SARS-CoV-2 nsp1: Bioinformatics, Potential Structural and Functional Features, and Implications for Drug/Vaccine Designs

Min, Yuan Qin; Mo, Qiong; Wang, Jun; Dèng, Fēi; Wang, Hualin; Ning, Yun Jia

doi:10.3389/fmicb.2020.587317

Cited by 67 publications

(74 citation statements)

References 58 publications

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“…While a previous study has established the crucial role played by N in viral genome processing and nucleocapsid assembly (Carlson et al, 2020), to the best of our knowledge there have been no prior reports specifically highlighting its ability to elevate lentiviral spike pseudovirus infectivity. It bears mentioning that similar to existent reports (Min et al, 2020;Schubert et al, 2020;Thoms et al, 2020;Lapointe et al, 2021;Zhang et al, 2021), the Nsp1 protein presumably exerts a detrimental effect on the host cell's protein translation, as indicated by the almost imperceptible extent of infectivity observed in its case (Figure 2A).…”

Section: Discussionsupporting

confidence: 83%

SARS CoV-2 Nucleoprotein Enhances the Infectivity of Lentiviral Spike Particles

Mishra

Sreepadmanabh

Ramdas

et al. 2021

Front. Cell. Infect. Microbiol.

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The establishment of SARS CoV-2 spike-pseudotyped lentiviral (LV) systems has enabled the rapid identification of entry inhibitors and neutralizing agents, alongside allowing for the study of this emerging pathogen in BSL-2 level facilities. While such frameworks recapitulate the cellular entry process in ACE2+ cells, they are largely unable to factor in supplemental contributions by other SARS CoV-2 genes. To address this, we performed an unbiased ORF screen and identified the nucleoprotein (N) as a potent enhancer of spike-pseudotyped LV particle infectivity. We further demonstrate that the spike protein is better enriched in virions when the particles are produced in the presence of N protein. This enrichment of spike renders LV particles more infectious as well as less vulnerable to the neutralizing effects of a human IgG-Fc fused ACE2 microbody. Importantly, this improvement in infectivity is observed with both wild-type spike protein as well as the D614G mutant. Our results hold important implications for the design and interpretation of similar LV pseudotyping-based studies.

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Section: Discussionsupporting

confidence: 83%

SARS CoV-2 Nucleoprotein Enhances the Infectivity of Lentiviral Spike Particles

Mishra

Sreepadmanabh

Ramdas

et al. 2021

Front. Cell. Infect. Microbiol.

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“…Since no significant mutations have been observed among the protein sequences across countries, NSP1 can be potentially targeted for the discovery of drugs that can hamper the rapid progression of COVID-19. Also, major challenges in the vaccine development for the virus is to tackle the rapid mutations on the target, which can be solved by targeting NSP1 for developing the vaccine [ 54 , 55 ]. The protein sequences of NSP1 from the alpha and beta family of coronaviruses were shown to have divergence among the families (α and β), however, partially conserved nature was reported within the family.…”

Section: Resultsmentioning

confidence: 99%

Modelling studies reveal the importance of the C-terminal inter motif loop of NSP1 as a promising target site for drug discovery and screening of potential phytochemicals to combat SARS-CoV-2

