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Using In Vitro and In-cell SHAPE to Investigate Small Molecule Induced Pre-mRNA Structural Changes
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Structure-Guided Design of a Bioactive Covalent Small Molecule Targeting a Riboswitch.

Chungen Li1,2, Xueyi Yang1,3, Kyle A Dickerson4

  • 1Department of Chemistry, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, 130 Scripps Way, Jupiter, Florida 33458, United States.

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|October 7, 2025
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Summary
This summary is machine-generated.

Researchers developed a phenylglyoxal-based covalent probe to target unpaired guanines in structured RNAs. This probe modulates flavin mononucleotide (FMN) riboswitch function, showing potential for RNA-targeted therapeutics.

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Area of Science:

  • Chemical Biology
  • RNA Therapeutics
  • Drug Discovery

Background:

  • Small molecules targeting RNA offer therapeutic potential.
  • Structured RNA elements are key regulators of biological processes.
  • Developing specific chemical probes for RNA is crucial.

Purpose of the Study:

  • To characterize a phenylglyoxal-based covalent probe targeting unpaired guanine residues.
  • To investigate the probe's ability to modulate flavin mononucleotide (FMN) riboswitch function.
  • To explore covalent modification strategies for bioactive RNA ligands.

Main Methods:

  • Structure-guided design of a covalent probe.
  • Synthesis and characterization of the phenylglyoxal derivative.
  • Assessing probe activity in a cellular reporter system for FMN riboswitch function.

Main Results:

  • The designed probe specifically targets unpaired guanines in structured RNAs.
  • Covalent modification at the intended site was confirmed.
  • The probe successfully modulated FMN riboswitch activity in a cellular context.

Conclusions:

  • Phenylglyoxal-based covalent probes can effectively target specific RNA structures.
  • Covalent modification represents a viable mechanism for modulating RNA function.
  • This approach holds promise for developing novel RNA-targeted therapeutics and chemical probes.