Restriction of SARS-CoV-2 replication by targeting programmed -1 ribosomal frameshifting

Area of Science:

• Molecular Biology
• Virology
• Drug Discovery

Background:

• Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) translation relies on programmed -1 ribosomal frameshift (-1 PRF).
• The impact of -1 PRF efficiency on SARS-CoV-2 replication remains largely unexplored.

Purpose of the Study:

• To identify compounds that modulate -1 PRF efficiency in SARS-CoV-2.
• To evaluate the antiviral potential of targeting -1 PRF.

Main Methods:

• Conducted an unbiased, reporter-based high-throughput compound screen.
• Tested identified compounds for their ability to inhibit SARS-CoV-2 -1 PRF.
• Assessed the effect of the inhibitor on viral replication in cell culture.

Main Results:

• Merafloxacin, a fluoroquinolone antibacterial, was identified as a potent inhibitor of SARS-CoV-2 -1 PRF.
• Merafloxacin's inhibitory effect is robust to mutations in the RNA pseudoknot and effective against other betacoronaviruses.
• Merafloxacin significantly impedes SARS-CoV-2 replication in Vero E6 cells.

Conclusions:

• Targeting -1 PRF is a viable antiviral strategy for SARS-CoV-2.
• Merafloxacin demonstrates proof-of-principle for -1 PRF-targeted antiviral therapy.
• This approach holds promise for combating SARS-CoV-2 and other coronavirus infections.