications. The present review article addresses the sensing applications of the catalytic functions of nanozymes consisting of metal nanoparticles, metal oxides, metal sulfides and cyanometallate nanoparticles, carbon-based nanomaterials and metal-organic-framework nanoparticles. The nanozymes emulate catalytic functions of oxidases or peroxidases and are employed as amplifying agents for sensing diverse analytes such as glucose, dopamine, NADH, thiols, phosphates and more. Moreover, the immobilization of nanozymes on electrodes provides versatile means to develop electrochemical sensing platforms. Different principles of the electrochemical sensing platforms, synthetic methodologies to deposit nanozymes on electrodes, and methods to establish electrical communication between the bulk conductive support and nanozyme particles are introduced. Electrochemical sensing platforms applying nanozyme-modified electrodes for the detection of analytes such as organophosphates, glucose and more are discussed. In particular, the application of nanozymes as amplifying labels for biosensor devices detecting proteins, DNA and microRNAs are addressed. Finally, the uses of nanozymes as functional constituents to design sense-and-treat systems are discussed. This is exemplified with the assembly of a bioreactor system for the sensing of glucose, the nanozyme-promoted generation of reactive oxygen species as cytotoxic agents towards cancer cells, and the autonomous nanozyme-based glucose-controlled release of insulin from nanocarrier devices. The future challenges in developing nanozyme-based sensors and sense-and-treat systems are presented.

Aptamer-Protein Structures Guide In Silico and Experimental Discovery of Aptamer-Short Peptide Recognition Complexes or Aptamer-Amino Acid Cluster Complexes.

A method to computationally and experimentally identify aptamers against short peptides or amino acid clusters is introduced. The method involves the selection of a well-defined protein aptamer complex and the extraction of the peptide sequence participating in the binding of the protein to the aptamer. The subsequent fragmentation of the peptide sequence into short peptides and the in silico docking-guided identification of affinity complexes between the miniaturized peptides and the antiprotein aptamer, followed by experimental validation of the binding features of the short peptides with the antiprotein aptamers, leads to the identification of new short peptide-aptamer complexes. This is exemplified with the identification of the pentapeptide RYERN as the scaffold that binds thrombin to the DNA thrombin aptamer (DNA TA). In silico docking studies followed by microscale thermophoresis (MST) experiments demonstrate that the miniaturized tripeptides RYE, YER, and ERN reveal selective binding affinities toward the DNA TA. In addition, docking and MST experiments show that the ribonucleotide-translated RNA TA shows related binding affinities of YER to the DNA TA. Most importantly, we demonstrate that the separated amino acids Y/E/R assemble as a three amino acid cluster on the DNA TA and RNA TA aptamers in spatial configurations similar to the tripeptide YER on the respective aptamers. The clustering phenomenon is selective for the YER tripeptide system. The method to identify binding affinities of miniaturized peptides to known antiprotein aptamers and the specific clustering of single amino acids on the aptamers is further demonstrated by in silico and experimental identification of the binding of the tripeptide RET and the selective clustering of the separated amino acids R/E/T onto a derivative of the AS1411 aptamer against the nucleolin receptor protein.

Switchable and dynamic G-quadruplexes and their applications.

G-Quadruplexes attract growing interest as functional constituents in biology, chemistry, nanotechnology, and material science. In particular, the reversible dynamic reconfiguration of G-quadruplexes provides versatile means to switch DNA nanostructures, reversibly control catalytic functions of DNA assemblies, and switch material properties and functions. The present review article discusses the switchable dynamic reconfiguration of G-quadruplexes as central functional and structural motifs that enable diverse applications in DNA nanotechnology and material science. The dynamic reconfiguration of G-quadruplexes has a major impact on the development of DNA switches and DNA machines. The integration of G-quadruplexes with enzymes yields supramolecular assemblies exhibiting switchable catalytic functions guided by dynamic G-quadruplex topologies. In addition, G-quadruplexes act as important building blocks to operate constitutional dynamic networks and transient dissipative networks mimicking complex biological dynamic circuitries. Furthermore, the integration of G-quadruplexes with DNA nanostructures, such as origami tiles, introduces dynamic and mechanical features into these static frameworks. Beyond the dynamic operation of G-quadruplex structures in solution, the assembly of G-quadruplexes on bulk surfaces such as electrodes or nanoparticles provides versatile means to engineer diverse electrochemical and photoelectrochemical devices and to switch the dynamic aggregation/deaggregation of nanoparticles, leading to nanoparticle assemblies that reveal switchable optical properties. Finally, the functionalization of hydrogels, hydrogel microcapsules, or nanoparticle carriers, such as SiO2 nanoparticles or metal-organic framework nanoparticles, yields stimuli-responsive materials exhibiting shape-memory, self-healing, and controlled drug release properties. Indeed, G-quadruplex-modified nanomaterials find growing interest in the area of nanomedicine. Beyond the impressive G-quadruplex-based scientific advances achieved to date, exciting future developments are still anticipated. The review addresses these goals by identifying the potential opportunities and challenges ahead of the field in the coming years.

