Targeting RNA with small molecules-A safety perspective

Area of Science:

• Molecular Biology
• Drug Discovery
• Medicinal Chemistry

Background:

• Ribonucleic acid (RNA) plays critical roles in cellular functions and disease.
• Small molecule-RNA targeting (smRNA targeting) has emerged as a significant therapeutic strategy.
• Current drug discovery efforts primarily focus on RNA as a primary target.

Purpose of the Study:

• To explore the largely uninvestigated role of RNA as a secondary (off) target in small molecule drug programs.
• To discuss structure, target, and mechanism-driven safety considerations for smRNA therapeutics.
• To highlight methods for evaluating these parameters to enhance drug safety.

Main Methods:

• Literature review and perspective synthesis.
• Analysis of structure-activity relationships in smRNA targeting.
• Discussion of target and mechanism-based safety profiling.

Main Results:

• RNA is frequently an off-target in small molecule drug development, presenting both risks and opportunities.
• Understanding smRNA interactions requires detailed analysis of molecular structure, target engagement, and mechanism of action.
• Safety can be proactively managed by considering RNA as a potential off-target.

Conclusions:

• Evaluating RNA as a secondary target can lead to the development of safer small molecule drugs.
• Integrating safety assessments early in drug discovery is crucial for smRNA therapeutics.
• This perspective provides a framework for considering RNA off-target effects to improve drug safety profiles.