Fig. 6. Model for ZAP-S mediated inhibition of SARS-CoV-2 frameshifting.

1 Upon infection, the viral RNA is translated by the cellular machinery, and 40% of translation events yield the 1a/1b polyprotein through –1PRF. 2 Infection also leads to the induction of antiviral factors including ZAP-S. 3 ZAP-S binding to the frameshift RNA alters RNA refolding and thereby reduces the chance of elongating ribosomes to encounter the stimulatory structure. Thus, the elongation pause is too short for codon-anti-codon interactions to be established in the –1-frame and ZAP-S allows translation to proceed without a strong roadblock effect. This leads to termination at the canonical 0-frame UAA stop codon found just downstream of the slippery sequence. The resulting decrease in the amounts of the 1a/1b polypeptides reduces the levels of the viral RNA-dependent RNA polymerase (RdRP) from the –1-frame.