About this article
G-quadruplexes (or G4s) are four-stranded DNA and RNA structures that fold from guanine (G)-rich sequences. G4 are suspected to play key biological roles in human cells and diseases. Small molecules that selectively target G4s (or G4-ligands) can thus be used as modulators to gain insights into the cell circuitry where G4s are involved. While hundreds of G4-ligands have been designed, synthesized and used, most if not all of them are flat aromatic molecules prone to interact with the duplex-DNA (the major form of DNA within the nucleus), which mechanically decreases their specificity for G4s.
We have developed a brand new molecular design, following a biomimetic approach that hinges on the observation that G4s are stable secondary structures owing to the ability of Gs to self-associate to form G-quartets, and then of G-quartets to self-stack to form the columnar core of G4s. Therefore, using a synthetic G-quartet as a G4-ligand represents a unique example of biomimetic recognition of G4s, relying on a like-likes-like approach, which is the surest pledge for a very high G4-selectivity.
In this article, we report on the design, synthesis and use of synthetic G-quartet-based ligands, also referred to as TASQs (for template-assembled synthetic G-quartets). These TASQs are the latest prototypes of TASQs, being multivalent TASQs (that is why we refer to them as MultiTASQs) able to be functionalized in situ by click chemistry (both CuAAC and SPAAC) for optical imaging and affinity precipitation purposes. These bioorthogonal investigations thus provides unique information about G4 biology.
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Royal Society of Chemistry