Structure-activity relationship studies on divalent naphthalene diimide G quadruplex ligands with anticancer and antiparasitic activity.

Naphthalene diimide (NDI) is a central scaffold that has been commonly used in the design of G-quadruplex (G4) ligands. Previous work revealed notable anticancer activity of a disubstituted N-methylpiperazine propyl NDI G4 ligand. Here, we explored structure-activity relationship studies around ligand bis-N,N-2,7-(3-(4-methylpiperazin-1-yl)propyl)-1,4,5,8-naphthalenetetracarboxylic diimide, maintaining the central NDI core whilst modifying the spacer and the nature of the cationic groups. We prepared new disubstituted NDI derivatives of the original compound and examined their in vitro antiproliferative and antiparasitic activity. Several N-methylpiperazine propyl NDIs showed sub-micromolar activity against Trypanosoma brucei and Leishmania major parasites with up to 30 fold selectivity versus MRC-5 cells. The best compound was a dimorpholino NDI with an IC50 of 0.17 µM against T.brucei and 40 fold selectivity versus MRC-5 cells. However, no clear correlation between G4 binding of the new NDI derivatives and antiproliferative or antiparasitic activity was observed, indicating that other mechanisms of action may be responsible for the observed biological activity.

Assembly of Dynamic Gated and Cascaded Transient DNAzyme Networks.

The dynamic transient formation and depletion of G-quadruplexes regulate gene replication and transcription. This process was found to be related to various diseases such as cancer and premature aging. We report on the engineering of nucleic acid modules revealing dynamic, transient assembly and disassembly of G-quadruplex structures and G-quadruplex-based DNAzymes, gated transient processes, and cascaded dynamic transient reactions that involve G-quadruplex and DNAzyme structures. The dynamic transient processes are driven by functional DNA reaction modules activated by a fuel strand and guided toward dissipative operation by a nicking enzyme (Nt.BbvCI). The dynamic networks were further characterized by computational simulation of the experiments using kinetic models, allowing us to predict the dynamic performance of the networks under different auxiliary conditions applied to the systems. The systems reported herein could provide functional DNA machineries for the spatiotemporal control of G-quadruplex structures perturbing gene expression and thus provide a therapeutic means for related emergent diseases.

Gated Transient Dissipative Dimerization of DNA Tetrahedra Nanostructures for Programmed DNAzymes Catalysis.

Transient dissipative dimerization and transient gated dimerization of DNA tetrahedra nanostructures are introduced as functional modules to emulate transient and gated protein-protein interactions and emergent protein-protein guided transient catalytic functions, operating in nature. Four tetrahedra are engineered to yield functional modules that, in the presence of pre-engineered auxiliary nucleic acids and the nicking enzyme Nt.BbvCI, lead to the fueled transient dimerization of two pairs of tetrahedra. The dynamic transient formation and depletion of DNA tetrahedra are followed by transient FRET signals generated by fluorophore-labeled tetrahedra. The integration of two inhibitors within the mixture of the four tetrahedra and two auxiliary modules, fueling the transient dimerization, results in selective inhibitor-guided gated transient dimerization of two different DNA tetrahedra dimers. Kinetic models for the dynamic transient dimerization and gated transient dimerization of the DNA tetrahedra are formulated and computationally simulated. The derived rate-constants allow the prediction and subsequent experimental validation of the performance of the systems under different auxiliary conditions. In addition, by appropriate modification of the four tetrahedra structures, the triggered gated emergence of selective transient catalytic functions driven by the two pairs of DNA tetrahedra dimers is demonstrated.

