Optimization of Structure‐Guided Development of Chemical Probes for the Pseudoknot RNA of the Frameshift Element in SARS‐CoV‐2

• DOI: 10.1002/anie.202417961
• Publication Date: 2025-01-29T17:40:27Z
• Authors: Betül Ceylan; Jennifer Adam; Sabrina Toews; Frank Kaiser; Jonas Dörr; Daniel Scheppa; Jan‐Niklas Tants; Alexandria Smart; Julian Schoth; Susanne Philipp; Elke Stirnal; Jan Ferner; Christian Richter; Sridhar Sreeramulu; Neva Caliskan; Andreas Schlundt; Julia E. Weigand; Michael Göbel; Anna Wacker; Harald Schwalbe
• Keywords: Pseudoknot; Riboswitch; Nucleic acid structure

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