Small molecule recognition of disease-relevant RNA structures

Area of Science:

• Drug discovery and development
• Molecular biology
• Medicinal chemistry

Background:

• Small molecule targeting of RNA is a novel therapeutic strategy.
• Advances in RNA sequencing and structural biology fuel interest in targeting pathological RNAs.
• Historically, bacterial ribosomes were primary RNA targets; focus now shifts to human RNAs.

Purpose of the Study:

• To review recent advances in small molecule drug discovery targeting human pathological RNAs.
• To highlight the design of small molecule probes with high affinity and selectivity for RNA structures.
• To explore emerging RNA-targeting strategies like bleomycin A5 conjugates and ribonuclease targeting chimeras (RIBOTACs).

Main Methods:

• Design and synthesis of small molecule probes for RNA targets.
• Evaluation of compound affinity and selectivity for disease-causing RNAs (micromolar to nanomolar range).
• Assessment of RNA-targeting strategies, including targeted degradation approaches.

Main Results:

• Small molecule probes demonstrate selective engagement with pathological RNA structures.
• Emerging strategies like RIBOTACs achieve potent and selective RNA degradation.
• Compounds show efficacy in cell lines, patient-derived cells, and preclinical animal models.

Conclusions:

• Small molecule therapeutics targeting RNA function represent a promising frontier in medicine.
• Clinical progress, including a Phase II trial and FDA approval, validates this therapeutic approach.
• Targeted RNA modulation offers a bright future for treating human diseases.