Non-canonical nucleic acid structures in viruses: Regulatory modules and emerging antiviral targets

Beyond their primary sequence, viral genomes contain structural information encoded in the ability of DNA and RNA to fold into alternative conformations. These dynamic non-canonical nucleic acid structures include G-quadruplexes (G4s), i-Motifs (iMs), R-loops, G4-associated R-loops and left-handed Z-conformations. Among them, G4s have been most extensively investigated in viruses and have been reported to modulate transcription, replication, translation, latency and immune evasion. However, the functional interpretation of these structures remains highly context-dependent: similar topologies can either promote or restrict infection depending on genomic location, folding dynamics, protein interactors and the stage of the viral life cycle. Here, we discuss recent advances in viral non-canonical nucleic acid structures, emphasizing the level of evidence supporting their formation and function. We also assess emerging antiviral strategies based on structure-targeting ligands, highlighting both their translational potential and the unresolved challenges of selectivity, target engagement and pharmacological validation in infected cells.