Abstract
Simple SummaryFour-stranded nucleic acid secondary structures (quadruplexes) including DNA G-quadruplexes, RNA G-quadruplexes and i-Motifs display key regulatory functions in the human genome. Quadruplexes play an important role in telomere lengthening and the expression control of several cancer-related genes. In this context, quadruplex ligands are considered as potential strategies for anticancer drug discovery. Previous reviews are mainly focused on ligands targeting DNA G-quadruplexes, RNA G-quadruplexes and i-Motifs in a separate way, hindering a holistic study. The present review overcomes this limitation by providing a general overview of the recent research on ligands targeting the three different quadruplex structures in cancer.Nucleic acids can adopt alternative secondary conformations including four-stranded structures known as quadruplexes. To date, quadruplexes have been demonstrated to exist both in human chromatin DNA and RNA. In particular, quadruplexes are found in guanine-rich sequences constituting G-quadruplexes, and in cytosine-rich sequences forming i-Motifs as a counterpart. Quadruplexes are associated with key biological processes ranging from transcription and translation of several oncogenes and tumor suppressors to telomeres maintenance and genome instability. In this context, quadruplexes have prompted investigations on their possible role in cancer biology and the evaluation of small-molecule ligands as potential therapeutic agents. This review aims to provide an updated close-up view of the literature on quadruplex ligands in cancer therapy, by grouping together ligands for DNA and RNA G-quadruplexes and DNA i-Motifs.
Highlights
Nucleic acids have considerable potential to fold into three-dimensional secondary structures based on particular sequence motifs [1]
The results demonstrated that only one ligand functions through c-MYC G4 binding [145]
As demonstrated in the present review, an imbalance in quadruplex dynamics contributes to carcinogenesis, and its manipulation by quadruplex ligands provides a novel opportunity to defeat cancer
Summary
Nucleic acids have considerable potential to fold into three-dimensional secondary structures based on particular sequence motifs [1]. Single-stranded guanine-rich DNA sequences can fold into stable intramolecular and intermolecular four-stranded G-quadruplexes (G4s) [2]. Further studies established that many RNA sequences featuring G-tracts can fold into G4 structures, sometimes demonstrating increased thermodynamic stability and reduced steric hindrance [4]. Single-stranded cytosine-rich sequences can form hemiprotonated cytosine–cytosine base pairs (C–C+), adopting a structure called an i-Motif [5]. This structure is less known than other DNA structures, in part due to its Cancers 2021, 13, 3156.
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