Merafloxacin, also known as CI 934, is a fluoroquinolone antibacterial, which was also identified as a ?1 PRF inhibitor of SARS-CoV-2. Frameshift inhibition by merafloxacin is robust to mutations within the pseudoknot region and is similarly effective on ?1 PRF of other beta coronaviruses. Importantly, frameshift inhibition by merafloxacin substantially impedes SARS-CoV-2 replication in Vero E6 cells, thereby providing the proof of principle of targeting ?1 PRF as an effective antiviral strategy for SARS-CoV-2.