Abstract
Small-molecule ligands targeting nucleic acids have been explored as potential therapeutic agents. Duplex groove-binding ligands have been shown to recognize DNA in a sequence-specific manner. On the other hand, quadruplex-binding ligands exhibit high selectivity between quadruplex and duplex, but show limited discrimination between different quadruplex structures. Here we propose a dual-specific approach through the simultaneous application of duplex- and quadruplex-binders. We demonstrated that a quadruplex-specific ligand and a duplex-specific ligand can simultaneously interact at two separate binding sites of a quadruplex-duplex hybrid harbouring both quadruplex and duplex structural elements. Such a dual-specific targeting strategy would combine the sequence specificity of duplex-binders and the strong binding affinity of quadruplex-binders, potentially allowing the specific targeting of unique quadruplex structures. Future research can be directed towards the development of conjugated compounds targeting specific genomic quadruplex-duplex sites, for which the linker would be highly context-dependent in terms of length and flexibility, as well as the attachment points onto both ligands.
Highlights
To begin with, a quadruplex-duplex hybrid[33] (QDH1; Table S1 and Figure S1, Supporting Information) containing both a duplex segment harbouring six continuous A T base pairs and a quadruplex was titrated with th
Duplex-binder netropsin[34] (Fig. 1d), which was shown to recognize AT-rich regions, and the bisquinolinium quadruplex-binder Phen-DC335 (Fig. 2d), individually. 1D imino proton NMR spectrum of free QDH1 is shown in Fig. 1a: twelve major peaks were observed at 10.6–11.8 ppm, corresponding to the formation of a three-layered G-tetrad core; fourteen major peaks were observed at 12.4–14 ppm, corresponding to the formation of the duplex stem
We have proposed a targeting strategy based on the simultaneous application of duplex- and quadruplex-binding ligands
Summary
A quadruplex-duplex hybrid[33] (QDH1; Table S1 and Figure S1, Supporting Information) containing both a duplex segment harbouring six continuous A T base pairs and a quadruplex was titrated with th. 1D imino proton NMR spectrum of (a) free QDH1, (b) QDH1 bound with half the molar equivalent of netropsin, (c) QDH1 bound with equimolar ratio of netropsin, and (d) chemical structure of netropsin, a DNA minor groove-binder. At 1:1 DNA-to-ligand ratio, the duplex stem was fully bound with netropsin at the AT-rich binding site, as evidenced by the disappearance of the unbound duplex peaks (Fig. 1c), whereas the quadruplex peaks showed minimal change.
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