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MeSH Disease

HGNC Genes

SARS-CoV-2 proteins

NSP1 (5)

NSP3 (2)

NSP5 (2)

ORF1a (1)

ORF1ab (1)


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SARS-CoV-2 Proteins
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    Computational Analysis of Dynamic Allostery and Control in the three SARS-CoV- 2 non-structural proteins PROTEIN

    Authors: Igors Dubanevics; Charles Heaton; Carlos Riechmann; Tom C B McLeish; Theresa A Ramelot; Thomas B. Acton; Elena Moreno; Thomas Kehrer; Catherine A. Royer; Adolfo Garcia-Sastre; Robert M Krug; Gaetano T. Montelione

    doi:10.1101/2020.12.12.422477 Date: 2020-12-14 Source: bioRxiv

    Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which caused the COVID-19 pandemic MESHD, has no vaccine or antiviral drugs available to the public, at the time of writing. The virus non-structural proteins are promising drug targets because of their vital role in the viral cycle. A significant body of work has been focused on finding inhibitors which covalently and competitively bind the active site of the non-structural proteins, but little has been done to address regions other than the active site, i.e. for non-competitive inhibition. Here we extend previous work on the SARS-CoV-2 Mpro PROTEIN ( nsp5 HGNC) to three other SARS-CoV-2 proteins: host shutoff factor PROTEIN ( nsp1 HGNC), papain-like protease PROTEIN ( nsp3 HGNC, also known as PLpro PROTEIN) and RNA-dependent RNA-polymerase PROTEIN (nsp12, also known as RdRp) in complex PROTEIN with nsp7 and nsp8 cofactors. Using open-source software (DDPT) to construct Elastic Network Models (ENM) of the chosen proteins we analyse their fluctuation dynamics and thermodynamics, as well as using this protein family to study convergence and robustness of the ENM. Exhaustive 2-point mutational scans of the ENM and their effect on fluctuation free energies suggest several new candidate regions, distant from the active site, for control of the proteins function, which may assist the drug development based on the current small molecule binding screens. The results also provide new insights, including non-additive effects of double-mutation or inhibition, into the active biophysical research field of protein fluctuation allostery and its underpinning dynamical structure.

    Emerging of a SARS-CoV-2 viral strain with a deletion in nsp1

    Authors: Francesca Benedetti; Greg Snyder; Marta Giovanetti; Silvia Angeletti; Robert C. Gallo; Massimo Ciccozzi; Davide Zella

    doi:10.21203/rs.3.rs-62592/v1 Date: 2020-08-19 Source: ResearchSquare

    Background:The new Severe Acute Respiratory Syndrome Coronavirus-2 MESHD (SARS-CoV-2), which was first detected in Wuhan (China) in December of 2019 is responsible for the current global pandemic.Phylogenetic analysis revealed that it is similar to other betacoronaviruses, such as SARS-CoV and Middle-Eastern Respiratory Syndrome MESHD, MERS-CoV MESHD. Its genome is ∼30 kb in length and contains two large overlapping polyproteins, ORF1a PROTEIN and ORF1ab PROTEIN that encode for several structural and non-structural proteins. The non-structural protein 1 PROTEIN ( nsp1 HGNC) is arguably the most important pathogenic determinant, and previous studies on SARS-CoV indicate that it is both involved in viral replication and hampering the innate immune system response. Detailed experiments of site-specific mutagenesis and in vitro reconstitution studies determined that the mechanisms of action are mediated by i) the presence of specific amino acid residues of nsp1 HGNC and b) the interaction between the protein and the host’s small ribosomal unit. In fact, substitution of certain amino acids resulted in reduction of its negative effects.Methods: A total of 17928 genome sequences were obtained from the GISAID database (December 2019 to July 2020) from patients infected by SARS-CoV-2 from different areas around the world. Genomes alignment was performed using MAFFT (REFF) and the nsp1 HGNC genomic regions were identified using BioEdit and verified using BLAST. Nsp1 HGNC protein of SARS-CoV-2 with and without deletion have been subsequently modelled using I-TASSER.Results: We identified SARS-CoV-2 genome sequences, from several Countries, carrying a previously unknown deletion of 9 nucleotides in position 686-694, corresponding to the AA position 241-243 (KSF). This deletion was found in different geographical areas. Structural prediction modelling suggests an effect on the C-terminal tail structure.Conclusions: Modelling analysis of a newly identified deletion of 3 amino acids (KSF) of SARS-CoV-2 nsp1 HGNC suggests that this deletion could affect the structure of the C-terminal region of the protein, important for regulation of viral replication and negative effect on host’s gene expression. In addition, substitution of the two amino acids (KS) from nsp1 HGNC of SARS-CoV MESHD was previously reported to revert loss of interferon-alpha expression. The deletion that we describe indicates that SARS-CoV-2 is undergoing profound genomic changes. It is important to: i) confirm the spreading of this particular viral strain, and potentially of strains with other deletions in the nsp1 HGNC protein, both in the population of asymptomatic and pauci-symptomatic subjects, and ii) correlate these changes in nsp1 HGNC with potential decreased viral pathogenicity.

