RNA binding proteins are critical for RNA metabolism and regulating the temporal, spatial and functional dynamics of RNAs. Recent genetic and proteomic data reveal that RBPs are involved in many human deseases. Therefore finding small molecule regulators of RBP-RNA interactions can be used to study and evaluate RBPs as therapeutic targets.   RNA recognition motifs (RRMs) are the most common RNA binding domain. We have used Sex lethal protein and transformer RNA as models to identify small molecule inhibitors of RRM-RNA interaction. 42,560 compounds were screened by fluorescence anisotropy and three compounds were identified as hits. Compounds showed inhibition activity at high detergent concentration and in the presence of BSA, which indicates they are not aggregation-based promiscuous inhibitors. Compounds were found to bind the protein and not the RNA by fluorescence binding experiments. Further evaluation of these compounds revealed that one compound is a selective inhibitor for Sex lethal protein and another compound is a selective inhibitor for U1A protein, which is another RRM-containing protein. These compounds could serve as a starting point for the development of novel molecular probes of RRM-containing proteins, which may facilitate studies of important RRM-RNA complexes.

Small molecule inhibitors of RNA recognition motif-RNA interaction

243rd National Meeting (2012)

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