Do Drugs of Unknown Target Bind to Cellular RNAs?

The targets of numerous prescribed drugs remain unknown. Identifying these targets is crucial to enhance clinical treatments and reduce their toxicity.

Our preliminary analysis revealed that approximately 25% of these drugs resemble known RNA binders leading to hypothesize these binds to RNAs.

To study their interactions with the human transcriptome, we propose a platform that combines mass spectrometry-based screening and Reactivity-based RNA Profiling (RBRP) methods.

We will utilize chemoselective and bioorthogonal chemistry to modify these drugs for constructing a chemical probe library. Utilizing a "bind-enrich-release" strategy, this library will enable the identification of hits bound to cellular RNAs. Subsequently, the hits will undergo in-cell whole RNA profiling using RBRP.

The identified drug targets will be validated through a series of experiments including next-generation sequencing. This project is significant because it seeks to unveil the targets of drugs that have remained unknown for decades.

The success of this proposal will clarify the origin of toxicity, expite the process of identifying RNA targets, and provide crucial insights for new drug development.

The proposed project will be completed in three years, with one year dedicated to synthesis (SA1), one year for method application (SA2), and one year for RNA target validation (SA3). The supervision by Prof. Eric Kool at Stanford University will contribute significantly to the success of this project.