Corpus overview


Overview

MeSH Disease

HGNC Genes

SARS-CoV-2 proteins

NSP8 (9)

ComplexRdRp (5)

NSP12 (4)

NSP7 (4)

NSP3 (3)


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SARS-CoV-2 Proteins
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    Evolving Infection Paradox of SARS-CoV-2: Fitness Costs Virulence?

    Authors: A. S. M. Rubayet Ul Alam; Ovinu Kibria Islam; Md. Shazid Hasan; Mir Raihanul Islam; Shafi Mahmud; Hassan M. AlEmran; Iqbal K Jahid; Keith A. Crandall; M. Anwar Hossain

    doi:10.1101/2021.02.21.21252137 Date: 2021-02-23 Source: medRxiv

    Background: SARS-CoV-2 is continuously spreading worldwide at an unprecedented scale and evolved into seven clades according to GISAID where four (G, GH, GR and GV) are globally prevalent in 2020. These major predominant clades of SARS-CoV-2 are continuously increasing COVID-19 MESHD cases worldwide; however, after an early rise in 2020, the death-case ratio has been decreasing to a plateau. G clade viruses contain four co-occurring mutations in their genome (C241T+C3037T+C14408T: RdRp PROTEIN.P323L+A23403G:spike.D614G). GR, GH, and GV strains are defined by the presence of these four mutations in addition to the clade-featured mutation in GGG28881-28883AAC:N. RG203-204KR, G25563T: ORF3a PROTEIN.Q57H, and C22227T:spike.A222V+C28932T-N.A220V+G29645T, respectively. The research works are broadly focused on the spike protein PROTEIN mutations that have direct roles in receptor binding, antigenicity, thus viral transmission and replication fitness. However, mutations in other proteins might also have effects on viral pathogenicity and transmissibility. How the clade-featured mutations are linked with viral evolution in this pandemic through gearing their fitness MESHD and virulence is the main question of this study. Methodology: We thus proposed a hypothetical model, combining a statistical and structural bioinformatics approach, endeavors to explain this infection paradox by describing the epistatic effects of the clade-featured co-occurring mutations on viral fitness MESHD and virulence. Results and Discussion: The G and GR/GV clade strains represent a significant positive and negative association, respectively, with the death-case ratio (incidence rate ratio or IRR = 1.03, p <0.001 and IRR= 0.99/0.97, p < 0.001), whereas GH clade strains showed no association with the Docking analysis showed the higher infectiousness of a spike mutant through more favorable binding of G614 with the elastase-2 HGNC. RdRp PROTEIN mutation p.P323L significantly increased genome-wide mutations (p<0.0001) since more expandable RdRp PROTEIN (mutant)- NSP8 PROTEIN interaction may accelerate replication. Superior RNA stability and structural variation at NSP3 HGNC NSP3 PROTEIN:C241T might impact upon protein or RNA interactions. Another silent 5'UTR:C241T mutation might affect translational efficiency and viral packaging. These G-featured co-occurring mutations might increase the viral load, alter immune responses in host and hence can modulate intra-host genomic plasticity. An additional viroporin ORF3a PROTEIN:p.Q57H mutation, forming GH-clade, prevents ion permeability by cysteine (C81)-histidine (H57) inter-transmembrane-domain interaction mediated tighter constriction of the channel pore and possibly reduces viral release and immune response. GR strains, four G clade mutations and N:p.RG203-204KR, would have stabilized RNA interaction by more flexible and hypo-phosphorylated SR-rich region. GV strains seemingly gained the evolutionary advantage of superspreading event through confounder factors; nevertheless, N:p.A220V might affect RNA binding. Conclusion: These hypotheses need further retrospective and prospective studies to understand detailed molecular and evolutionary events featuring the fitness MESHD and virulence of SARS-CoV-2.

