Direct-acting antivirals and beyond: emerging approaches to targeting viral RNA and ribonucleoprotein complexes

RNA viruses, particularly respiratory-transmitted pathogens like SARS-CoV-2 and influenza, pose a significant and persistent threat to global public health. While vaccines and antiviral drugs have made substantial progress in preventing and controlling these infections, the threat remains, highlighting the need for novel therapeutic strategies. Small molecule and proteins-based therapeutics remain the primary forms of clinical interventions and a mainstay of drug development. Traditionally, these agents target viral or host proteins, including enzymes, receptors, ion channels, and other host factors. However, the landscape of antiviral drug discovery is expanding. Recent research has increasingly highlighted viral RNA (vRNA) and its associated binding proteins as critical and promising therapeutic targets. Beyond its role as a carrier of genetic information, vRNA is actively involved in essential steps of the viral life cycle, including transcription, translation, replication and interactions with host proteins. Therefore, a detailed understanding of vRNA structure and the proteins involved in its synthesis and processing is vital for rational drug design. This review focuses on the development of antiviral drugs and explores the potential of targeting the vRNA genome and vRNA binding proteins for therapeutic interventions.