Event Description
Nathan Baird, PhD,
University of the Sciences
“The (Forgotten) RNA World: Exploring a New Frontier in Drug Discovery” Given the demonstrated importance and therapeutic potential of RNA biology in human health and disease, the dearth of studies aimed at targeting structured RNAs with small molecules is alarming. RNA remains a disproportionately under-explored target for drug discovery owing in part to the limited number of protein-centric assays currently employed for the discovery of new small molecules targeting RNA. We have developed an efficient, high-throughput method to simultaneously screen chemical libraries and RNA structural space to discover novel chemical modulators of RNA structure and function. Using Förster resonance energy transfer (FRET), we generate multi-dimensional landscapes characterizing the conformations and thermodynamic stability of the cyclic di-GMP riboswitch in response to Mg2+, ligand, and temperature. Our landscape analysis uncovers an Mg2+otherwise hidden RNA-small molecule interaction that inhibits the function of this RNA through stabilization of an alternate conformation. This demonstrates that allosteric control of folding, rather than direct competition with cognate effectors, is a viable approach for pharmacologically targeting riboswitches and other structured RNA molecules.
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