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Design of small molecules targeting RNA structure from sequence.

Andrei Ursu1, Jessica L Childs-Disney1, Ryan J Andrews2

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Small molecules interacting with RNA (SMIRNAs) offer a new therapeutic paradigm beyond proteins. This review covers identifying RNA targets, screening for SMIRNAs, and developing advanced RNA-centric chemical probes for disease treatment.

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Area of Science:

  • Medicinal Chemistry
  • RNA Therapeutics
  • Chemical Biology

Background:

  • Traditional drug discovery focuses on proteins, limiting therapeutic targets.
  • A new frontier involves small molecules interacting with RNA (SMIRNAs) for disease study and treatment.
  • Developing robust platforms for rational SMIRNA design is crucial for expanding drug pipelines.

Purpose of the Study:

  • To review key advancements in small molecule RNA therapeutics.
  • To highlight methods for identifying and validating RNA targets for small molecule intervention.
  • To discuss strategies for designing and optimizing SMIRNAs, including novel chemical probe modalities.

Main Methods:

  • Transcriptome-wide identification and validation of structured RNA motifs in disease-associated RNAs.
  • High-throughput screening and the Inforna strategy for identifying SMIRNAs by decoding RNA 3D structure and small molecule interactions.
  • Target validation methods assessing the link between RNA modulation and cellular phenotypic outcomes.

Main Results:

  • Established methods for identifying disease-relevant RNA motifs directly from sequence.
  • Developed screening approaches and lead identification strategies (Inforna) for SMIRNAs.
  • Highlighted emergent modalities converting SMIRNAs into RNA cleavers and degraders.

Conclusions:

  • Small molecule RNA therapeutics represent a rapidly growing field with significant potential.
  • Advances in RNA target identification, screening, and chemical probe development are key.
  • Overcoming challenges in developing potent and selective RNA-centric chemical probes is essential for future success.