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Published on: July 3, 2013
Live cell screening to identify RNA-binding small molecule inhibitors of the pre-let-7-Lin28 RNA-protein interaction
Sydney L Rosenblum1, Dalia M Soueid2, George Giambasu3
1Program in Chemical Biology, University of Michigan 210 Washtenaw Avenue Ann Arbor MI 48109 USA algarner@umich.edu.
Abstract:
Dysregulation of the networking of RNA-binding proteins (RBPs) and RNAs drives many human diseases, including cancers, and the targeting of RNA-protein interactions (RPIs) has emerged as an exciting area of RNA-targeted drug discovery. Accordingly, methods that enable the discovery of cell-active small molecule modulators of RPIs are needed to propel this emerging field forward. Herein, we describe the application of live-cell assay technology, RNA interaction with protein-mediated complementation assay (RiPCA), for high-throughput screening to identify small molecule inhibitors of the pre-let-7d-Lin28A RPI. Utilizing a combination of RNA-biased small molecules and virtual screening hits, we discovered an RNA-binding small molecule that can disrupt the pre-let-7-Lin28 interaction demonstrating the potential of RiPCA for advancing RPI-targeted drug discovery.
Insights
Researchers developed a new live-cell assay, RiPCA, to find small molecules that disrupt disease-driving RNA-protein interactions (RPIs). This method successfully identified a compound targeting the pre-let-7d-Lin28A interaction, advancing RNA-targeted drug discovery.
Area of Science:
- Biochemistry
- Molecular Biology
- Pharmacology
Background:
- Dysregulated RNA-binding protein (RBP) and RNA interactions contribute to human diseases, including cancer.
- Targeting RNA-protein interactions (RPIs) is a promising strategy for RNA-targeted drug discovery.
- Developing cell-active small molecule modulators of RPIs is crucial for this field.
Purpose of the Study:
- To apply live-cell assay technology for high-throughput screening (HTS) of small molecule inhibitors of RPIs.
- To identify novel small molecules that modulate specific RPIs relevant to human diseases.
- To demonstrate the utility of the RNA interaction with protein-mediated complementation assay (RiPCA) in drug discovery.
Main Methods:
- Implementation of the RNA interaction with protein-mediated complementation assay (RiPCA) for live-cell screening.
- Utilizing a combination of RNA-biased small molecules and virtual screening hits.
- Screening for inhibitors of the pre-let-7d-Lin28A RPI.
Main Results:
- Successful application of RiPCA for HTS of small molecule modulators of RPIs.
- Discovery of an RNA-binding small molecule capable of disrupting the pre-let-7d-Lin28A interaction.
- Validation of RiPCA as a viable technology for RPI-targeted drug discovery.
Conclusions:
- The RiPCA assay is effective for identifying cell-active small molecule inhibitors of RPIs.
- This study identified a novel small molecule inhibitor of the pre-let-7d-Lin28A interaction.
- RiPCA technology holds significant potential for advancing the field of RPI-targeted drug discovery.