    Detection of the new SARS-CoV-2 variant B.1.526 with the Spike E484K mutation in South America

    Authors: Juan Fernández Cadena; Mindy Muñoz; Gabriel Morey León; Rubén Armas-González; Darlyn Amaya Márquez; Katheryn Sacheri Viteri; Paúl Cárdenas & USFQ-COVID Consortium; Fernando Valiente-Echeverría; Ricardo Soto Rifo; Derly Andrade Molina

    doi:10.21203/rs.3.rs-248965/v1 Date: 2021-02-17 Source: ResearchSquare

    Here, we report two sequences of the new SARS-CoV-2 variant recently detected and designed as B.1.526. This variant carries the immune escape-associated mutation E484K and additional mutations in the S, N, NSP2 PROTEIN NSP2 HGNC, NSP3 HGNC NSP3 PROTEIN, NSP4 PROTEIN NSP4 HGNC, NSP6 PROTEIN, NSP8 PROTEIN, NSP12 PROTEIN and NSP13 PROTEIN genes. Viral sequences were obtained from an individual traveling from the US to Equator with a negative RT-PCR and from one of his closest contacts that became infected. These cases should be considered an alert for the potential circulation of a new variant of concern with the E484K mutation in South America

    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

    SARS-CoV-2 infection MESHD severity is linked to superior humoral immunity against the spike

    Authors: Jenna J. Guthmiller; Olivia Stovicek; Jiaolong Wang; Siriruk Changrob; Lei Li; Peter Halfmann; Nai-Ying Zheng; Henry Utset; Christopher T. Stamper; Haley L. Dugan; William D. Miller; Min Huang; Ya-Nan Dai; Christopher A. Nelson; Paige D. Hall; Maud Jansen; Kumaran Shanmugarajah; Jessica S. Donington; Florian Krammer; Daved Fremont; Andrzej Joachimiak; Yoshihiro Kawaoka; Vera Tesic; Maria Lucia Madariaga; Patrick C Wilson; Martin Pettersson; Mattew R. Reese; Thomas Rogers; Michelle I Rossulek; Jean G Sathish; Claire Steppan; Martyn Ticehurst; Lawrence W. Updyke; Yuao Zhu; Jun Wang; Arnab K Chatterjee; Andrew D Mesecar; Annaliesa S. Anderson; Charlotte Allerton

    doi:10.1101/2020.09.12.294066 Date: 2020-09-13 Source: bioRxiv

    Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is currently causing a global pandemic. The antigen specificity and kinetics of the antibody response mounted against this novel virus are not understood in detail. Here, we report that subjects with a more severe SARS-CoV-2 infection MESHD exhibit a larger antibody response against the spike and nucleocapsid protein PROTEIN and epitope spreading to subdominant viral antigens, such as open reading frame 8 and non-structural proteins PROTEIN. Subjects with a greater antibody response mounted a larger memory B cell response against the spike, but not the nucleocapsid protein PROTEIN. Additionally, we revealed that antibodies against the spike are still capable of binding the D614G spike mutant and cross-react with the SARS-CoV-1 receptor binding domain. Together, this study reveals that subjects with a more severe SARS-CoV-2 infection MESHD exhibit a greater overall antibody response to the spike and nucleocapsid protein PROTEIN and a larger memory B cell response against the spike.

    Suppression of MDA5 HGNC-mediated antiviral immune responses by NSP8 PROTEIN of SARS-CoV-2

