G-quadruplex DNA and RNA structures (G4)

G-quadruplexes (G4s) are non-canonical, four-stranded secondary structures formed by guanine-rich sequences in DNA and RNA [1, 3]. These structures are stabilized by Hoogsteen hydrogen bonding between four guanine bases, forming planar G-tetrads that stack on top of each other, often coordinated by a central potassium or sodium cation [3, 9]. G4s are prevalent in functionally significant genomic regions, including telomeres, oncogene promoters (such as c-MYC, c-KIT, and KRAS), and the untranslated regions (UTRs) of mRNA [4, 5]. They play critical roles in regulating essential cellular processes like gene transcription, translation, DNA replication, and telomere maintenance [1, 9]. In disease contexts, particularly cancer, G4 stabilization can repress the expression of potent oncogenes or inhibit telomerase activity, leading to cell cycle arrest or apoptosis [1, 11]. Small molecule ligands designed to target G4s, such as Pidnarulex (CX-5461), are being investigated for their ability to induce synthetic lethality in DNA repair-deficient cells, such as those with BRCA1/2 mutations [11]. RNA G-quadruplexes (rG4s) are also emerging as targets for their roles in mRNA splicing and translation regulation, particularly in neurodegenerative diseases like ALS [5, 8]. However, achieving high selectivity for specific G4 topologies over others remains a significant therapeutic challenge due to the structural similarity of different G4 motifs [2, 10].

Other names

G-quadruplexG4 nucleic acidG-quartetG-tetradGuanine quadruplexrG4

Stabilization of G-quadruplex structures to inhibit transcription of oncogenes, interfere with telomere maintenance, or induce DNA damage and synthetic lethality.