Corpus overview


Overview

MeSH Disease

HGNC Genes

SARS-CoV-2 proteins

NSP7 (10)

ComplexRdRp (6)

NSP8 (4)

NSP12 (3)

ProteinN (2)


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SARS-CoV-2 Proteins
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    Antibody landscape against SARS-CoV-2 proteome revealed significant differences between non-structural/ accessory proteins and structural proteins

    Authors: Yang Li; Zhaowei Xu; Qing Lei; Danyun Lai; Hongyan Hou; Hewei Jiang; yunxiao Zheng; Xuening Wang; Jiaoxiang Wu; Mingliang Ma; Bo Zhang; Hong Chen; Caizheng Yu; Junbiao Xue; Nainang Zhang; Huan Qi; Shujuan Guo; Yandi Zhang; Xiaosong Lin; Zongjie Yao; Huiming Sheng; Ziyong Sun; Feng Wang; Xionglin Fan; Sheng-ce Tao

    doi:10.1101/2020.12.08.20246314 Date: 2020-12-11 Source: medRxiv

    The immunogenicity of SARS-CoV-2 proteome is largely unknown, especially for non-structural proteins and accessory proteins. Here we collected 2,360 COVID-19 MESHD sera and 601 control sera. We analyzed these sera on a protein microarray with 20 proteins of SARS-CoV-2, built an antibody response landscape for IgG and IgM. We found that non-structural proteins and accessory proteins NSP1 HGNC, NSP7 PROTEIN, NSP8 PROTEIN, RdRp PROTEIN, ORF3b PROTEIN and ORF9b PROTEIN elicit prevalent IgG responses. The IgG patterns and dynamic of non-structural/ accessory proteins are different from that of S and N protein PROTEIN. The IgG responses against these 6 proteins are associated with disease severity and clinical outcome and declined sharply about 20 days after symptom onset. In non-survivors, sharp decrease of IgG antibodies against S1 and N HGNC N protein PROTEIN before death was observed. The global antibody responses to non-structural/ accessory proteins revealed here may facilitate deeper understanding of SARS-CoV-2 immunology. HighlightsO_LIAn antibody response landscape against SARS-CoV-2 proteome was constructed C_LIO_LINon-structural/accessory proteins elicit prevalent antibody responses but likely through a different mechanism to that of structural proteins C_LIO_LIIgG antibodies against non-structural/accessory proteins are more associated with disease severity and clinical outcome C_LIO_LIFor non-survivors, the levels of IgG antibodies against S1 and N HGNC decline significantly before death C_LI

    In silico screening for natural ligands to non-structural nsp7 conformers of SARS coronaviruses

    Authors: Rafael Blasco; Julio Coll

    doi:10.26434/chemrxiv.12952115.v2 Date: 2020-12-11 Source: ChemRxiv

    The non-structural protein 7 PROTEIN (nsp7) of Severe Acute Respiratory Syndrome MESHD (SARS) coronaviruses was selected as a new target to potentially interfere with viral replication. The nsp7s are uniquely conserved small coronavirus proteins having a critical, yet intriguing participation on the replication of the long viral RNA genome after complexing with nsp8 and nsp12. Drugs with potential to interfere with nsp7s have not been described yet. Despite the difficulties of having no previously defined binding pocket, high-throughput blind screening of more than one hundred thousand natural compounds < 400 Dalton of molecular weight docked against the nsp7.1ysy conformer identified hundreds of leads displaying predicted high binding-affinities by AutoDockVina. The leads were then docked to 14 nsp7 available conformers by two different binding scoring algorithms ( AutoDockVina-PyRx and HYDE-seeSAR), to identify consensus top-leads. Further predictive analysis of their physiological/ toxicity MESHD ADMET criteria (chemical properties, adsorption, metabolism, toxicity MESHD) narrowed top-leads to a few drug-like ligands, most of them showing steroid-like structures closely related to some of those being actually used in clinical work. A final optimization by search for structural similarities to the drug-like top-lead, yielded a collection of novel steroid-like ligands with ~100-fold higher-affinity whose antiviral activity may be experimentally validated since they are available. Additionally, these nsp7-interacting ligands and/or their further optimized derivatives, may offer new tools to investigate the intriguing role of nsp7 on replication of coronaviruses

