Targeting RNA structures with small molecules.

Area of Science:

• Molecular biology
• Drug discovery
• Genetics

Background:

• 3D RNA structures are crucial for biological functions and implicated in diseases.
• Therapeutic targeting of RNA structures with small molecules is an emerging field.
• Advances in computational tools and strategies enhance RNA-targeted drug development.

Purpose of the Study:

• To describe strategies for identifying, validating, and optimizing small molecules targeting the functional transcriptome.
• To provide a roadmap for advancing RNA-targeted small molecule therapeutics.

Main Methods:

• Utilizing computational tools to predict evolutionarily conserved RNA structures.
• Developing strategies to expand the mode of action for RNA-targeting small molecules.
• Facilitating interactions between small molecules and cellular machinery.

Main Results:

• Existing RNA-targeted small molecules employ diverse mechanisms, including splicing modulation (e.g., molecular glues like branaplam and risdiplam), translation inhibition, and functional RNA structure deactivation.
• Successful identification, validation, and optimization strategies are crucial for therapeutic advancement.

Conclusions:

• Targeting the functional transcriptome with small molecules represents a promising therapeutic frontier.
• A clear roadmap is essential for the progression of these RNA-targeting agents into clinical practice over the next decade.