Development of new antiviral medication against the beta-coronavirus SARS-CoV-2 (SCoV2) is actively being pursued. Both NMR spectroscopy and crystallography as structural screening technologies have been utilised to screen the viral proteome for binding to fragment libraries. Here, we report on NMR screening of elements of the viral RNA genome with two different ligand libraries using 1H-NMR-screening experiments and 1H and 19F NMR-screening experiments for fluorinated compounds. We screened against the 5'-terminal 119 nucleotides located in the 5'-untranslated region of the RNA genome of SCoV2 and further dissected the four stem-loops into its constituent RNA elements to test specificity of binding of ligands to shorter and longer viral RNA stretches. The first library (DRTL-F library) is enriched in ligands binding to RNA motifs, while the second library (DSI-poised library) represents a fragment library originally designed for protein screening. Conducting screens with two different libraries allows us to compare different NMR screening methodologies, describe NMR screening workflows, validate the two different fragment libraries, and derive initial leads for further downstream medicinal chemistry optimisation.
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