<i>In vivo</i>structural characterization of the whole SARS-CoV-2 RNA genome identifies host cell target proteins vulnerable to re-purposed drugs

Sun, Lei; Pan, Li; Ju, Xiaohui; Rao, Jian Yu; Huang, Wenze; Zhang, Shaojun; Xiong, Tuanlin; Xu, Kui; Zhou, Xiaolin; Ren, Lili; Ding, Qiang; Wang, Jianwei; Zhang, Qiangfeng Cliff

doi:10.1101/2020.07.07.192732

Cited by 28 publications

(59 citation statements)

References 56 publications

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“…However, our data did not support the folding of the stem-loop pseudoknot at the 3′ UTR. Of note, two recent studies using SHAPE methods to map the structure of SARS-CoV-2 inside cells similarly failed to identify this pseudoknot (Huston et al, 2020;Sun et al, 2020) , raising questions regarding its stability in vivo .…”

Section: The Utrs Of Sars-cov-2 Interact With Distal Genomic Regionsmentioning

confidence: 99%

“…For example, interactions between promoters and enhancers dictate the rate of transcription along the eukaryotic genome (Rowley and Corces, 2018) . Great effort is being made to reveal the structural landscapes of the SARS-CoV-2 genome (Andrews et al, 2020;Huston et al, 2020;Kelly et al, 2020;Lan et al, 2020;Manfredonia et al, 2020;Ryder, 2020;Sanders et al, 2020;Sun et al, 2020) .…”

Section: The Utrs Of Sars-cov-2 Interact With Distal Genomic Regionsmentioning

confidence: 99%

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The short- and long-range RNA-RNA Interactome of SARS-CoV-2

Ziv

Price

Shalamova

et al. 2020

Preprint

106

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The Coronaviridae are a family of positive-strand RNA viruses that includes SARS-CoV-2, the etiologic agent of the COVID-19 pandemic. Bearing the largest single-stranded RNA genomes in nature, coronaviruses are critically dependent on long-distance RNA-RNA interactions to regulate the viral transcription and replication pathways. Here we experimentally mapped the in vivo RNA-RNA interactome of the full-length SARS-CoV-2 genome and its subgenomic mRNAs. We uncovered a network of RNA-RNA interactions spanning tens of thousands of nucleotides. These interactions reveal that the viral genome adopts alternative topologies inside cells and undergoes genome cyclization. In addition, the SARS-CoV-2 genome and subgenomic mRNAs engage in different interactions with host RNAs. Most importantly, we discovered a long-range RNA-RNA interaction - the FSE-arch - that encircles the programmed ribosomal frame-shifting element. The FSE-arch is conserved in the related MERS-CoV virus and is under purifying selection. Our findings illuminate RNA-based mechanisms governing replication, discontinuous transcription, and translation of coronaviruses, and will aid future efforts to develop antiviral strategies.

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Section: The Utrs Of Sars-cov-2 Interact With Distal Genomic Regionsmentioning

confidence: 99%

Section: The Utrs Of Sars-cov-2 Interact With Distal Genomic Regionsmentioning

confidence: 99%

The short- and long-range RNA-RNA Interactome of SARS-CoV-2

Ziv

Price

Shalamova

et al. 2020

Preprint

106

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“…Chemical reactivity from Manfredonia, et al (8), Huston, et al (6), and Sun, et al (5) are publicly available at http://www.incarnatolab.com/datasets/SARS_Manfredonia_2020.php, http://www.github.com/pylelab/SARS-CoV-2_SHAPE_MaP_structure, and http://rasp.zhanglab.net respectively. DMS reactivity data from Lan, et al (3) and and SHAPE reactivity data from Iserman, et al 7were obtained by request.…”

Section: Secondary Structure Modelingmentioning

confidence: 99%

“…The COVID-19 outbreak has rapidly spread through the world, presenting an urgent need for therapeutics targeting the betacoronavirus SARS-CoV-2. RNA-targeting antivirals have potential to be effective against SARS-CoV-2, as the virus's RNA genome harbors conserved regions predicted to have stable secondary structures (1,2) that have been verified by chemical probing (3)(4)(5)(6)(7)(8), some of which have been shown to be essential for the life cycle of related betacoronaviruses (9). Efforts to identify small molecules that target stereotyped 3D RNA folds have advanced over recent years (10), making RNA structures like those in SARS-CoV-2 potentially attractive targets for small molecule drugs.…”

Section: Introductionmentioning

confidence: 99%

De novo 3D models of SARS-CoV-2 RNA elements and small-molecule-binding RNAs to aid drug discovery

Rangan

Watkins

Chacón

et al. 2020

Preprint

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The rapid spread of COVID-19 motivates development of antivirals targeting conserved molecular machinery of the SARS-CoV-2 virus. The SARS-CoV-2 genome includes conserved RNA elements that offer potential targets for RNA-targeting small-molecule drugs, but 3D structures of most of these elements have not been experimentally characterized. Here, we provide a dataset called 'FARFAR2-SARS-CoV-2', a collection of 3D coordinates modeled using Rosetta's FARFAR2 algorithm, including de novo models for thirteen RNA elements in SARS-CoV-2 and homology models for a fourteenth. These elements comprise SL1, SL2, SL3, SL4, SL5, putative SL6 and SL7 in the extended 5′ UTR, as well as the entire extended 5′ UTR; the frameshifting element (FSE) from the SARS-CoV-2 ORF1a/b gene and a putative dimer of FSE; and the extended pseudoknot, hypervariable region, and the s2m of the 3′ UTR, as well as the entire 3′ UTR. For five of these elements (SL1, SL2, SL3, FSE, s2m), convergence of lowest predicted energy structures supports their accuracy in capturing low energy states that might be targeted for small molecule binding. To aid efforts to discover small molecule RNA binders guided by computational models, we provide a second benchmarking dataset called 'FARFAR2-Apo-Riboswitch', which consists of similarly prepared Rosetta-FARFAR2 models for RNA riboswitch aptamer regions that bind small molecules. Both datasets include up to 400 3D models for each RNA element, which may facilitate drug discovery approaches targeting dynamic ensembles of low-energy excited states of RNA molecules.

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“…C241 is located in the 5'UTR of the viral RNA, 25 nucleotides upstream of the AUG start codon. SHAPE analysis of viral RNA predicted it in the loop of SL5b (Sun et al 2020). The SHAPE activity of C241 and neighboring residues in the loop are low in in vivo probing than in vitro probing, suggesting these residues may be bound by protein or engaged in long-range RNA interactions under in vivo conditions, and thus are protected from 2'-OH modification in SHAPE analysis.…”

mentioning

confidence: 99%