Identifying Inhibitors of -1 Programmed Ribosomal Frameshifting in a Broad Spectrum of Coronaviruses

Area of Science:

• Virology
• Drug Discovery
• Molecular Biology

Background:

• Recurrent zoonotic coronavirus (CoV) outbreaks necessitate broad-spectrum therapeutics.
• Programmed ribosomal frameshifting (-1 PRF) is a conserved mechanism in CoV replication, making its regulatory elements a potential drug target.

Purpose of the Study:

• To investigate if small-molecule inhibitors of SARS-CoV-2 -1 PRF exhibit activity against a range of bat CoVs and MERS-CoV.
• To validate viral mRNA frameshift signals as a viable target for pan-coronaviral therapeutics.

Main Methods:

• Evaluation of six SARS-CoV-2 -1 PRF inhibitors against frameshift signals from various bat CoVs and MERS-CoV.
• Utilized negative control viruses to assess specificity of inhibitor activity.

Main Results:

• Some inhibitors demonstrated potent activity against specific subsets of CoV -1 PRF signals.
• The serine protease inhibitor nafamostat significantly suppressed -1 PRF in multiple CoV frameshift signals.
• Inhibitor activity was specific, with limited effects on negative control viruses.

Conclusions:

• Small-molecule ligands can be developed to specifically inhibit -1 PRF across a broad spectrum of CoVs.
• Viral frameshift signals represent a promising and viable target for the development of pan-coronaviral therapeutics.