Rational Design of Small Molecules Targeting Oncogenic Noncoding RNAs from Sequence.

Area of Science:

• Biochemistry
• Molecular Biology
• Drug Discovery

Background:

• Noncoding RNAs (ncRNAs) play crucial regulatory roles in gene expression and biological functions, despite comprising a large portion of the human transcriptome.
• Dysregulation of ncRNAs is linked to various diseases, highlighting the need for therapeutic strategies targeting these molecules.
• Small molecules offer advantages for drug development, including lead optimization and the ability to target structured RNA regions, but designing them for ncRNAs has been challenging.

Purpose of the Study:

• To describe rational design approaches for developing small molecules that target biological non-ribosomal RNAs.
• To introduce enabling technologies for identifying and annotating small molecule-RNA interactions.
• To facilitate the identification of
• Main_Methods
• Main_Results
• Conclusions

Main Methods:

• Two-dimensional combinatorial screening (2DCS) for library-versus-library selection to identify RNA motif-small molecule binding preferences.
• Development of Inforna, a computational tool for mining annotated RNA motif-small molecule interactions against RNA targets or transcriptomes.
• Utilizing tools for RNA structure annotation from sequence to guide rational design.

Main Results:

• Identification of specific RNA motif-small molecule interactions through 2DCS, generating a comprehensive interaction landscape.
• Successful application of Inforna to analyze these interactions, enabling target identification.
• Demonstration of a rational, target-agnostic approach for identifying druggable RNAs.

Conclusions:

• Small molecule targeting of noncoding RNAs is achievable through rational design, moving beyond traditional screening methods.
• 2DCS and computational analysis provide powerful tools for understanding and exploiting RNA-small molecule interactions.
• This approach holds promise for developing novel therapeutics by targeting disease-associated RNA structures.