Prabhu

Rajamanikandan

Sureshan

et al. 2021

Journal of Molecular Graphics and Modelling

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COVID-19 pandemic causative SARS-CoV-2 coronavirus is still rapid in progression and transmission even after a year. Understanding the viral transmission and impeding the replication process within human cells are considered as the vital point to control and overcome COVID-19 infection. Non-structural Protein 1, one among the proteins initially produced upon viral entry into human cells, instantly binds with the human ribosome and inhibit the host translation process by preventing the mRNA attachment. However, the formation of NSP1 bound Ribosome complex does not affect the viral replication process. NSP1 plays an indispensable role in modulating the host gene expression and completely steals the host cellular machinery. The full-length structure of NSP1 is essential for the activity in the host cell and importantly the loop connecting N and C- terminal domains are reported to play a role in ribosome binding. Due to the unavailability of the experimentally determined full-length structure of NSP1, we have modelled the complete structure using comparative modelling and the stability and conformational behaviour of the modelled structure was evaluated through molecular dynamics simulation. Interestingly, the present study reveals the significance of the inter motif loop to serves as a potential binding site for drug discovery experiments. Further, we have screened the phytochemicals from medicinal plant sources since they were used for several hundred years that minimizes the traditional drug development time. Among the 5638 phytochemicals screened against the functionally associated binding site of NSP1, the best five phytochemicals shown high docking score of -9.63 to -8.75 kcal/mol were further evaluated through molecular dynamics simulations to understand the binding affinity and stability of the complex. Prime MM-GBSA analysis gave the relative binding free energies for the top five compounds (dihydromyricetin, 10-demethylcephaeline, dihydroquercetin, pseudolycorine and tricetin) in the range of -45.17 kcal/mol to -37.23 kcal/mol, indicating its binding efficacy in the predicted binding site of NSP1. The density functional theory calculations were performed for the selected five phytochemicals to determine the complex stability and chemical reactivity. Thus, the identified phytochemicals could further be used as effective anti-viral agents to overcome COVID-19 and as well as several other viral infections.

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“…Deciphering the mechanism by which viral-host protein-protein interactions induce the molecular pathogenesis of infection is key to identifying novel drug candidates for clinical trials (24). It has been reported that the observed differences of SARS-CoV-2 and SARS-CoV in terms of their pathogenicity and epidemiology are likely attributed to the complex interactions between various viral and host factors (35). Hence, in our study we also aimed at the identification of the human proteins interacting with P0DTC4.…”

Section: Discussionmentioning

confidence: 99%

“…Computational approaches for vaccine and drug design-as the one mentioned above-have guided the development of novel therapeutic strategies during the last decade. In silico methodology has widely been used for the identification of drugs and vaccine candidate epitopes against several bacteria and viruses including SARS-CoV-2 (2,11,27,28,35,46,48,57). Most of these studies have focused on the spike proteins and viral RNA-polymerases as potential vaccine and drug targets (46) while very few studies involve viroporin E as a vaccine or drug target candidate (11,46).…”

Section: Introductionmentioning

confidence: 99%

In silico investigation of the viroporin E as a vaccine target against SARS-CoV-2

Rouka

Gourgoulianis

Zarogiannis

2021

American Journal of Physiology-Lung Cellular and Molecular Phys

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Viroporins, integral viral membrane ion channel proteins, interact with host-cell proteins deregulating physiological processes and activating inflammasomes. Severity of COVID-19 might be associated with hyperinflammation, thus we aimed at the complete immunoinformatic analysis of the SARS-CoV-2 viroporin E, P0DTC4. We also identified the human proteins interacting with P0DTC4 and the enriched molecular functions of the corresponding genes. The complete sequence of P0DTC4 in FASTA format was processed in 10 databases relative to secondary and tertiary protein structure analyses and prediction of optimal vaccine epitopes. Three more databases were accessed for the retrieval and the molecular functional characterization of the P0DTC4 human interactors. The immunoinformatics analysis resulted in the identification of 4 discontinuous B-cell epitopes along with 1 linear B-cell epitope and 11 T-cell epitopes which were found to be antigenic, immunogenic, non-allergen, non-toxin and unable to induce autoimmunity thus fulfilling prerequisites for vaccine design. The functional enrichment analysis showed that the predicted host interactors of P0DTC4 target the cellular acetylation network. Two of the identified host-cell proteins-BRD2 and BRD4- have been shown to be promising targets for anti-viral therapy. Thus, our findings have implications for COVID-19 therapy and indicate that viroporin E could serve as a promising vaccine target against SARS-CoV-2. Validation experiments are required to complement these in-silico results.

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SARS-CoV-2 nsp1: Bioinformatics, Potential Structural and Functional Features, and Implications for Drug/Vaccine Designs

Cited by 67 publications

References 58 publications

SARS CoV-2 Nucleoprotein Enhances the Infectivity of Lentiviral Spike Particles

SARS CoV-2 Nucleoprotein Enhances the Infectivity of Lentiviral Spike Particles

Modelling studies reveal the importance of the C-terminal inter motif loop of NSP1 as a promising target site for drug discovery and screening of potential phytochemicals to combat SARS-CoV-2

In silico investigation of the viroporin E as a vaccine target against SARS-CoV-2

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