Targeting SARS-CoV-2 programmed -1 ribosomal frameshifting: structural dynamics and RNA-directed antiviral strategies.

Programmed -1 ribosomal frameshifting (-1 PRF) is a translational recoding mechanism used by many RNA viruses to regulate the expression of viral replication proteins. In coronaviruses, including SARS-CoV-2, -1 PRF is controlled by a conserved frameshift stimulation element containing a three-stemmed RNA pseudoknot located downstream of a slippery sequence. Studies have shown that conformational dynamics, mechanical stability, and structural variability of the pseudoknot influence ribosome pausing and frameshifting efficiency, identifying viral RNA structures as potential antiviral targets. This review outlines the structural organization, mechanistic basis, and conformational dynamics of viral frameshifting pseudoknots, with emphasis on the SARS-CoV-2 frameshift stimulation element. Advances in cryo-electron microscopy, single-molecule biophysics, molecular dynamics simulations, and computational modeling have identified multiple pseudoknot conformations involved in translational recoding and ribosome-RNA interactions. RNA-targeted therapeutic approaches used to suppress or modulate -1 PRF are also discussed, including small-molecule RNA binders, antisense oligonucleotides, peptide nucleic acids, and ribonuclease-targeting chimeras. These approaches act on distinct aspects of RNA structure, conformational flexibility, and stability to inhibit viral translation or promote selective RNA degradation. Major challenges include selective targeting of highly dynamic RNA structures, optimization of intracellular delivery, and minimizing off-target effects. Integration of structural biology, computational modeling, and RNA-targeted therapeutic strategies may support the development of next-generation antivirals targeting conserved viral RNA regulatory elements.