Exploring the Druggability of Conserved RNA Regulatory Elements in the SARS‐CoV‐2 Genome
Sridhar Sreeramulu, Christian Richter, Hannes Berg, Maria A. Wirtz Martin, Betül Ceylan, Tobias Matzel, Jennifer Adam, Nadide Altincekic, Kamal Azzaoui, Jasleen Kaur Bains, Marcel J. J. Blommers, Jan Ferner, Boris Fürtig, Michael Göbel, J. Tassilo Grün, Martin Hengesbach, Katharina F. Hohmann, Daniel Hymon, Božana Knezic, Jason Martins, Klara R. Mertinkus, Anna Niesteruk, Stephen A. Peter, Dennis J. Pyper, Nusrat S. Qureshi, Ute Scheffer, Andreas Schlundt, Robbin Schnieders, Elke Stirnal, Alexey Sudakov, Alix Tröster, Jennifer Vögele, Anna Wacker, Julia E. Weigand, Julia Wirmer‐Bartoschek, Jens Wöhnert, Harald Schwalbe
Abstract
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 1 H‐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.