Enzyme-Loaded Hemin/G-Quadruplex-Modified ZIF-90 Metal-Organic Framework Nanoparticles: Bioreactor Nanozymes for the Cascaded Oxidation of N-hydroxy-l-arginine and Sensing Applications.

Biocatalytic cascades are challenging to operate in homogeneous solution, where diffusional mass transport hinders efficient communication between the reactive components. There is great interest in developing devices to perform such transformations in confined environments, which increase the efficiency of the cascaded process by generating high local concentrations of the reactive species. Herein, a bioreactor-nanozyme assembly is introduced for the cascaded aerobic oxidation of N-hydroxy-l-arginine (NOHA) to citrulline in the presence of glucose. The reaction mimics a key step in the nitric oxide synthase oxidation of l-arginine in nature. The system consists of glucose oxidase (GOx)-loaded hemin/G-quadruplex (hemin/G4)-modified ZIF-90 metal-organic framework nanoparticles. The aerobic oxidation of glucose by GOx yields H2 O2 that fuels the hemin/G4-catalyzed oxidation of NOHA into citrulline. The process driven by the bioreactor-nanozyme system is ≈sixfold enhanced compared to the homogeneous mixture of the biocatalysts, due to its operation in the confined environment of the nanoparticles. Extension to a three-step cascade is then demonstrated using a bioreactor composed of ß-galactosidase/GOx-loaded hemin/G4-modified ZIF-90 nanoparticles activating the cascaded oxidation of NOHA to citrulline, in the presence of lactose. Moreover, the bioreactor-nanozyme hybrid is applied as a functional optical sensor of glucose, using fluorescence or chemiluminescence as readout signals.

Photoresponsive DNA materials and their applications.

Photoresponsive nucleic acids attract growing interest as functional constituents in materials science. Integration of photoisomerizable units into DNA strands provides an ideal handle for the reversible reconfiguration of nucleic acid architectures by light irradiation, triggering changes in the chemical and structural properties of the nanostructures that can be exploited in the development of photoresponsive functional devices such as machines, origami structures and ion channels, as well as environmentally adaptable 'smart' materials including nanoparticle aggregates and hydrogels. Moreover, photoresponsive DNA components allow control over the composition of dynamic supramolecular ensembles that mimic native networks. Beyond this, the modification of nucleic acids with photosensitizer functionality enables these biopolymers to act as scaffolds for spatial organization of electron transfer reactions mimicking natural photosynthesis. This review provides a comprehensive overview of these exciting developments in the design of photoresponsive DNA materials, and showcases a range of applications in catalysis, sensing and drug delivery/release. The key challenges facing the development of the field in the coming years are addressed, and exciting emergent research directions are identified.

Bioinspired Artificial Photosynthetic Systems.

Mimicking photosynthesis using artificial systems, as a means for solar energy conversion and green fuel generation, is one of the holy grails of modern science. This perspective presents recent advances towards developing artificial photosynthetic systems. In one approach, native photosystems are interfaced with electrodes to yield photobioelectrochemical cells that transform light energy into electrical power. This is exemplified by interfacing photosystem I (PSI) and photosystem II (PSII) as an electrically contacted assembly mimicking the native Z-scheme, and by the assembly of an electrically wired PSI/glucose oxidase biocatalytic conjugate on an electrode support. Illumination of the functionalized electrodes led to light-induced generation of electrical power, or to the generation of photocurrents using glucose as the fuel. The second approach introduces supramolecular photosensitizer nucleic acid/electron acceptor complexes as functional modules for effective photoinduced electron transfer stimulating the subsequent biocatalyzed generation of NADPH or the Pt-nanoparticle-catalyzed evolution of molecular hydrogen. Application of the DNA machineries for scaling-up the photosystems is demonstrated. A third approach presents the integration of artificial photosynthetic modules into dynamic nucleic acid networks undergoing reversible reconfiguration or dissipative transient operation in the presence of auxiliary triggers. Control over photoinduced electron transfer reactions and photosynthetic transformations by means of the dynamic networks is demonstrated.

