Abstract: Using small molecules to modulate RNA stability is an emerging paradigm which holds promise to greatly expand the space of druggable biomolecules. In this talk I will present two applications of targeted RNA degradation using small molecules. Firstly, we devised a click chemistry- and degradation-based method to map RNA modifications, meCLICK-Seq. This unorthodox approach enabled the discovery of widespread methylation in low-abundance RNA species, greatly expanding the map of the known methylome. We then harnessed the degradation strategy to develop small molecules which bind and degrade targeted RNAs in a structure-dependent manner. We thus rationally designed anti-SARS-CoV-2 agents which compromise its genomic RNA and exert an anti-viral effect in cellular and mouse models of SARS-CoV-2 infection. Altogether, these novel RNA manipulation methods enable new, diverse applications, both for basic research and development of therapeutics.
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