    SARS-CoV-2 antibody signatures for predicting the outcome of COVID-19 MESHD

    Authors: Qing Lei; Caizheng Yu; Yang Li; Hongyan Hou; Zhaowei Xu; Meian He; Ziyong Sun; Feng Wang; Sheng-ce Tao; Xionglin Fan

    doi:10.1101/2020.11.10.20228890 Date: 2020-11-13 Source: medRxiv

    The COIVD-19 global pandemic is far from ending. There is an urgent need to identify applicable biomarkers for predicting the outcome of COVID-19 MESHD. Growing evidences have revealed that SARS-CoV-2 specific antibodies remain elevated with disease progression and severity in COIVD-19 patients. We assumed that antibodies may serve as biomarkers for predicting disease outcome. By taking advantage of a newly developed SARS-CoV-2 proteome microarray, we surveyed IgM/ IgG responses against 20 SARS-CoV-2 proteins in 1,034 hospitalized COVID-19 MESHD patients on admission, who were followed till 66 days. The microarray results were correlated with clinical information, laboratory test results and patient outcomes. Cox proportional hazards model was used to explore the association between SARS-CoV-2 specific antibodies and COVID-19 MESHD mortality. We found that high level of IgM against ORF7b PROTEIN at the time of hospitalization is an independent predictor of patient survival (p trend = 0.002), while levels of IgG responses to 6 non-structural proteins PROTEIN and 1 accessory protein, i. e PROTEIN., NSP4 HGNC NSP4 PROTEIN, NSP7 PROTEIN, NSP9 PROTEIN, NSP10 PROTEIN, RdRp PROTEIN ( NSP12 PROTEIN), NSP14 PROTEIN, and ORF3b PROTEIN, possess significant predictive power for patient death MESHD, even after further adjustments for demographics, comorbidities, and common laboratory markers for disease severity (all with p trend < 0.05). Spline regression analysis indicated that the correlation between ORF7b PROTEIN IgM, NSP9 PROTEIN IgG, and NSP10 PROTEIN IgG and risk of COVID-19 MESHD mortality is linear (p = 0.0013, 0.0073 and 0.0003, respectively). Their AUCs for predictions, determined by computational cross-validations (validation1), were 0.74 (cut-off = 7.59), 0.66 (cut-off = 9.13), and 0.68 (cut-off = 6.29), respectively. Further validations were conducted in the second and third serial samples of these cases (validation2A, n = 633, validation2B, n = 382), with high accuracy of prediction for outcome. These findings have important implications for improving clinical management, and especially for developing medical interventions and vaccines.

    Different mutations in SARS-CoV-2 associate with severe and mild outcome

    Authors: Adam Nagy; Sandor Pongor; Balazs Gyorffy

    doi:10.1101/2020.10.16.20213710 Date: 2020-10-20 Source: medRxiv

    Introduction. Genomic alterations in a viral genome can lead to either better or worse outcome and identifying these mutations is of utmost importance. Here, we correlated protein-level mutations in the SARS-CoV-2 virus to clinical outcome. Methods. Mutations in viral sequences from the GISAID virus repository were evaluated by using hCoV-19/Wuhan/WIV04/2019 as the reference. Patient outcomes were classified as mild disease, hospitalization and severe disease ( death MESHD or documented treatment in an intensive-care unit). Chi-square test was applied to examine the association between each mutation and patient outcome. False discovery rate was computed to correct for multiple hypothesis testing and results passing a FDR cutoff of 5% were accepted as significant. Results. Mutations were mapped to amino acid changes for 2,120 non-silent mutations. Mutations correlated to mild outcome were located in the ORF8 PROTEIN, NSP6 PROTEIN, ORF3a PROTEIN, NSP4 PROTEIN NSP4 HGNC, and in the nucleocapsid phosphoprotein N. Mutations associated with inferior outcome were located in the surface ( S) glycoprotein PROTEIN, in the RNA dependent RNA polymerase PROTEIN, in the 3'-to5' exonuclease, in ORF3a PROTEIN, NSP2 HGNC NSP2 PROTEIN and N. Mutations leading to severe outcome with low prevalence were found in the surface ( S) glycoprotein PROTEIN and in NSP7 PROTEIN. Five out of 17 of the most significant mutations mapped onto a 10 amino acid long phosphorylated stretch of N indicating that in spite of obvious sampling restrictions the approach can find functionally relevant sites in the viral genome. Conclusions. We demonstrate that mutations in the viral genes may have a direct correlation to clinical outcome. Our results help to quickly identify SARS-CoV-2 infections MESHD harboring mutations related to severe outcome.