Integration of photocatalytic and dark-operating catalytic biomimetic transformations through DNA-based constitutional dynamic networks.

Nucleic acid-based constitutional dynamic networks (CDNs) have recently emerged as versatile tools to control a variety of catalytic processes. A key challenge in the application of these systems is achieving intercommunication between different CDNs to mimic the complex interlinked networks found in cellular biology. In particular, the possibility to interface photochemical 'energy-harvesting' processes with dark-operating 'metabolic' processes, in a similar way to plants, represents an up to now unexplored yet enticing research direction. The present study introduces two CDNs that allow the intercommunication of photocatalytic and dark-operating catalytic functions mediated by environmental components that facilitate the dynamic coupling of the networks. The dynamic feedback-driven intercommunication of the networks is accomplished via information transfer between the two CDNs effected by hairpin fuel strands in the environment of the system, leading to the coupling of the photochemical and dark-operating modules.

Imide Condensation as a Strategy for the Synthesis of Core-Diversified G-Quadruplex Ligands with Anticancer and Antiparasitic Activity*.

A facile imide coupling strategy for the one-step preparation of G-quadruplex ligands with varied core chemistries is described. The G-quadruplex stabilization of a library of nine compounds was examined using FRET melting experiments, and CD, UV-Vis, fluorescence and NMR titrations, identifying several compounds that were capable of stabilizing G-quadruplex DNA with interesting selectivity profiles. The best G4 ligand was identified as compound 3, which was based on a perylene scaffold and exhibited 40-fold selectivity for a telomeric G-quadruplex over duplex DNA. Surprisingly, a tetra-substituted flexible core, compound 11, also exhibited selective stabilization of G4 DNA over duplex DNA. The anticancer and antiparasitic activity of the library was also examined, with the lead compound 3 exhibiting nanomolar inhibition of Trypanosoma brucei with 78-fold selectivity over MRC5 cells. The cellular localization of this compound was also studied via fluorescence microscopy. We found that uptake was time dependant, with localization outside the nucleus and kinetoplast that could be due to strong fluorescence quenching in the presence of small amounts of DNA.

Cytotoxic (cis,cis-1,3,5-triaminocyclohexane)ruthenium(II)-diphosphine complexes; evidence for covalent binding and intercalation with DNA.

We report cytotoxic ruthenium(ii) complexes of the general formula [RuCl(cis-tach)(diphosphine)]+ (cis-tach = cis-cis-1,3,5-triaminocyclohexane) that have been characterised by 1H, 13C and 31P{1H} NMR spectroscopy, mass spectrometry, X-ray crystallography and elemental analysis. The kinetics of aquation and stability of the active species have been studied, showing that the chlorido ligand is substituted by water at 298 K with first order rate constants of 10-2-10-3 s-1, ideal for potential clinical use as anti-tumour agents. Strong interactions with biologically relevant duplex and quadruplex DNA models correlate with the activity observed with A549, A2780 and 293T cell lines, and the degree of activity was found to be sensitive to the chelating diphosphine ligand. A label-free ptychographic cell imaging technique recorded cell death processes over 4 days. The Ru(ii) cis-tach diphosphine complexes exhibit anti-proliferative effects, in some cases outperforming cisplatin and other cytotoxic ruthenium complexes.

Visible-light photoswitching of ligand binding mode suggests G-quadruplex DNA as a target for photopharmacology.

We report the selective targeting of telomeric G4 DNA with a dithienylethene ligand and demonstrate the robust visible-light mediated switching of the G4 ligand binding mode and G-tetrad structure in physiologically-relevant conditions. The toxicity of the ligand to cervical cancer cells is modulated by the photoisomeric state of the ligand, indicating for the first time the potential of G4 to serve as a target for photopharmacological strategies.

Stiff-Stilbene Ligands Target G-Quadruplex DNA and Exhibit Selective Anticancer and Antiparasitic Activity.

