Genomics functional analysis and drug screening of SARS-CoV-2

Chen, Long Cong; Zhong, Li

doi:10.1016/j.gendis.2020.04.002

Cited by 57 publications

(66 citation statements)

References 41 publications

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“…The proposed miR1307 has been suggested as a therapeutic target in the prevention of SARS-CoV-2 infection. Therefore, more studies on in silico patterns within the SARS-CoV-2 genome may provide a deeper understanding about miR-based novel therapeutics [117,118]. MERS shows greater divergence across these segments and the two milder symptom viruses show even greater differences or even significant sequence gaps.…”

Section: Discussionmentioning

confidence: 99%

The Prediction of miRNAs in SARS-CoV-2 Genomes: hsa-miR Databases Identify 7 Key miRs Linked to Host Responses and Virus Pathogenicity-Related KEGG Pathways Significant for Comorbidities

Arısan

Dart

Grant

et al. 2020

Viruses

102

165

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Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is a member of the betacoronavirus family, which causes COVID-19 disease. SARS-CoV-2 pathogenicity in humans leads to increased mortality rates due to alterations of significant pathways, including some resulting in exacerbated inflammatory responses linked to the “cytokine storm” and extensive lung pathology, as well as being linked to a number of comorbidities. Our current study compared five SARS-CoV-2 sequences from different geographical regions to those from SARS, MERS and two cold viruses, OC43 and 229E, to identify the presence of miR-like sequences. We identified seven key miRs, which highlight considerable differences between the SARS-CoV-2 sequences, compared with the other viruses. The level of conservation between the five SARS-CoV-2 sequences was identical but poor compared with the other sequences, with SARS showing the highest degree of conservation. This decrease in similarity could result in reduced levels of transcriptional control, as well as a change in the physiological effect of the virus and associated host-pathogen responses. MERS and the milder symptom viruses showed greater differences and even significant sequence gaps. This divergence away from the SARS-CoV-2 sequences broadly mirrors the phylogenetic relationships obtained from the whole-genome alignments. Therefore, patterns of mutation, occurring during sequence divergence from the longer established human viruses to the more recent ones, may have led to the emergence of sequence motifs that can be related directly to the pathogenicity of SARS-CoV-2. Importantly, we identified 7 key-microRNAs (miRs 8066, 5197, 3611, 3934-3p, 1307-3p, 3691-3p, 1468-5p) with significant links to KEGG pathways linked to viral pathogenicity and host responses. According to Bioproject data (PRJNA615032), SARS-CoV-2 mediated transcriptomic alterations were similar to the target pathways of the selected 7 miRs identified in our study. This mechanism could have considerable significance in determining the symptom spectrum of future potential pandemics. KEGG pathway analysis revealed a number of critical pathways linked to the seven identified miRs that may provide insight into the interplay between the virus and comorbidities. Based on our reported findings, miRNAs may constitute potential and effective therapeutic approaches in COVID-19 and its pathological consequences.

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Section: Discussionmentioning

confidence: 99%

The Prediction of miRNAs in SARS-CoV-2 Genomes: hsa-miR Databases Identify 7 Key miRs Linked to Host Responses and Virus Pathogenicity-Related KEGG Pathways Significant for Comorbidities

Arısan

Dart

Grant

et al. 2020

Viruses

102

165

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“…As of 24 June 2020, newly emerged SARS-CoV-2 had spread to 216 countries, with more than 9.0 million confirmed cases and 469 000 deaths. Despite the large number of related studies, the focus has largely involved basic sequence analysis and drug screening [33][34][35], whereas the mechanisms of SARS-CoV-2 proteins are unclear.…”