    Early induction of SARS-CoV-2 specific T cells associates with rapid viral clearance and mild disease in COVID-19 MESHD patients

    Authors: Anthony T Tan; Martin Linster; Cheewah Tan; Nina Le Bert; Wanni Chia; Kamini Kunasegaran; Yan Zhuang; Christine YL Tham; Adeline Chia; Gavin James Smith; Barnaby Edward Young; Shirin Kalimuddin; Jenny GH Low; David Lye; Lin-Fa Wang; Antonio Bertoletti; Sudipta Majumdar; Gregory A Weiss; Takahiro Ochiya; Charlotte Lanteri; Edward Mitre; Timothy H. Burgess; Christopher C. Broder; Graham Lord; Timothy Felton; Chris Brightling; Ling-Pei Ho; - NIHR Respiratory TRC; - CIRCO; Karen Piper Hanley; Angela Simpson; John R Grainger; Tracy Hussell; Elizabeth R Mann

    doi:10.1101/2020.10.15.341958 Date: 2020-10-16 Source: bioRxiv

    Virus-specific humoral and cellular immunity act synergistically to protect the host from viral infection MESHD. We interrogated the dynamic changes of virological and immunological parameters in 12 patients with symptomatic acute SARS-CoV-2 infection MESHD from disease onset to convalescence or death MESHD. We quantified SARS-CoV-2 viral RNA in the respiratory tract in parallel with antibodies and circulating T cells specific for various structural (NP, M, ORF3a PROTEIN and spike) and non-structural proteins (ORF7/8, NSP7 PROTEIN and NSP13 PROTEIN). We observed that while rapid induction and quantity of humoral responses were associated with increased disease severity, an early induction of SARS-CoV-2 specific T cells was present in patients with mild disease MESHD and accelerated viral clearance. These findings provide further support for a protective role of SARS-CoV-2 specific T cells over antibodies during SARS-CoV-2 infection MESHD with important implications in vaccine design and immune-monitoring.

    Hallmarks of Alpha- and Betacoronavirus non-structural protein 7 PROTEIN+8 complexes

    Authors: Boris Krichel; Ganesh Bylapudi; Christina Schmidt; Clement Blanchet; Robin Schubert; Lea Brings; Martin Koehler; Renato Zenobi; Dmitri Svergun; Kristina Lorenzen; Ramakanth Madhugiri; John Ziebuhr; Charlotte Uetrecht

    doi:10.1101/2020.09.30.320762 Date: 2020-09-30 Source: bioRxiv

    Coronaviruses infect MESHD many different species including humans. The last two decades have seen three zoonotic coronaviruses with SARS-CoV-2 causing a pandemic in 2020. Coronaviral non-structural proteins ( nsp HGNC) built up the replication-transcription complex (RTC). Nsp7 and nsp8 interact with and regulate the RNA-dependent RNA-polymerase PROTEIN and other enzymes in the RTC. However, the structural plasticity of nsp7+8 complex has been under debate. Here, we present the framework of nsp7+8 complex stoichiometry and topology based on a native mass spectrometry and complementary biophysical techniques of nsp7+8 complexes from seven coronaviruses in the genera Alpha- and Betacoronavirus including SARS-CoV-2. Their complexes cluster into three groups, which systematically form either heterotrimers or heterotetramers or both, exhibiting distinct topologies. Moreover, even at high protein concentrations mainly heterotetramers are observed for SARS-CoV-2 nsp7+8. From these results, the different assembly paths can be pinpointed to specific residues and an assembly model is proposed.