G-quadruplex nucleic acid structures have long been studied as anticancer targets whilst their potential in antiparasitic therapy has only recently been recognized and barely explored. Herein, we report the synthesis, biophysical characterization, and in vitro screening of a series of stiff-stilbene G4 binding ligands featuring different electronics, side-chain chemistries, and molecular geometries. The ligands display selectivity for G4 DNA over duplex DNA and exhibit nanomolar toxicity against Trypasanoma brucei and HeLa cancer cells whilst remaining up to two orders of magnitude less toxic to non-tumoral mammalian cell line MRC-5. Our study demonstrates that stiff-stilbenes show exciting potential as the basis of selective anticancer and antiparasitic therapies. To achieve the most efficient G4 recognition the scaffold must possess the optimal electronics, substitution pattern and correct molecular configuration.

Enhanced sampling molecular dynamics simulations correctly predict the diverse activities of a series of stiff-stilbene G-quadruplex DNA ligands.

Ligands with the capability to bind G-quadruplexes (G4s) specifically, and to control G4 structure and behaviour, offer great potential in the development of novel therapies, technologies and functional materials. Most known ligands bind to a pre-formed topology, but G4s are highly dynamic and a small number of ligands have been discovered that influence these folding equilibria. Such ligands may be useful as probes to understand the dynamic nature of G4 in vivo, or to exploit the polymorphism of G4 in the development of molecular devices. To date, these fascinating molecules have been discovered serendipitously. There is a need for tools to predict such effects to drive ligand design and development, and for molecular-level understanding of ligand binding mechanisms and associated topological perturbation of G4 structures. Here we study the G4 binding mechanisms of a family of stiff-stilbene G4 ligands to human telomeric DNA using molecular dynamics (MD) and enhanced sampling (metadynamics) MD simulations. The simulations predict a variety of binding mechanisms and effects on G4 structure for the different ligands in the series. In parallel, we characterize the binding of the ligands to the G4 target experimentally using NMR and CD spectroscopy. The results show good agreement between the simulated and experimentally observed binding modes, binding affinities and ligand-induced perturbation of the G4 structure. The simulations correctly predict ligands that perturb G4 topology. Metadynamics simulations are shown to be a powerful tool to aid development of molecules to influence G4 structure, both in interpreting experiments and to help in the design of these chemotypes.

Exploring ultraviolet photoinduced charge-transfer dynamics in a model dinucleotide of guanine and thymine.

An understanding of the initial photoexcited states of DNA is essential to unravelling deleterious photoinduced chemical reactions and the intrinsic ultrafast photoprotection of the genetic code for all life. In our combined experimental and theoretical study, we have elucidated the primary non-radiative relaxation dynamics of a model nucleotide of guanine and thymine (2'-deoxyguanosine 3'-monophosphate 5'-thymidine, d(GpT)) in buffered aqueous solution. Experimentally, we unequivocally demonstrate that the Franck-Condon excited states of d(GpT) are significantly delocalised across both nucleobases, and mediate d(G+pT-) exciplex product formation on an ultrafast (<350 fs) timescale. Theoretical studies show that the nature of the vertical excited states is very dependent on the specific geometry of the dinucleotide, and dictate the degree of delocalised, charge-transfer or localised character. Our mechanism for prompt exciplex formation involves a rapid change in electronic structure and includes a diabatic surface crossing very close to the Franck-Condon region mediating fast d(G+pT-) formation. Exciplexes are quickly converted back to neutral ground state molecules on a ∼10 ps timescale with a high quantum yield, ensuring the photostability of the nucleotide sequence.

A Photoresponsive Stiff-Stilbene Ligand Fuels the Reversible Unfolding of G-Quadruplex DNA.

The polymorphic nature of G-quadruplex (G4) DNA structures points to a range of potential applications in nanodevices and an opportunity to control G4 in biological settings. Light is an attractive means for the regulation of oligonucleotide structure as it can be delivered with high spatiotemporal precision. However, surprisingly little attention has been devoted towards the development of ligands for G4 that allow photoregulation of G4 folding. We report a novel G4-binding chemotype derived from stiff-stilbene. Surprisingly however, whilst the ligand induces high stabilization in the potassium form of human telomeric DNA, it causes the unfolding of the same G4 sequence in sodium buffer. This effect can be reversed on demand by irradiation with 400 nm light through deactivation of the ligand by photo-oxidation. By fuelling the system with the photolabile ligand, the conformation of G4 DNA was switched five times.