Exploring the druggability of conserved RNA regulatory elements in the SARS-CoV-2 genome

  • 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.
Author:Sridhar SreeramuluORCiD, Christian RichterORCiD, Hannes Berg, Maria Alexandra Wirtz MartinORCiD, Betül Ceylan, Tobias Matzel, Jennifer Adam, Nadide AltınçekiçORCiDGND, Kamal Azzaoui, Jasleen Kaur BainsORCiD, Marcel Jules José Blommers, Jan FernerORCiDGND, Boris FürtigORCiDGND, Michael Göbel, J. Tassilo GrünORCiDGND, Martin HengesbachORCiDGND, Katharina F. Hohmann, Daniel Hymon, Bozana Knezic, Jason N. Martins, Klara Rebecca MertinkusORCiD, Anna Niesteruk, Stephen A. PeterGND, Dennis J. Pyper, Nusrat QureshiORCiDGND, Ute Scheffer, Andreas SchlundtORCiD, Robbin Schnieders, Elke Stirnal, Alexey Sudakov, Alix Friederike Tröster, Jennifer VögeleORCiD, Anna WackerORCiDGND, Julia WeigandORCiDGND, Julia Wirmer-BartoschekORCiD, Jens WöhnertORCiDGND, Harald SchwalbeORCiDGND
Parent Title (English):Angewandte Chemie
Place of publication:Weinheim
Document Type:Article
Date of Publication (online):2021/06/23
Date of first Publication:2021/06/23
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2022/04/05
Tag:Covid19-nmr; NMR spectroscopy; RNA; SARS-CoV-2; fragment screening
Page Number:10
First Page:19191
Last Page:19200
The work has been conducted in the international consortium of Covid19-NMR (covid19-nmr.de). Work at BMRZ is supported by the state of Hesse. Work in Covid19-nmr was supported by the Goethe Corona Funds, by the IWB-EFRE-program 20007375 of state of Hesse, the DFG through CRC902: “Molecular Principles of RNA-based regulation.” and through infrastructure funds (project numbers: 277478796, 277479031, 392682309, 452632086, 70653611) and by European Union's Horizon 2020 research and innovation program iNEXT-discovery under grant agreement No 871037. We thank Peter Maas (SPECS) for providing the compound D01 as a kind gift. Open access funding enabled and organized by Projekt DEAL.
Institutes:Biochemie, Chemie und Pharmazie
Wissenschaftliche Zentren und koordinierte Programme / Zentrum für Biomolekulare Magnetische Resonanz (BMRZ)
Dewey Decimal Classification:5 Naturwissenschaften und Mathematik / 54 Chemie / 540 Chemie und zugeordnete Wissenschaften
5 Naturwissenschaften und Mathematik / 57 Biowissenschaften; Biologie / 570 Biowissenschaften; Biologie
6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Licence (German):License LogoCreative Commons - Namensnennung 4.0