    SARS-CoV-2 Nsp1 HGNC binds ribosomal mRNA channel to inhibit translation

    Authors: Katharina Schubert; Evangelos D. Karousis; Ahmad Jomaa; Alain Scaiola; Blanca Echeverria; Lukas-Adrian Gurzeler; Marc Leibundgut; Volker Thiel; Oliver Muehlemann; Nenad Ban

    doi:10.1101/2020.07.07.191676 Date: 2020-07-07 Source: bioRxiv

    The non-structural protein 1 PROTEIN ( Nsp1 HGNC), also referred to as the host shutoff factor PROTEIN, is the first viral protein that is synthesized in SARS-CoV-2 infected MESHD human cells to suppress host innate immune functions1,2. By combining cryo-electron microscopy and biochemical experiments, we show that SARS-CoV-2 Nsp1 HGNC binds to the human 40S subunit in ribosomal complexes including the 43S pre-initiation complex. The protein inserts its C-terminal domain at the entrance to the mRNA channel where it interferes with mRNA binding. We observe potent translation inhibition in the presence of Nsp1 HGNC in lysates from human cells. Based on the high-resolution structure of the 40S- Nsp1 HGNC complex, we identify residues of Nsp1 HGNC crucial for mediating translation inhibition. We further show that the full-length 5’ untranslated region of the genomic viral mRNA stimulates translation in vitro, suggesting that SARS-CoV-2 combines inhibition of translation by Nsp1 HGNC with efficient translation of the viral mRNA to achieve expression of viral genes3.Competing Interest StatementThe authors have declared no competing interest.View Full Text

    Comparative analysis of non structural protein 1 PROTEIN of SARS-COV2 with SARS-COV1 and MERS-COV: An in silico study

    Authors: Ankur Chaudhuri

    doi:10.1101/2020.06.09.142570 Date: 2020-06-10 Source: bioRxiv

    The recently emerged SARS-COV2 caused a major pandemic of coronavirus disease MESHD ( COVID-19 MESHD). The main goal of this study is to elucidate the structural conformations of non structural protein 1 PROTEIN(nsp1), prediction of epitope sites and identification of important residues for targeted therapy against COVID-19 MESHD. In this study, molecular modelling coupled with molecular dynamics simulations were performed to analyse the conformational change of SARS-COV1, SARS-COV2 and MERS-COV at molecular level. Free energy landscape was constructed by using the first (PC1) and second (PC2) principle components. From the sequence alignment it was observed when compared to SERS-COV1 28 mutations are present in SERS-COV2 nsp1 protein. Several B-cell and T-cell epitopes were identified by immunoinformatics study. The {Delta}G values for SARS-COV1, SARS-COV2 and MERS-COV nsp1 proteins were 4.44, 5.82 and 6.15 kJ/mol respectively. SARS-COV2 nsp1 protein binds with the interface region of the palm and finger domain of POLA1 by using hydrogen bonds and salt bridges interactions. The present study provided a comprehensive structural model of nsp1 by threading process. The MD simulation parameters indicated that all three nsp1 proteins were stable during the simulation run. These findings can be used to develop therapeutics specific against COVID-19 MESHD. HighlightsO_LIStructural elucidation at molecular level of nsp1 of SARS-COV1, SARS-COV2, and MERS-COV C_LIO_LIIdentifications of epitopes by immunoinformatics approach C_LIO_LISARS-COV2 nsp1 cover a large conformational space due to greater flexibility C_LIO_LIMolecular docking between SARS-COV2 nsp1 and POLA1 to identify important residues C_LIO_LIStructural insights of nsp1 could be used in drug design process against COVID-19 MESHD C_LI Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=130 SRC="FIGDIR/small/142570v1_ufig1.gif" ALT="Figure 1"> View larger version (48K): org.highwire.dtl.DTLVardef@d71bbborg.highwire.dtl.DTLVardef@5dbe87org.highwire.dtl.DTLVardef@87b421org.highwire.dtl.DTLVardef@143171d_HPS_FORMAT_FIGEXP M_FIG C_FIG

