This perspective highlights the emerging significance of noncanonical nucleic acid structures-such as G-quadruplexes, Z-DNA/Z-RNA, and cruciforms-in viral genomes. Once considered structural oddities, these motifs are now recognized as critical regulators of viral replication, transcription, genome stability, and host-pathogen interactions. Despite mounting evidence of their functional relevance and therapeutic potential, these structures remain largely overlooked in virology and antiviral drug development. Their unique conformations offer highly specific molecular targets, with several small molecules already demonstrating the ability to modulate viral gene expression by stabilizing or destabilizing these motifs. The persistent underestimation of non-B DNA/RNA structures represents a missed opportunity in the fight against viral diseases. By synthesizing recent discoveries and emphasizing their biological and pharmacological promise, we aim to elevate awareness and catalyze interdisciplinary research. Harnessing the structural diversity of viral genomes could unlock novel antiviral strategies with high specificity and minimal off-target effects.

Department of Biology and Ecology Faculty of Science University of Ostrava Ostrava Czech Republic

Institute of Biophysics of the Czech Academy of Sciences Brno Czech Republic

School of Biological Sciences University of East Anglia Norwich United Kingdom

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