Significance A large variety of RNA viruses, including the novel coronavirus SARS-CoV-2, contain specific RNA structures that promote programmed ribosomal frameshifting (PRF) to regulate viral gene expression. From a high-throughput compound screen, we identified a PRF inhibitor for SARS-CoV-2 and found that it substantially impeded viral replication in cultured cells. Interestingly, the compound could target not only SARS-CoV-2 but also other coronaviruses that use similar RNA structures to promote frameshifting. These results suggest targeting PRF is a plausible, effective, and broad-spectrum antiviral strategy for SARS-CoV-2 and other coronaviruses. 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.
【저자키워드】 translation, ribosomal frameshifting, RNA pseudoknot, merafloxacin, 【초록키워드】 SARS-CoV-2, coronavirus, Mutation, Gene Expression, Antiviral, translation, severe acute respiratory syndrome Coronavirus, Novel coronavirus, RNA, Viral, viral replication, RNA viruses, VERO E6 cells, respiratory, inhibitor, RNA structure, SARS-CoV-2 replication, betacoronaviruses, Open reading frame, regulate, Efficiency, Vero E6, acute respiratory syndrome, Frame, ribosomal frameshift, acute respiratory syndrome coronavirus, acute respiratory syndrome coronavirus 2, principle, other coronaviruses, Compound, novel coronavirus SARS-CoV-2, cultured cells, ORF1b, viral gene expression, frameshift, effective, robust, other coronavirus, changes in, in viral, variety, promote, promoted, impede, Significance, 【제목키워드】 restriction,