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Review
. 2020 Oct 1;1866(10):165878.
doi: 10.1016/j.bbadis.2020.165878. Epub 2020 Jun 13.

Insights into SARS-CoV-2 genome, structure, evolution, pathogenesis and therapies: Structural genomics approach

Ahmad Abu Turab Naqvi  1 , Kisa Fatima  2 , Taj Mohammad  1 , Urooj Fatima  3 , Indrakant K Singh  4 , Archana Singh  5 , Shaikh Muhammad Atif  6 , Gururao Hariprasad  7 , Gulam Mustafa Hasan  8 , Md Imtaiyaz Hassan  9
Affiliations
Review

Insights into SARS-CoV-2 genome, structure, evolution, pathogenesis and therapies: Structural genomics approach

Ahmad Abu Turab Naqvi et al. Biochim Biophys Acta Mol Basis Dis. .

Abstract

The sudden emergence of severe respiratory disease, caused by a novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has recently become a public health emergency. Genome sequence analysis of SARS-CoV-2 revealed its close resemblance to the earlier reported SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV). However, initial testing of the drugs used against SARS-CoV and MERS-CoV has been ineffective in controlling SARS-CoV-2. The present study highlights the genomic, proteomic, pathogenesis, and therapeutic strategies in SARS-CoV-2 infection. We have carried out sequence analysis of potential drug target proteins in SARS-CoV-2 and, compared them with SARS-CoV and MERS viruses. Analysis of mutations in the coding and non-coding regions, genetic diversity, and pathogenicity of SARS-CoV-2 has also been done. A detailed structural analysis of drug target proteins has been performed to gain insights into the mechanism of pathogenesis, structure-function relationships, and the development of structure-guided therapeutic approaches. The cytokine profiling and inflammatory signalling are different in the case of SARS-CoV-2 infection. We also highlighted possible therapies and their mechanism of action followed by clinical manifestation. Our analysis suggests a minimal variation in the genome sequence of SARS-CoV-2, may be responsible for a drastic change in the structures of target proteins, which makes available drugs ineffective.

Keywords: COVID-19; Comparative genomics; Drug target; Molecular basis of pathogenesis; Molecular evolution; SARS-CoV-2.

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Conflict of interest statement

Declaration of competing interest All authors of the manuscript declare to have no conflicts of interest.

Figures

Unlabelled Image
Graphical abstract
Fig. 1
Fig. 1
Schematic representation of the SARS-CoV-2 structure and its mode of host entry.
Fig. 2
Fig. 2
Genome architecture of SARS-CoV-2. A. Representation of the reference genome of SARS-CoV-2 showing the protein-coding regions and GC content of the genome. B. Representation of 5′ capped mRNA has a leader sequence (LS), poly-A tail at 3′ end, and 5′ and 3′ UTR. It consists of ORF1a, ORF1b, Spike (S), ORF3a, Envelope (E), Membrane (M), ORF6, ORF7a, ORF7b, ORF8, Nucleocapsid (N), and ORF10 (Ref 31).
Fig. 3
Fig. 3
Graph illustrating the disordering tendency of each residue in SARS-CoV2 polyprotein. The dotted line is the threshold value of 0.5.
Fig. 4
Fig. 4
Multiple sequence alignment of A. RBD of the spike glycoprotein, B. Envelope protein, C. Membrane protein, D. MSA of nucleoprotein showing regions of sequence conservation.
Fig. 5
Fig. 5
MSA of the Replicase polyprotein 1a and 1ab showing sequence conservation in macrodomains. A. Papain like domain, B. Main protease, C. Highly dissimilar, and flanking regions. D. The macro domain of Replicase polyprotein 1ab, E. Papain like domain, F. Main protease, and G. RdRp domain.
Fig. 6
Fig. 6
Structural comparison of RBDs of S protein for all four strains. A. Superposed image of BAT CoV S RBD protein (lime green) and SARS-CoV-2 (red) (RMSD: 2.3 Å), B. Surface representation of superimposed RBD of BAT-CoV and SARS-CoV-2. C. Superposed image of RBD of MERS-CoV S protein (light orange) and SARS-CoV-2 (light blue) (RMSD: 8.6 Å), D. Surface representation of the RBD of MERS-CoV and SARS-CoV-2, E. Superposed image of RBD of SARS-CoV S protein (warm pink) and SARS-CoV-2 (slate) (RMSD: 1.5 Å), F. Surface representation of the RBD of SARS-CoV and SARS-CoV-2.
Fig. 7
Fig. 7
Structural comparison of Replicase polyprotein 1ab main protease for all four strains. A. Superposed image, and B. Surface representation of the main protease of BAT-CoV (warm pink) and SARS-CoV-2 (pale green) (RMSD: 1.9 Å). C. Superposed image, and D. Surface representation of main protease MERS-CoV (salmon) and SARS-CoV-2 (pale green) (RMSD: 2.7 Å), E. Superposed image and F. Surface representation of the main protease of SARS-CoV (yellow) and SARS-CoV-2 (pale green) (RMSD: 1.1 Å).
Fig. 8
Fig. 8
The life cycle of SARS-CoV-2 showing potential drug targets in the host cell. The S protein of the virus binds to the cellular receptor (ACE2) followed by the entry of the viral RNA genome into the host cell. After the genome entry into the cell translation of structural and NSPs follows. ORF1a and ORF1ab are translated to produce polyproteins pp1a and pp1ab, which are further cleaved by the proteases that are encoded by ORF1a to yield 16 non-structural proteins (nsp1-nsp16). Assembly and budding into the lumen of the ERGIC (Endoplasmic Reticulum Golgi Intermediate Compartment) then follow. Virions are finally released from the infected cell through exocytosis. In this life cycle of coronavirus, multiple stages are being seen as potential druggable targets, and drugs working like S protein inhibitors, RNA dependent RNA polymerase inhibitors (remdesivir, fivipiravir, galidesivir, ribavirin), protease inhibitors (lopinavir, ritonavir, nafamostat), drugs altering the endosomal pH (chloroquine, hydroxychloroquine), JAK-STAT inhibitors (fedratinib, baricitinib), monoclonal antibodies (tocilizumab) have been proposed to show promising effects against the novel virus. Taking cas- based approach from previously encountered viruses like SARS and MERS many drugs are facing clinical trials. This figure was adapted from reference [103].
Fig. 9
Fig. 9
Showing role of ACE2 in SARS-CoV-2 infection.
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