1. Exploring the Druggability of Conserved RNA Regulatory Elements in the SARS‐CoV‐2 Genome
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Martin Hengesbach, Jennifer Adam, Sridhar Sreeramulu, Maria Alexandra Wirtz Martin, Jan Ferner, Boris Fürtig, Dennis J. Pyper, Nadide Altincekic, Daniel Hymon, Robbin Schnieders, Ute Scheffer, Betül Ceylan, Klara R. Mertinkus, Marcel J. J. Blommers, Jasleen Kaur Bains, Kamal Azzaoui, Julia E. Weigand, Julia Wirmer-Bartoschek, Anna Niesteruk, Anna Wacker, Tobias Matzel, Christian Richter, Stephen A. Peter, J Tassilo Grün, Jason N Martins, Alix Tröster, Bozana Knezic, Katharina F. Hohmann, Michael W. Göbel, Harald Schwalbe, Hannes Berg, Alexey Sudakov, Elke Stirnal, Jens Wöhnert, Andreas Schlundt, Nusrat S. Qureshi, and Jennifer Vögele
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Coronavirus disease 2019 (COVID-19) ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Proton Magnetic Resonance Spectroscopy ,Druggability ,Drug Evaluation, Preclinical ,Computational biology ,010402 general chemistry ,Ligands ,01 natural sciences ,Genome ,Catalysis ,Small Molecule Libraries ,03 medical and health sciences ,NMR spectroscopy ,In vivo ,Nucleotide ,Research Articles ,Covid Virus ,030304 developmental biology ,Covid19-nmr ,chemistry.chemical_classification ,0303 health sciences ,Molecular Structure ,SARS-CoV-2 ,RNA ,fragment screening ,General Medicine ,General Chemistry ,Nuclear magnetic resonance spectroscopy ,0104 chemical sciences ,3. Good health ,chemistry ,Nucleic Acid Conformation ,RNA, Viral ,Research Article - Abstract
SARS‐CoV‐2 contains a positive single‐stranded RNA genome of approximately 30 000 nucleotides. Within this genome, 15 RNA elements were identified as conserved between SARS‐CoV and SARS‐CoV‐2. By nuclear magnetic resonance (NMR) spectroscopy, we previously determined that these elements fold independently, in line with data from in vivo and ex‐vivo structural probing experiments. These elements contain non‐base‐paired regions that potentially harbor ligand‐binding pockets. Here, we performed an NMR‐based screening of a poised fragment library of 768 compounds for binding to these RNAs, employing three different 1H‐based 1D NMR binding assays. The screening identified common as well as RNA‐element specific hits. The results allow selection of the most promising of the 15 RNA elements as putative drug targets. Based on the identified hits, we derive key functional units and groups in ligands for effective targeting of the RNA of SARS‐CoV‐2., The RNA genome of SARS‐CoV‐2 contains 15 independently folded regulatory RNA elements. By NMR‐based fragment screening, the RNA target space for small molecule binding, functional mapping and inhibition is defined.
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