Ceylan, Betul and Adam, Jennifer and Toews, Sabrina and Kaiser, Frank and Doerr, Jonas and Scheppa, Daniel and Tants, Jan-Niklas and Smart, Alexandria and Schoth, Julian and Philipp, Susanne and Stirnal, Elke and Ferner, Jan and Richter, Christian and Sreeramulu, Sridhar and Caliskan, Neva and Schlundt, Andreas and Weigand, Julia E. and Goebel, Michael and Wacker, Anna and Schwalbe, Harald (2025) Optimization of Structure-Guided Development of Chemical Probes for the Pseudoknot RNA of the Frameshift Element in SARS-CoV-2. ANGEWANDTE CHEMIE-INTERNATIONAL EDITION, 64 (9): e202417961. ISSN , 1521-3773
Full text not available from this repository. (Request a copy)Abstract
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 pseudo-knot 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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | ; SARS-CoV-2; rameshift element; NMR spectroscopy; RNA targeting; RNA drugs |
| Subjects: | 500 Science > 540 Chemistry & allied sciences 500 Science > 570 Life sciences |
| Divisions: | Biology, Preclinical Medicine > Institut für Biochemie, Genetik und Mikrobiologie > Lehrstuhl für Biochemie III |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 02 Jun 2026 11:51 |
| Last Modified: | 02 Jun 2026 11:51 |
| URI: | https://pred.uni-regensburg.de/id/eprint/67397 |
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