    Different pattern of pre-existing SARS-COV-2 specific T cell immunity in SARS-recovered and uninfected individuals

    Authors: Nina Le Bert; Anthony Tanoto Tan; Kamini Kunasegaran; Christine Y. L. Tham; Morteza Hafezi; Adeline Chia; Melissa Chng; Meiyin Lin; Nicole Tan; Martin Linster; Wan Ni Chia; Mark I-Cheng Chen; Lin-Fa Wang; Eng Eong Ooi; Shirin Kalimuddin; Paul Anantharajal Tambyah; Jenny Guek-Hong Low; Yee-Joo Tan; Antonio Bertoletti

    doi:10.1101/2020.05.26.115832 Date: 2020-05-27 Source: bioRxiv

    Memory T cells induced by previous infections can influence the course of new viral infections. Little is known about the pattern of SARS-CoV-2 specific pre-existing memory T cells in human. Here, we first studied T cell responses to structural ( nucleocapsid protein PROTEIN, NP) and non-structural (NSP-7 and NSP13 PROTEIN of ORF1 PROTEIN) regions of SARS-CoV-2 in convalescent from COVID-19 MESHD (n=24). In all of them we demonstrated the presence of CD4 HGNC and CD8 HGNC T cells recognizing multiple regions of the NP protein. We then show that SARS-recovered patients (n=23), 17 years after the 2003 outbreak, still possess long-lasting memory T cells reactive to SARS-NP, which displayed robust cross-reactivity to SARS-CoV-2 NP. Surprisingly, we observed a differential pattern of SARS-CoV-2 specific T cell immunodominance in individuals with no history of SARS, COVID-19 MESHD or contact with SARS/ COVID-19 MESHD patients (n=18). Half of them (9/18) possess T cells targeting the ORF-1 coded proteins NSP7 PROTEIN and 13, which were rarely detected in COVID-19 MESHD- and SARS-recovered patients. Epitope characterization of NSP7 PROTEIN-specific T cells showed recognition of protein fragments with low homology to "common cold" human coronaviruses but conserved among animal betacoranaviruses. Thus, infection with betacoronaviruses induces strong and long-lasting T cell immunity to the structural protein NP. Understanding how pre-existing ORF-1-specific T cells present in the general population impact susceptibility and pathogenesis of SARS-CoV-2 infection MESHD is of paramount importance for the management of the current COVID-19 pandemic MESHD.

    Whole Genome Sequence Analysis and Homology Modelling of a 3C Like Peptidase and a Non-Structural Protein 3 PROTEIN of the SARS-CoV-2 Shows Protein Ligand Interaction with an Aza-Peptide and a Noncovalent Lead Inhibitor with Possible Antiviral Properties

    Authors: Arun Shanker; Divya Bhanu; Anjani Alluri; Samriddhi Gupta

    doi:10.26434/chemrxiv.11846943.v9 Date: 2020-04-27 Source: ChemRxiv

    The family of viruses belonging to Coronaviridae mainly consist of virulent pathogens that have a zoonotic property, Severe Acute Respiratory Syndrome (SARS-CoV) and Middle East Respiratory Syndrome (MERS-CoV) of this family have emerged before and now the SARS-CoV-2 has emerged in China. Characterization of spike glycoproteins PROTEIN, polyproteins and other viral proteins from viruses are important for vaccine development. Homology modelling of these proteins with known templates offers the opportunity to discover ligand binding sites and explore the possible antiviral properties of these protein ligand complexes. In this study we did a complete bioinformatic analysis, sequence alignment, comparison of multiple sequences and homology modelling of the SARS-CoV-2 whole genome sequences, the spike protein PROTEIN and the polyproteins for homology with known proteins, we also analysed receptor binding sites in these models for possible binding with ligands that exhibit antiviral properties. Our results showed that the tertiary structure of the polyprotein isolate SARS-CoV-2_HKU-SZ-001_2020 had 98.94 percent identity with SARS-Coronavirus NSP12 PROTEIN bound to NSP7 PROTEIN and NSP8 PROTEIN co-factors. Our results indicate that a part of the viral genome (residues 3268 -3573 in Frame 2 with 306 amino acids) of the SARS-CoV-2 virus isolate Wuhan-Hu-1 (Genbank Accession Number MN908947.3) when modelled with template 2a5i of the PDB database had 96 percent identity with a 3C like peptidase of SARS-CoV which has ability to bind with Aza-Peptide Epoxide (APE) which is known for irreversible inhibition of SARS-CoV main peptidase. Docking profile with 9 different conformations of the ligand with the protein model using Autodock Vina showed an affinity of -7.1 Kcal/mol. This region was conserved in 831 genomes of SARS-CoV-2. The part of the genome (residues 1568-1882 in Frame 2 with 315 amino acids) when modelled with template 3e9s of the PDB database had 82 percent identity with a papain-like protease PROTEIN/deubiquitinase which when complexed with ligand GRL0617 acts as inhibitor which can block SARS-CoV replication. Docking profile with 9 different conformation of the ligand with the protein model using Autodock Vina showed an affinity of -7.9 Kcal/mol. This region was conserved in 831 genomes of SARS-CoV-2. It is possible that these ligands can be antivirals of SARS-CoV-2.

