Covalent Probes Reveal Small-Molecule Binding Pockets in Structured RNA and Enable Bioactive Compound Design.

ABSTRACT: The SARS-CoV-2 frameshift stimulation element (FSE) is a critical RNA structure that is essential for viral replication and represents a promising target for antiviral intervention. Here, Chemical Cross-Linking and Isolation by Pull-down (Chem-CLIP) covalent target validation and binding site mapping was applied, to identify small-molecule binding pockets within the FSE and ultimately develop a ligandability map. These studies employed ∼ 190 Chem-CLIP fragments, including the fluoroquinolone merafloxacin, previously shown to interact with this element. Covalent mapping defined merafloxacin's binding pocket at a nucleotide-level resolution and revealed interactions that, along with structure-based design, efficient one-pot on-plate synthesis and competitive displacement assays, enabled the

SUBMITTER: Kovachka S 

PROVIDER: S-EPMC12532193 | biostudies-literature | 2025 Oct

REPOSITORIES: biostudies-literature