The physiochemical characteristics of RNA makes it a very challenging target for small-molecule drug discovery, highlighting the necessity for alternative approaches to targeting RNA biology. With the development of technologies for genome-wide query of RNA molecules and RNA-binding proteins (RBPs) enabling the discovery of RNA-protein interactions (RPIs), many of which have since been linked to human diseases, there are now countless RPIs that have been presented as potential for novel therapeutics. Despite increasing interest in developing strategies for targeting therapeutically relevant RNAs and RPIs, there remains a lack of enabling technologies for the discovery and development of RPI inhibitors. To fill in this technological gap, I have developed an assay for the dynamic cellular monitoring of RPIs. To address this technological gap, I have developed an assay for the dynamic cellular monitoring of RPIs. In the assay, termed RNA interaction with Protein-mediated Complementation Assay (RiPCA), cellular RPIs are monitored via protein complementation of Promega’s NanoLuc® Binary Technology (NanoBiT). We recently reported our proof-of-concept development of a RiPCA protocol capable of detecting the interaction between pre-microRNA, pre-let-7, and its RBP, Lin28. Current efforts to continue developing this technology include (1) optimizing RiPCA as a high-throughput platform to enable screening of pre-let-7/Lin28 inhibitors and (2) adapting RiPCA to detect additional RPIs, including additional pre-miRNA-RBP interactions, but also RPIs involving mRNAs, lncRNAs, and expanded repeats.

RiPCA: A cellular assay for the detection of RNA-protein interactions

ACS Fall 2021

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