MicroRNAs (miRNAs) comprise a large family of small, ~21?23 nucleotide noncoding RNAs that have emerged as key post-transcriptional regulators of gene expression and act by silencing the translation of target mRNAs. To date, there are ~1,000 predicted human miRNAs believed to control the activity of >60% of all protein-coding genes. Not surprisingly, these small RNAs have been shown to play crucial roles in nearly all aspects of human biology from development to disease. Alteration of miRNA expression, up- or downregulation, has been linked to cancer, obesity, diabetes, viral infections and autoimmune, inflammatory, neurodegenerative and cardiovascular diseases among others. These connections have made the targeting of miRNAs attractive as a novel therapeutic strategy. Our overall goal is to discover and develop selective small molecule inhibitors of miRNA maturation, thus providing the basis for next-generation miR-targeted therapeutics for the treatment of human disease. To do so, we have developed a conceptually new and innovative approach for assaying RNA-small molecule interactions that takes advantage of the power of catalytic signal amplification combined with the selectivity and bioorthogonality of click chemistry. Through this platform assay technology, which we term catalytic assay using enzyme-linked click chemistry assay or cat- ELCCA, we have designed a method that can be implemented in high-throughput, is virtually free of false read- outs and is general for all miRNAs. We propose to further develop and apply cat-ELCCA toward the discovery of pre-miRNA-selective ligands that can be used as chemical probes for targeting miRNAs in disease.

Public Health Relevance

RNA plays a key role in gene expression by serving as an intermediate between DNA and protein; however, RNA can play additional cellular roles and a class of small non-coding RNAs called microRNAs have emerged as important regulators in the conversion from RNA to protein. Despite the link between faulty or dysregulated microRNAs and human disease, drug discovery efforts in this area have lagged due to a lack of knowledge of the types of compounds, or small molecules, that could serve as useful drug leads. We have developed conceptually new and innovative platform assay technology for detecting RNA-small molecule interactions in high-throughput that we will apply to discover microRNA-selective compounds that will provide the basis for the development of next-generation, RNA-targeted small molecule therapeutics for the management of human health.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Fabian, Miles
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University of Michigan Ann Arbor
Schools of Pharmacy
Ann Arbor
United States
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Garner, Amanda L (2018) cat-ELCCA: catalyzing drug discovery through click chemistry. Chem Commun (Camb) 54:6531-6539
Lorenz, Daniel A; Vander Roest, Steve; Larsen, Martha J et al. (2018) Development and Implementation of an HTS-Compatible Assay for the Discovery of Selective Small-Molecule Ligands for Pre-microRNAs. SLAS Discov 23:47-54
Lorenz, Daniel A; Garner, Amanda L (2016) A click chemistry-based microRNA maturation assay optimized for high-throughput screening. Chem Commun (Camb) 52:8267-70