Programmed -1 ribosomal frameshifting in SARS-CoV-2: molecular mechanisms and implications for antiviral targeting

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genome is organized into two functional regions. The 5' region comprises an open reading frame (ORF1a) that encodes the polyprotein pp1a and, through a programmed frameshifting event, enables the production of the extended polyprotein pp1ab. These polyproteins are processed by the viral proteases 3CLpro and PLpro into 16 nonstructural proteins (nsps). Nsps 1-11 participate in polyprotein processing, formation, and regulation of the replication-transcription complex, and modulation of host immune responses. Nsps 12-16 form the core of the viral RNA synthesis machinery and are primarily associated with RNA-dependent RNA polymerase activity, proofreading, capping, and RNA modification, while also functioning in coordination with additional nsps. The 3' functional region of the genome encodes structural (S, E, M, and N) and accessory proteins (e.g., 3a, 6, 7a, 8, and 9b) that contribute to viral assembly, replication efficiency, and pathogenicity. Synthesis of pp1ab depends on a programmed -1 ribosomal frameshifting (-1 PRF) event mediated by cis-acting RNA elements that induce a one-nucleotide shift in the 5' direction of the ribosome. This mechanism is critical for maintaining the stoichiometric balance of replication proteins. Here, we review recent current insights into the molecular mechanisms and structural dynamics of -1 PRF in SARS-CoV-2 and discuss its potential as a therapeutic target for antiviral intervention across clinically relevant coronaviruses.