Researchers Develop New Strategy to Design Small Molecules for Antiviral Intervention

Strategic Insights -

Researchers from the Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology (UF-Scripps) have developed a new strategy for designing small molecules that bind to RNA structures, offering a promising approach to antiviral intervention. This research, published in the Journal of the American Chemical Society, focuses on the SARS-CoV-2 frameshift stimulation element (FSE), a critical RNA structure essential for viral replication.

Key Takeaways:

  • The study employed Chemical Cross-Linking and Isolation by Pull-down (Chem-CLIP) to identify small-molecule binding pockets within the FSE and develop a ligandability map.
  • The research involved 190 Chem-CLIP fragments, including the fluoroquinolone merafloxacin, which was previously shown to interact with the FSE.
  • Covalent mapping defined merafloxacin's binding pocket at a nucleotide-level resolution and revealed interactions that enabled the development of bioactive compounds with antiviral activity.
  • Complementary chemical probing with dimethyl sulfate (DMS) in the presence of a bioactive ligand revealed changes in local RNA folding.
  • The findings support a strategy to design and discover small molecules that bind RNA structures and advance our understanding of RNA-ligand interactions.

Statistics:

  • 190 Chem-CLIP fragments were used in the study to identify binding pockets within the FSE.
  • 4 recurring cavities were identified in FSE structures derived from cryogenic-electron microscopy (cryo-EM) studies.
  • The research involved the development of bioactive compounds with antiviral activity.
  • The study was published in the Journal of the American Chemical Society in 2025.

Sources:

  • Covalent Probes Reveal Small-Molecule Binding Pockets in Structured RNA and Enable Bioactive Compound Design. Journal of the American Chemical Society, 2025.