Photoresponsive Control of G-Quadruplex DNA Systems

Abstract

G-quadruplex (G4) oligonucleotide secondary structures have recently attracted significant attention as therapeutic targets owing to their occurrence in human oncogene promoter sequences and the genome of pathogenic organisms. G4s also demonstrate interesting catalytic activities in their own right, as well as the ability to act as scaffolds for the development of DNA-based materials and nanodevices. Owing to this diverse range of opportunities to exploit G4 in a variety of applications, several strategies to control G4 structure and function have emerged. Interrogating the role of G4s in biology requires the delivery of small-molecule ligands that promote its formation under physiological conditions, while exploiting G4 in the development of responsive nanodevices is normally achieved by the addition and sequestration of the metal ions required for the stabilization of the folded structure. Although these strategies prove successful, neither allows the system in question to be controlled externally. Meanwhile, light has proven to be an attractive means for the control of DNA-based systems as it is noninvasive, can be delivered with high spatiotemporal precision, and is orthogonal to many chemical and biological processes. A plethora of photoresponsive DNA systems have been reported to date; however, the vast majority deploy photoreactive moieties to control the stability and assembly of duplex DNA hybrids. Despite the unique opportunities afforded by the regulation of G-quadruplex formation in biology, catalysis, and nanotechnology, comparatively little attention has been devoted to the design of photoresponsive G4-based systems. In this Perspective, we consider the potential of photoresponsive G4 assemblies and examine the strategies that may be used to engineer these systems toward a variety of applications. Through an overview of the main developments in the field to date, we highlight recent progress made toward this exciting goal and the emerging opportunities that remain ripe for further exploration in the coming years.

Figure 1

(a) Photoregulation of G4 formation using E–Z photoisomerization of the photoresponsive 8-fluorenylvinyl group. Reproduced with permission from ref (64). Copyright 2009 Wiley. (b) Photoresponsive formation of an intermolecular G4 from azobenzene-linked nucleotides. Reproduced with permission from ref (65). Copyright 2016 Wiley. (c) Control of G4/thrombin binding by anthracene photodimerization.

Figure 2

Photocaged G4 2 and 3 based on nitroveratryl caging group (red), which is cleaved upon irradiation with 365 nm light.

Figure 3

Reversible folding and unfolding of the G4 induced by the photoresponsive azobenzene 4. First, the G4 formation was induced in the presence of E-4, which was dissociated by irradiation with UV light at 350 nm and, finally, the stretched oligomer folded into the G4 again upon irradiation with visible light.

Figure 4

Switchable control of thrombin activity by exploiting the host–guest chemistry of G4 ligand 4.

Figure 5

(a) Structure of azobenzene derivatives 5 and 6 as photoresponsive G4 ligands. (b) UV/vis spectra of compound 6 prior to irradiation (top line) and under visible light at various reaction times (0–120 s) followed by the UV irradiation at 350 nm. (c) CD spectra of human telomeric DNA in the absence presence of compound 5 and the corresponding reversible G4 conformations upon photoirradiation. Reproduced with permission from ref (75). Copyright 2011 Royal Society of Chemistry.

Figure 6

Structure of azobenzene derivatives 7 and the corresponding photoisomerization process using UV/vis light. (b) Schematic representation showing the complexation process between the photochrome and the telomeric G4 DNA via stacking on the top/bottom of the quartets. Reproduced with permission from ref (77). Copyright 2018 Royal Society of Chemistry. (c) Structure of azobenzene 8 as photoresponsive G4 ligands.

Figure 7

Suggested binding modes of the E,E-9 and E,Z-9 isomers telomeric G4 DNA and c-myc G4 DNA, respectively. Adapted with permission from ref (79). Copyright 2012 Elsevier.

Figure 8

Reversible unfolding of G4 DNA using the photoresponsive stiff-stilbene 10. Reproduced with permission from ref (80). Copyright 2019 Wiley.

Figure 9

Suggested binding modes of the two photochromic forms 12c/12o to telo23 G4 DNA and cartoon representation of the responsive G4/ligand system. Adapted with permission from ref (81). Copyright 2020 Royal Society of Chemistry.