Proc Natl Acad Sci U S A . Restriction of SARS-CoV-2 replication by targeting programmed -1 ribosomal frameshifting

[tetano]

Proc Natl Acad Sci U S A


. 2021 Jun 29;118(26):e2023051118.
doi: 10.1073/pnas.2023051118.
Restriction of SARS-CoV-2 replication by targeting programmed -1 ribosomal frameshifting


Yu Sun[SUP] 1 [/SUP], Laura Abriola[SUP] 2 [/SUP], Rachel O Niederer[SUP] 3 [/SUP], Savannah F Pedersen[SUP] 4 [/SUP], Mia M Alfajaro[SUP] 5 6 [/SUP], Valter Silva Monteiro[SUP] 6 [/SUP], Craig B Wilen[SUP] 5 6 [/SUP], Ya-Chi Ho[SUP] 4 [/SUP], Wendy V Gilbert[SUP] 3 [/SUP], Yulia V Surovtseva[SUP] 2 [/SUP], Brett D Lindenbach[SUP] 7 [/SUP], Junjie U Guo[SUP] 8 [/SUP]



Affiliations

• PMID: 34185680
• DOI: 10.1073/pnas.2023051118

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.

Keywords: RNA pseudoknot; coronavirus; merafloxacin; ribosomal frameshifting; translation.