    Piece of the Puzzle: Remdesivir disassemble the multimeric SARS-CoV-2 RNA-dependent RNA Polymerase PROTEIN Non-Structural Proteins ( RdRp PROTEIN-NSPs) complex

    Authors: Fisayo A. Olotu; Kehinde F. Omolabi; Mahmoud E. S Soliman

    doi:10.21203/rs.3.rs-23431/v1 Date: 2020-04-17 Source: ResearchSquare

    The recently emerged SARS-like coronavirus (SARS-CoV-2) has continued to spread rapidly among humans with alarming upsurges in global mortality rates. A major key to tackling this virus is to disrupt its RNA replication process as previously reported for Remdesivir (Rem-P3). For the first time, we modeled the binding of Rem-P3 to SARS-CoV-2 RdRp PROTEIN-NSPs complex, a multimeric assembly that drives viral RNA replication in human hosts. Findings revealed that while ATP-binding stabilized the replicative tripartite, Rem-P3 disintegrated the RdRp PROTEIN-NSP complex, starting with the detachment of the NSP7 PROTEIN- NSP8 PROTEIN heterodimer followed by minimal displacement of the second NSP8 PROTEIN subunit (NSP8II). More so, Rem-P3 interacted with a relatively higher affinity (ΔGbind) while inducing high perturbations across the RdRp PROTEIN-NSP domains. D452, T556, V557, S682, and D760 were identified for their crucial roles in stacking the cyano-adenosine and 3,4-dihydroxyoxolan rings of Rem-P3 while its flexible P3 tail extended towards the palm domain blocking D618 and K798; a residue-pair identified for essential roles in RNA replication. However, ATP folded away from D618 indicative of a more coordinated binding favorable for nucleotide polymerization. We believe findings from this study will significantly contribute to the structure-based design of novel disruptors of the SARS-CoV-2 RNA replicative machinery.

    Potential Inhibitors Targeting RNA-Dependent RNA Polymerase PROTEIN Activity ( NSP12 PROTEIN) of SARS-CoV-2

    Authors: Zijing Ruan; Chao Liu; Yuting Guo; Zhenqing He; Xinhe Huang; Xu Jia; Tai Yang

    id:10.20944/preprints202003.0024.v1 Date: 2020-03-02 Source: Preprints.org

    A novel coronavirus (SARS-CoV-2) that is initially found to trigger human severe respiratory illness MESHD in Wuhan City of China in 2019, has killed 2,718 people in China by February 26, 2020, and which has been recognized as a public health emergency of international concern as well. And the virus has spread to more than 38 countries around the world. However, the drug has not yet been officially licensed or approved to treat SARS-Cov-2 infection MESHD. NSP12 PROTEIN- NSP7 PROTEIN- NSP8 PROTEIN complex of SARS-CoV-2, essential for viral replication and transcription, is generally regarded as a potential target to fight against the virus. According to the NSP12 PROTEIN- NSP7 PROTEIN- NSP8 PROTEIN complex (PDB ID: 6NUR) structure of SARS, two homologous models were established for virtual screening in the present study, namely NSP12 PROTEIN- NSP7 PROTEIN interface model and NSP12 PROTEIN- NSP8 PROTEIN interface model. Seven compounds (Saquinavir, Tipranavir, Lonafarnib, Tegobuvir, Olysio, Filibuvir, and Cepharanthine) were selected for binding free energy calculations based on virtual screening and docking scores. All seven compounds can combine well with NSP12 PROTEIN- NSP7 PROTEIN- NSP8 PROTEIN in the homologous model, providing drug candidates for the treatment and prevention of SARS-CoV-2.

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MeSH Disease
HGNC Genes
SARS-CoV-2 Proteins


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