Selective Small Molecule Recognition of RNA Base Pairs

Area of Science:

• Medicinal Chemistry
• Molecular Biology
• Drug Discovery

Background:

• The human transcriptome contains diverse RNA types, but only bacterial ribosomal RNA (rRNA) is a validated small molecule drug target.
• Noncoding RNAs, crucial for cellular functions, possess secondary structures with base-paired regions that remain largely unexploited therapeutically.
• A significant gap exists in small molecules designed to specifically target RNA base pairs, hindering RNA-based therapeutic development.

Purpose of the Study:

• To address the unmet need for small molecules that can selectively bind to RNA base pairs.
• To identify and characterize novel chemical entities capable of targeting RNA base pairs for potential therapeutic applications.

Main Methods:

• Utilized chemoinformatics to design and synthesize an RNA-focused chemical library enriched in nitrogen-containing heterocycles.
• Screened the library for compounds exhibiting binding affinity to RNA base pairs.
• Characterized the selectivity and binding modes of identified binders towards specific RNA base pairs and distinguished between RNA and DNA.

Main Results:

• Identified six novel, selective small molecule binders of RNA base pairs, all derived from benzimidazoles.
• Compounds with expanded aromatic polycycles selectively targeted AU base pairs, while those with urea side chains targeted GC base pairs.
• Two GC-pair binders demonstrated orientation selectivity (5'GG/3'CC vs. 5'GC/3'CG), and all binders showed >50-fold selectivity for RNA over DNA.

Conclusions:

• Established foundational knowledge for targeting RNA base pairs with small molecules.
• Demonstrated the potential of benzimidazole derivatives as scaffolds for developing selective RNA-binding agents.
• These findings pave the way for exploiting RNA as a target for novel chemical probes and lead therapeutics.