Restriction of SARS-CoV-2 Replication by Targeting Programmed -1 Ribosomal Frameshifting In Vitro

Yu Sun; Laura Abriola; Rachel O. Niederer; Savannah F. Steinhauser; Mia Madel Alfajaro; Valter Silva Monteiro; Craig B. Wilen; Ya‐Chi Ho; Wendy V. Gilbert; Yulia V. Surovtseva; Brett D. Lindenbach; Junjie U. Guo

doi:10.1073/pnas.2023051118

Molecular BiologyProceedings of the National Academy of SciencesJun 14, 2021

Peer-reviewed journal article

Restriction of SARS-CoV-2 Replication by Targeting Programmed -1 Ribosomal Frameshifting In Vitro

Yu Sun iD, Laura Abriola iD, Rachel O. Niederer iD, Savannah F. Steinhauser iD, Mia Madel Alfajaro iD, Valter Silva Monteiro iD, Craig B. Wilen iD, Ya‐Chi Ho iD, Wendy V. Gilbert iD, Yulia V. Surovtseva iD, Brett D. Lindenbach iD, Junjie U. Guo iD

Abstract

Translation of open reading frame 1b (ORF1b) in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) requires programmed -1 ribosomal frameshifting (-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 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.

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