Light-triggered stapling of biologically relevant DNA tetraplexes results in increased topological, thermodynamic, and metabolic stability.

G-quadruplexes (G4s) and intercalated-motifs (IMs) are secondary, tetraplexed DNA structures abundant in non-coding regions of the genome, and recognised as potential therapeutic targets. Given their affinity for human proteins, G4 structures are investigated as potential decoys and aptamers. However, G4s tend to adopt different conformations depending on the exact environmental conditions, and often only one displays the specifically desired biological activity. The less intensively studied I-motifs are typically unstable at neutral pH, rendering their potential application in biological context challenging. We herein report on a photochemical method for “stapling” relevant tetraplexed-structures, to increase their stability, lock their topology and enhance their enzymatic resistance, while maintaining biological activity. The chemical structure and topology of the stapled Thrombin Binding Aptamer (TBA) model system was spectroscopically characterised and rationalised in silico. The method was expanded to other G4- and IM-prone sequences, hinting towards potential application of such stapled structures in a therapeutic context.