Covalent small-molecule-RNA complex formation enables cellular profiling of small-molecule-RNA interactions

Area of Science:

• Chemical Biology
• Molecular Biology
• Drug Discovery

Background:

• Targeting cellular RNA with small molecules is a promising therapeutic strategy.
• Developing potent and selective RNA-targeting agents remains challenging.
• Understanding RNA-drug interactions is crucial for drug development.

Purpose of the Study:

• To design novel small molecules with enhanced reactivity towards cellular RNA targets.
• To improve the efficacy of RNA-targeting compounds in cell culture.
• To establish a method for cell-wide RNA target profiling.

Main Methods:

• Design and synthesis of small molecules with specific reactivity profiles.
• In vitro assays to evaluate compound activity against RNA targets.
• Cell-based assays to assess compound performance and target engagement.
• Development of a cell-wide profiling technique to identify RNA targets.

Main Results:

• The designed small molecules demonstrated significantly improved activity against RNA targets, with an enhancement factor of approximately 2500 in cell culture.
• The approach enabled the identification of cellular RNA targets for the developed compounds.
• The strategy proved effective for cell-wide profiling of RNA targets.

Conclusions:

• A novel strategy for designing reactive small molecules targeting cellular RNA has been established.
• This approach offers a substantial improvement in the potency of RNA-targeting compounds.
• The method provides a powerful tool for RNA target identification and profiling, advancing RNA-targeted drug discovery.