Lock and key: locked G quadruplexes could be the key to new modalities in nucleic acid therapeutics.

G quadruplexes are secondary structures formed by G-rich sequences in DNA/RNA. They are critical regulatory centres for gene activation and chromosome stability. Malfunctions in their number or topology often results in ailments such as frontotemporal dementia, amyotrophic lateral sclerosis, coronary heart disease, anaemia, and various cancers. Proteins and ligands can bind to them only if the quadruplex topology matches their requirements. Hence, stabilizing or destabilizing this topology can have profound implications in therapeutics. Novel nucleic acid modalities involving intra-conjugated G4s are an interesting prospect as they have a fixed topology without the use of additional ligand stabilizers. They could also efficiently bind to G4-associated proteins and have important consequences in clinical research and development. In this opinion, a justification for the development of these modalities is presented by highlighting their advantages and the potential applications that can be unlocked by locking G4 sequences.