Identifying and validating small molecules interacting with RNA (SMIRNAs).

Area of Science:

• Chemical Biology
• Molecular Biology
• Drug Discovery

Background:

• High throughput sequencing identifies disease-related RNA alterations.
• RNA structures themselves can directly cause disease.
• Targeting structured RNA with small molecules is a challenging but promising therapeutic strategy.

Purpose of the Study:

• To discuss emerging strategies for designing small molecules interacting with RNA (SMIRNAs).
• To present target validation and profiling methods for SMIRNAs.
• To enable SMIRNAs to address opportunities in chemical biology and disease treatment.

Main Methods:

• 2-dimensional combinatorial screening (2DCS) for identifying small molecules that bind RNA 3D folds.
• Mining 2DCS data against transcriptomes to identify targetable folded RNA structures.
• Utilizing Chemical Cross-Linking and Isolation by Pull-down (Chem-CLIP) and RiboSNAP for target validation in cells.

Main Results:

• Development of methods to design high affinity, selective, bioactive SMIRNAs.
• Identification of specific folded RNA structures amenable to small molecule targeting.
• Definition of targets engaged by SMIRNAs in cellular contexts and rules for molecular recognition.

Conclusions:

• SMIRNAs offer a viable approach to target disease-causing RNA structures.
• Integrated experimental and computational methods facilitate SMIRNA lead identification and validation.
• These approaches are applicable in vitro, in cells, and in preclinical disease models, paving the way for novel therapeutics.