Sun Yu, Abriola Laura, Niederer Rachel O, Pedersen Savannah F, Alfajaro Mia M, Silva Monteiro Valter, Wilen Craig B, Ho Ya-Chi, Gilbert Wendy V, Surovtseva Yulia V, Lindenbach Brett D, Guo Junjie U
Department of Neuroscience, Yale University School of Medicine, New Haven, CT 06520.
Yale Center for Molecular Discovery, Yale University, West Haven, CT 06516.
Proc Natl Acad Sci U S A. 2021 Jun 29;118(26). doi: 10.1073/pnas.2023051118.
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.
严重急性呼吸综合征冠状病毒2（SARS-CoV-2）开放阅读框1b（ORF1b）的翻译需要由RNA假结促进的程序性-1核糖体移码（-1 PRF）。目前尚不清楚SARS-CoV-2复制对-1 PRF效率变化的敏感程度。通过基于报告基因的无偏高通量化合物筛选，我们鉴定出氟喹诺酮类抗菌药物莫西沙星是SARS-CoV-2的-1 PRF抑制剂。莫西沙星对移码的抑制作用对假结区域内的突变具有抗性，并且对其他β冠状病毒的-1 PRF同样有效。与-1 PRF在病毒基因表达中的重要作用一致，莫西沙星阻碍了SARS-CoV-2在Vero E6细胞中的复制，从而为将-1 PRF作为SARS-CoV-2和其他冠状病毒可行且有效的抗病毒策略提供了原理证明。
