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Exploring the Druggability of Conserved RNA Regulatory Elements in the SARS-CoV-2 Genome.

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.

SUBMITTER: Sreeramulu S

PROVIDER: S-EPMC8426693 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

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Exploring the Druggability of Conserved RNA Regulatory Elements in the SARS-CoV-2 Genome.

Sreeramulu Sridhar S Richter Christian C Berg Hannes H Wirtz Martin Maria A MA Ceylan Betül B Matzel Tobias T Adam Jennifer J Altincekic Nadide N Azzaoui Kamal K Bains Jasleen Kaur JK Blommers Marcel J J MJJ Ferner Jan J Fürtig Boris B Göbel Michael M Grün J Tassilo JT Hengesbach Martin M Hohmann Katharina F KF Hymon Daniel D Knezic Bozana B Martins Jason N JN Mertinkus Klara R KR Niesteruk Anna A Peter Stephen A SA Pyper Dennis J DJ Qureshi Nusrat S NS Scheffer Ute U Schlundt Andreas A Schnieders Robbin R Stirnal Elke E Sudakov Alexey A Tröster Alix A Vögele Jennifer J Wacker Anna A Weigand Julia E JE Wirmer-Bartoschek Julia J Wöhnert Jens J Schwalbe Harald H

Angewandte Chemie (International ed. in English) 20210803 35

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 ...[more]

PMID: 34161644

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Project description:The emergence of a new coronavirus (CoV), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), responsible for severe respiratory disease in humans termed coronavirus disease of 2019 (COVID-19), became a new global threat for health and the economy. The SARS-CoV-2 genome is about a 29,800-nucleotide-long plus-strand RNA that can form functionally important secondary and higher-order structures called cis-acting RNA elements. These elements can interact with viral proteins, host proteins, or other RNAs and be involved in regulating translation and replication processes of the viral genome and encapsidation of the virus. However, the cis-acting RNA elements and their biological roles in SARS-CoV-2 as well as their comparative analysis in the closely related viral genome have not been well explored, which is very important to understand the molecular mechanism of viral infection and pathogenies. In this study, we used a bioinformatics approach to identify the cis-acting RNA elements in the SARS-CoV-2 genome. Initially, we aligned the full genomic sequence of six different CoVs, and a phylogenetic analysis was performed to understand their evolutionary relationship. Next, we predicted the cis-acting RNA elements in the SARS-CoV-2 genome using the structRNAfinder tool. Then, we annotated the location of these cis-acting RNA elements in different genomic regions of SARS-CoV-2. After that, we analyzed the sequence conservation patterns of each cis-acting RNA element among the six CoVs. Finally, the presence of cis-acting RNA elements across different CoV genomes and their comparative analysis was performed. Our study identified 12 important cis-acting RNA elements in the SARS-CoV-2 genome; among them, Corona_FSE, Corona_pk3, and s2m are highly conserved across most of the studied CoVs, and Thr_leader, MAT2A_D, and MS2 are uniquely present in SARS-CoV-2. These RNA structure elements can be involved in viral translation, replication, and encapsidation and, therefore, can be potential targets for better treatment of COVID-19. It is imperative to further characterize these cis-acting RNA elements experimentally for a better mechanistic understanding of SARS-CoV-2 infection and therapeutic intervention.

Dataset Information

Exploring the Druggability of Conserved RNA Regulatory Elements in the SARS-CoV-2 Genome.

Publications

Exploring the Druggability of Conserved RNA Regulatory Elements in the SARS-CoV-2 Genome.

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