RNA as a target: A new perspective for FDA-approved drug repurposing

Authors

• SA Owens
• M Yang
• S Balaratnam
• JA Spivey
• AG Solomon
• BJ Moore
• JS Schneekloth Jr

Abstract

RNA is emerging as an intriguing target for drug discovery since it plays a vital role in bioprocesses and modulates protein expression on the translational level. Around 85% of the genome is transcribed into RNA, while 1-2% of the genome encodes for proteins. This opens the door to targeting a whole new set of proteins (e.g., oncoproteins) that were previously considered undruggable with more traditional direct protein targeting methods. Moreover, recent studies indicate that some FDA-approved drugs may also bind to RNA. Here, we completed a bioinformatic study to identify G-quadruplexes (rG4s), a non-canonical secondary structure of RNA. We discovered a unique rG4 located at the 5’-UTR of an oncogene, an ideal location for translational inhibition. Using a novel small molecule microarray (SMM) approach for high-throughput drug screening, we were able to identify FDA-approved drugs that bind to this RNA at micromolar level. We then tested various analogs of one specific FDA-approved drug and performed biophysical assays to determine binding affinity and stabilization effects. In addition, these compounds could significantly down-regulate the protein expression in a Luciferase reporter assay. Overall, our study presents a way to efficiently identify RNA-binding FDA-approved drugs, which is significant to drug repurposing and off-target effect studies.

Scientific Focus Area: Chemical Biology

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