Targeting the RNA genome of SARS-CoV-2 is a viable option for antiviral drug development. We explored three ligand binding sites of the core pseudoknot RNA of the SARS-CoV-2 frameshift element. We iteratively optimized ligands, based on improved affinities, targeting these binding sites and report on structural and dynamic properties of the three identified binding sites. Available experimental 3D structures of the pseudoknot element were compared to SAXS and NMR data to validate its dominant folding state in solution. In order to experimentally map in silico predicted binding sites, NMR assignments of the majority of nucleobases were achieved by segmental labeling of the pseudoknot RNA and isotope-filtered NMR experiments at 1.2 GHz, demonstrating the value of NMR spectroscopy to supplement modelling and docking data. Optimized ligands with enhanced affinity were shown to specifically inhibit frameshifting without affecting 0-frame translation in cell-free translation assays, establishing the frameshift element as target for drug-like ligands of low molecular weight.