Small molecule-RNA targeting: starting with the fundamentals

Area of Science:

• Medicinal Chemistry
• Chemical Biology
• RNA Therapeutics

Background:

• Small molecules offer therapeutic potential by targeting RNA, but selectivity remains a challenge due to RNA's dynamic nature and competition with abundant ribosomal RNA.
• Fewer than 150 chemical probes target non-ribosomal RNA, highlighting a gap in RNA-targeted drug development.

Purpose of the Study:

• To improve small molecule targeting strategies for RNA.
• To gain fundamental insights into small molecule:RNA recognition.
• To identify privileged RNA topologies and chemical spaces for drug discovery.

Main Methods:

• Synthesized RNA-binding scaffolds to study small molecule:RNA recognition principles.
• Analyzed physicochemical, structural, and spatial properties of RNA ligands.
• Employed pattern recognition to identify targetable RNA topologies and visualize structural changes.

Main Results:

• Revealed general principles governing small molecule:RNA recognition, affinity, and selectivity.
• Identified distinct properties of RNA-targeting ligands compared to protein-targeting ligands.
• Developed a public platform with datasets and tools to aid RNA ligand discovery.
• Identified RNA topologies amenable to differential small molecule recognition.

Conclusions:

• Fundamental insights into RNA recognition mechanisms enable functional targeting of RNA structures in biological systems.
• Developed guiding principles and assays to accelerate the development of RNA-targeted chemical probes.
• This research paves the way for new therapeutic approaches targeting RNA for various diseases.