Modulating gene expression by RNA-targeting chimeras

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Project Summary RNA-binding small molecules have the potential to modulate the expression of genes whose protein products were previously considered “undruggable.” Risdiplam, targeting a precursor mRNA, was recently approved for the treatment of spinal muscular atrophy (SMA) and demonstrates the specificity and safety attainable by this approach. Although a variety of small-molecule scaffolds have been uncovered as RNA-binding ligands, their use is hampered by (1) lack of specificity and (2) unpredictable function. We propose a research program that will provide RNA-targeting chemical probes that will avoid these drawbacks. Inspired by Proteolysis Targeting Chimera (PROTAC) technology, we are designing chimeric molecules that will target RNA specifically and carry (deliver) the ability to induce RNA degradation or inhibit RNA translation, in a highly predictable manner. Our initial efforts towards an RNA-targeting chimera platform use a newly discovered RNA-binding coumarin derivative as a model and fine-tune its preferential binding properties through chemical modification. Through structural optimization, which includes using a “bidentate” RNA ligand strategy, we expect to achieve RNA- binding selectivity equal to or greater than that of oligonucleotides. At the same time, we propose to develop and optimize three novel effectors to precisely degrade RNA targets or inhibit the target RNA translation. These new effectors have shown promising results in inhibiting Zika virus (an RNA virus) gene expression. Ultimately, our proposed work will generate a top-down method for designing selective gene expression inhibitors that are independent of the gene's protein product. The long-term goal of our lab is to build a medicinal chemistry platform for making gene-specific and patient-specific therapies using RNA-binding small molecules. In this process, we will not only generate various tool compounds for studying important disease- modifying genes, but also combine computational and experimental technologies to understand the detailed mechanism of RNA-small molecule recognition.