Section: Discussionmentioning

confidence: 99%

Lysine 164 is critical for SARS-CoV-2 Nsp1 inhibition of host gene expression

Shen

Zhang

Yang

et al. 2021

Journal of General Virology

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The emerging pathogen severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused social and economic disruption worldwide, infecting over 9.0 million people and killing over 469 000 by 24 June 2020. Unfortunately, no vaccine or antiviral drug that completely eliminates the transmissible disease coronavirus disease 2019 (COVID-19) has been developed to date. Given that coronavirus nonstructural protein 1 (nsp1) is a good target for attenuated vaccines, it is of great significance to explore the detailed characteristics of SARS-CoV-2 nsp1. Here, we first confirmed that SARS-CoV-2 nsp1 had a conserved function similar to that of SARS-CoV nsp1 in inhibiting host-protein synthesis and showed greater inhibition efficiency, as revealed by ribopuromycylation and Renilla luciferase (Rluc) reporter assays. Specifically, bioinformatics and biochemical experiments showed that by interacting with 40S ribosomal subunit, the lysine located at amino acid 164 (K164) was the key residue that enabled SARS-CoV-2 nsp1 to suppress host gene expression. Furthermore, as an inhibitor of host-protein expression, SARS-CoV-2 nsp1 contributed to cell-cycle arrest in G0/G1 phase, which might provide a favourable environment for virus production. Taken together, this research uncovered the detailed mechanism by which SARS-CoV-2 nsp1 K164 inhibited host gene expression, laying the foundation for the development of attenuated vaccines based on nsp1 modification.

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“…The DUF3655 region seems to have evaded virological, medical and pharmaceutical scrutiny so far (e.g. Chen and Zhong, 2020;Wei et al, 2020). We suggest that it is probably involved in a unique rate-limiting step of the coronavirus replicative cycle, and may make CoV infections susceptible to drugs, like chloroquine, that increase cellular pH (https://www.sciencemediacentre.org/expert-reaction-to-questions-around-potential-treatmentsfor-covid-19/ March 18 2020).…”

Section: Discussionmentioning

confidence: 99%

Comparisons of the genome of SARS-CoV-2 and those of other betacoronaviruses

Rodríguez‐Román

Gibbs

2020

Preprint

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The genome of SARS-CoV-2 virus causing the worldwide pandemic of COVID-19 is most closely related to viral metagenomes isolated from bats and, more distantly, pangolins. All are of sarbecoviruses of the genus Betacoronavirus. We have unravelled their recombinational and mutational histories. All showed clear evidence of recombination, most events involving the 3’ half of the genomes. The 5’ region of their genomes was mostly recombinant free, and a phylogeny calculated from this region confirmed that SARS-CoV-2 is closer to RmYN02 than RaTG13, and showed that SARS-CoV-2 diverged from RmYN02 at least 26 years ago, and both diverged from RaTG13 at least 37 years ago; recombinant regions specific to these three viruses provided no additional information as they matched no other Genbank sequences closely. Simple pairwise comparisons of genomes show that there are three regions where most non-synonymous changes probably occurred; the DUF3655 region of the nsp3, the S gene and ORF 8 gene. Differences in the last two of those regions have probably resulted from recombinational changes, however differences in the DUF3655 region may have resulted from selection. A hexamer of the proteins encoded by the nsp3 region may form the molecular pore spanning the double membrane of the coronavirus replication organelle (Wolff et al., 2020), and perhaps the acidic polypeptide encoded by DUF3655 lines it, and presents a novel target for pharmaceutical intervention.

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Genomics functional analysis and drug screening of SARS-CoV-2

Cited by 57 publications

References 41 publications

The Prediction of miRNAs in SARS-CoV-2 Genomes: hsa-miR Databases Identify 7 Key miRs Linked to Host Responses and Virus Pathogenicity-Related KEGG Pathways Significant for Comorbidities

The Prediction of miRNAs in SARS-CoV-2 Genomes: hsa-miR Databases Identify 7 Key miRs Linked to Host Responses and Virus Pathogenicity-Related KEGG Pathways Significant for Comorbidities

Lysine 164 is critical for SARS-CoV-2 Nsp1 inhibition of host gene expression

Comparisons of the genome of SARS-CoV-2 and those of other betacoronaviruses

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