    Authors: Ziwei Yang; Xiaolin Zhang; Fan Wang; Peihui Wang; Xiaojuan Li; Ersheng Kuang

    doi:10.1101/2020.08.12.247767 Date: 2020-08-12 Source: bioRxiv

    Melanoma differentiation-associated gene-5 HGNC ( MDA5 HGNC) acts as a cytoplasmic RNA sensor to detect viral dsRNA and mediates type I interferon ( IFN HGNC) signaling and antiviral innate immune responses to infection by RNA viruses. Upon recognition of viral dsRNA, MDA5 HGNC is activated with K63-linked polyubiquitination and then triggers the recruitment of MAVS HGNC and activation of TBK1 HGNC and IKK, subsequently leading to IRF3 HGNC and NF-{kappa}B HGNC phosphorylation. Great numbers of symptomatic and severe infections of SARS-CoV-2 MESHD are spreading worldwide, and the poor efficacy of treatment with type I interferon and antiviral agents indicates that SARS-CoV-2 escapes from antiviral immune responses via an unknown mechanism. Here, we report that SARS-CoV-2 nonstructural protein 8 ( NSP8 PROTEIN) acts as an innate immune suppressor and inhibits type I IFN signaling to promote infection of RNA viruses. It downregulates the expression of type I IFNs, IFN HGNC-stimulated genes and proinflammatory cytokines by binding to MDA5 HGNC and impairing its K63-linked polyubiquitination. Our findings reveal that NSP8 PROTEIN mediates innate immune evasion during SARS-CoV-2 infection MESHD and may serve as a potential target for future therapeutics for SARS-CoV-2 infectious diseases MESHD.

    Global variation in the SARS-CoV-2 proteome reveals the mutational hotspots in the drug and vaccine candidates

    Authors: L Ponoop Prasad Patro; Chakkarai Sathyaseelan; Patil Pranita Uttamrao; Thenmalarchelvi Rathinavelan

    doi:10.1101/2020.07.31.230987 Date: 2020-07-31 Source: bioRxiv

    To accelerate the drug and vaccine development against the severe acute respiratory syndrome MESHD virus 2 (SARS-CoV-2), a comparative analysis of SARS-CoV-2 proteome has been performed in two phases by considering manually curated 31389 whole genome sequences from 84 countries. Among the 9 mutations that occur at a high significance (T85I-NPS2, L37F- NSP6 PROTEIN, P323L- NSP12 PROTEIN, D614G-spike, Q57H- ORF3a PROTEIN, G251V- ORF3a PROTEIN, L84S- ORF8 PROTEIN, R203K-nucleocapsid and G204R-nucleocapsid), R203K-nucleocapsid and G204R-nucleocapsid are co-occurring (dependent) mutations and P323L- NSP12 PROTEIN and D614G-spike often appear simultaneously. Other notable variations that appear with a moderate to low significance are, M85- NSP1 HGNC deletion, D268- NSP2 HGNC NSP2 PROTEIN deletion, 112 amino acids deletion in ORF8 PROTEIN, a phenylalanine insertion amidst F34-F36 ( NSP6 PROTEIN) and several co-existing (dependent) substitution/deletion (I559V & P585S in NSP2 HGNC NSP2 PROTEIN, P504L & Y541C in NSP13 PROTEIN, G82 & H83 deletions in NSP1 HGNC and K141, S142 & F143 deletions in NSP2 HGNC NSP2 PROTEIN) mutations. P323L- NSP12 PROTEIN, D614G-spike, L37F- NSP6 PROTEIN, L84S- ORF8 PROTEIN and the sequences deficient of the high significant mutations have led to 4 major SARS-CoV-2 clades. The top 5 countries bearing all the high significant and majority of the moderate significant mutations are: USA, England, Wales, Australia and Scotland. Further, the majority of the significant mutations have evolved in the first phase and have already transmitted around the globe indicating the positive selection pressure. Among the 26 SARS-CoV-2 proteins, nucleocapsid PROTEIN protein, ORF3a PROTEIN, ORF8 PROTEIN, RNA dependent RNA polymerase PROTEIN and spike exhibit a higher heterogeneity compared with the rest of the proteins. However, NSP9 PROTEIN, NSP10 PROTEIN, NSP8 PROTEIN, the envelope protein PROTEIN and NSP4 HGNC NSP4 PROTEIN are highly resistant to mutations and can be exploited for drug/vaccine development.

    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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