    A Proposed Randomized, Double Blind, Placebo Controlled Study Evaluating Doxycycline for the Prevention of COVID-19 MESHD Infection and Disease In Healthcare Workers with Ongoing High Risk Exposure to COVID-19 MESHD

    Authors: Paul A Yates; Ashton M Leone; Elias Reichel

    doi:10.1101/2020.05.11.20098525 Date: 2020-05-18 Source: medRxiv

    This paper proposes both a rationale and potential study design for evaluation of low dose doxycycline (20mg BID HGNC) for the prevention of COVID-19 MESHD infection in exposed health care workers. More generally, it provides a potential study design blueprint to other investigators for any interventional COVID-19 MESHD study looking to evaluate interventions for prevention or treatment of COVID-19 MESHD infection. This specific study described is a randomized, double blind, placebo controlled study to evaluate the efficacy and safety of doxycycline for the prevention of COVID-19 MESHD infection and disease in healthcare workers with ongoing high risk exposure to COVID-19 MESHD. This study would consist of a 50-day Treatment Period (Day 0-Day 50), followed by an End of Study Visit, approximately 30 days after completion of study drug dosing. Initially, for approximately the first 4 to 6 weeks, an initial open-label arm would be enrolled with up to 1938 subjects who will be assigned to take 20mg doxycycline BID HGNC. In the double blind, placebo controlled arms approximately 3,692 participants would be randomized to either doxycycline or placebo for 50 days. Doxycycline is a rational candidate drug to be evaluated for repurposing against SARS-CoV-2. Doxycycline is a generally safe tetracycline derivative that has been available for decades, most commonly dosed at 100mg BID HGNC to treat bacterial infections MESHD. However, in addition to its anti-microbial properties, doxycycline (and more generally tetracycline derivatives) may have a role as an effective anti-viral agent and as an anti-inflammatory drug. Early studies indicate potential efficacy of minocycline against respiratory syncytial virus (RSV) [12], and doxycycline against Dengue and Chikungunya infection MESHD[9, 10]. In addition, doxycycline is known or proposed to target several pathways that regulate viral replication. [13, 14, 15]. Doxycycline is a particularly attractive candidate as a COVID-19 MESHD prophylactic given it has been used in clinical practice for decades and maintains an excellent safety profile as demonstrated in multiple clinical studies. Any effective prophylaxis for COVID-19 MESHD should be able to demonstrate high efficacy at preventing infection and/or lowering severity of disease. Equally important, it should demonstrate this efficacy at dosing levels that are highly unlikely to precipitate any untoward severe side effects. Doxycycline has been selected based on its ability to: 1) inhibit metalloproteinases (MMPs), implicated in initial viral entry into the cell as well as in acute respiratory distress syndrome MESHD ( ARDS MESHD) associated with severe COVID-19 MESHD infection [13, 16]; 2) potential to inhibit Papain-like proteinase ( PLpro PROTEIN) responsible for proteolytic cleavage of the replicase polyprotein to release non-structural proteins 1 PROTEIN, 2 & 3 (Nsp1, Nsp2 and Nsp3) all essential for viral replication. [19]; 3) potential to inhibit 3C-like main protease PROTEIN ( 3CLpro PROTEIN) or Nsp5 which is cleaved from the polyproteins causes further cleavage of Nsp4-16 and mediates maturation of Nsps which is essential in the virus lifecycle. [19]; 4) act as an ionophore help transport Zinc intracellularly, increasing cellular concentrations of Zinc to inhibit viral replication. [6, 15]; 5) inhibit Nf-kB which may lower inflammatory response to COVID-19 MESHD infection, and lower risk of viral entry due to decreasing DPP4 cell surface receptor. [20, 21]; 6) inhibits (specifically low-dose doxycycline) expression of CD147/EMMPRIN that may be necessary for SARS-CoV-2 entry into T lymphocytes [22, 23].

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MeSH Disease
HGNC Genes
SARS-CoV-2 Proteins


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