Targeting non-coding RNA to treat genetic diseases

Although the majority of the human genome is non-coding (98%) most drugs currently available target only 0.1% of disease-related proteins.  The reason for this lies in the fact that although RNA has huge potential to encode disease variants its structure is challenging to determine due to the number of conformational states it can adopt. Drugs to date have been shown to display low selectivity, poor cellular uptake, and high toxicity.

The development of compounds that disrupt the RNA structure and epigenetic function requires scientists to identify small molecules that bind to non-coding RNA. A new scalable method to screen RNA-targeting compounds was needed in order to identify protein hits.

A team from Merck used automated ligand identification system (ALIS) technology to screen 50,000 compounds and then used bioSAXS high-performance liquid chromatography (HPLC) at Diamond to determine the size and shape distributions of small molecules that could bind to a specific type of non-coding RNA called Xist. This research technique enabled the researcher to identify the breadth and width of the molecular weight distribution.

BioSAXS enabled the group to visualise the 3D structure of RepA (a protein involved in the replication of DNA in bacteria) in solution and study the effects of the X1 compound on its conformation and protein displacement.

This study will form the foundation of future studies to treat X-chromosome-linked diseases such as Rett syndrome.

Discover what the team found.