Restriction of SARS-CoV-2 replication by targeting programmed −1 ribosomal frameshifting
Yu Sun, Laura Abriola, Rachel O. Niederer, Savannah F. Pedersen, Mia Madel Alfajaro, Valter Silva Monteiro, Craig B. Wilen, Ya‐Chi Ho, Wendy V. Gilbert, Yulia V. Surovtseva, Brett D. Lindenbach, Junjie U. Guo
Abstract
Translation of open reading frame 1b (ORF1b) in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) requires a programmed -1 ribosomal frameshift (-1 PRF) promoted by an RNA pseudoknot. The extent to which SARS-CoV-2 replication may be sensitive to changes in -1 PRF efficiency is currently unknown. Through an unbiased, reporter-based high-throughput compound screen, we identified merafloxacin, a fluoroquinolone antibacterial, as a -1 PRF inhibitor for SARS-CoV-2. Frameshift inhibition by merafloxacin is robust to mutations within the pseudoknot region and is similarly effective on -1 PRF of other betacoronaviruses. Consistent with the essential role of -1 PRF in viral gene expression, merafloxacin impedes SARS-CoV-2 replication in Vero E6 cells, thereby providing proof-of-principle for targeting -1 PRF as a plausible and effective antiviral strategy for SARS-CoV-2 and other coronaviruses.