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MeSH Disease

HGNC Genes

SARS-CoV-2 proteins

ProteinS (117)

ProteinN (9)

ORF8 (5)

ProteinE (3)

ORF1ab (3)


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SARS-CoV-2 Proteins
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    Estimated Spike Evolution and Impact of Emerging SARS-CoV-2 MESHD Variants

    Authors: Yong Lu; Kun Han; Gang Xue; Ningbo Zheng; Guangxu Jin

    doi:10.1101/2021.05.06.21256705 Date: 2021-05-10 Source: medRxiv

    The severe acute respiratory syndrome coronavirus 2 MESHD (SARS-CoV-2), the virus that causes COVID-19 MESHD, has been mutating and thus variants emerged. This suggests that SARS-CoV-2 could mutate at an unsteady pace. Supportive evidence comes from the accelerated evolution which was revealed by tracking mutation rates of the genomic location of Spike protein PROTEIN. This process is sponsored by a small portion of the virus population but not the largest viral clades. Moreover, it generally took one to six months for current variants that caused peaks of COVID-19 MESHD cases and deaths to survive selection pressure. Based on this statistic result and the above speedy Spike evolution, another upcoming peak would come around July 2021 and disastrously attack Africa, Asia, Europe, and North America. This is the prediction generated by a mathematical model on evolutionary spread. The reliability of this model and future trends out of it comes from the comprehensive consideration of factors mainly including mutation rate, selection course, and spreading speed. Notably, if the prophecy is true, then the new wave will be the first determined by accelerated Spike evolution.

    A novel class of TMPRSS2 HGNC inhibitors potently block SARS-CoV-2 and MERS-CoV viral entry and protect human epithelial lung cells

    Authors:

    doi:10.1101/2021.05.06.442935 Date: 2021-05-06 Source: bioRxiv

    The host cell serine protease TMPRSS2 HGNC is an attractive therapeutic target for COVID-19 MESHD drug discovery. This protease activates the Spike protein PROTEIN of Severe Acute Respiratory Syndrome Coronavirus 2 MESHD (SARS-CoV-2) and of other coronaviruses and is essential for viral spread in the lung. Utilizing rational structure-based drug design (SBDD) coupled to substrate specificity screening of TMPRSS2 HGNC, we have discovered a novel class of small molecule ketobenzothiazole TMPRSS2 HGNC inhibitors with significantly improved activity over existing irreversible inhibitors Camostat and Nafamostat. Lead compound MM3122 (4) has an IC50 of 340 pM against recombinant full-length TMPRSS2 HGNC protein, an EC50 of 430 pM in blocking host cell entry into Calu-3 human lung epithelial cells of a newly developed VSV SARS-CoV-2 MESHD chimeric virus, and an EC50 of 74 nM in inhibiting cytopathic effects induced by SARS-CoV-2 virus in Calu-3 cells. Further, MM3122 blocks Middle East Respiratory Syndrome Coronavirus (MERS-CoV) cell entry MESHD with an EC50 of 870 pM. MM3122 has excellent metabolic stability, safety, and pharmacokinetics in mice with a half-life of 8.6 hours in plasma and 7.5 h in lung tissue, making it suitable for in vivo efficacy evaluation and a promising drug candidate for COVID-19 MESHD treatment.

    Uncovering cryptic pockets in the SARS-CoV-2 spike PROTEIN glycoprotein

    Authors: Lorena Zuzic; Firdaus Samsudin; Aishwary Tukaram Shivgan; Palur V Raghuvamsi; Jan K Marzinek; Alister Boags; Conrado Pedebos; Nikhil Kumar Tulsian; Jim Warwicker; Paul MacAry; Max Crispin; Syma Khalid; Ganesh S Anand; Peter J Bond

    doi:10.1101/2021.05.05.442536 Date: 2021-05-05 Source: bioRxiv

    The recent global COVID-19 pandemic MESHD has prompted a rapid response in terms of vaccine and drug development targeting the viral pathogen, severe acute respiratory syndrome coronavirus 2 MESHD (SARS-CoV-2). In this work, we modelled a complete membrane-embedded SARS-CoV-2 spike PROTEIN SARS-CoV-2 spike MESHD ( S) protein PROTEIN, the primary target of vaccine and therapeutics development, based on available structural data and known glycan content. We then used molecular dynamics ( MD MESHD) simulations to study the system in the presence of benzene probes designed to enhance discovery of cryptic, potentially druggable pockets on the S protein PROTEIN surface. We uncovered a novel cryptic pocket with promising druggable properties located underneath the 617-628 loop, which was shown to be involved in the formation of S protein PROTEIN multimers on the viral surface. A marked multi-conformational behaviour of this loop in simulations was validated using hydrogen-deuterium exchange mass spectrometry (HDX-MS) experiments, supportive of opening and closing dynamics. Interestingly, the pocket is also the site of the D614G mutation, known to be important for SARS-CoV-2 fitness MESHD, and within close proximity to mutations in the novel SARS-CoV-2 strains B.1.1.7 and B.1.1.28, both of which are associated with increased transmissibility and severity of infection. The pocket was present in systems emulating both immature and mature glycosylation states, suggesting its druggability may not be dependent upon the stage of virus maturation. Overall, the predominantly hydrophobic nature of the cryptic pocket, its well conserved surface, and proximity to regions of functional relevance in viral assembly and fitness MESHD are all promising indicators of its potential for therapeutic targeting. Our method also successfully recapitulated hydrophobic pockets in the receptor binding domain and N-terminal domain associated with detergent or lipid binding in prior cryo-electron microscopy (cryo-EM) studies. Collectively, this work highlights the utility of the benzene mapping approach in uncovering potential druggable sites on the surface of SARS-CoV-2 targets.

    SARS-CoV-2 spike PROTEIN protein induces brain pericyte immunoreactivity in absence of productive viral infection

    Authors: Rayan Khaddaj-Mallat; Natija Aldib; Anne-Sophie Paquette; Aymeric Ferreira; Sarah Lecordier; Maxime Bernard; Armen Saghatelyan; Ayman ElAli

    doi:10.1101/2021.04.30.442194 Date: 2021-05-03 Source: bioRxiv

    COVID-19 MESHD is a respiratory disease MESHD caused by severe acute respiratory syndrome coronavirus-2 MESHD (SARS-CoV-2). COVID-19 MESHD pathogenesis causes vascular-mediated neurological disorders MESHD via still elusive mechanisms. SARS-CoV-2 infects host MESHD cells by binding to angiotensin-converting enzyme 2 HGNC (ACE2), a transmembrane receptor that recognizes the viral spike (S) protein PROTEIN. Brain pericytes were recently shown to express ACE2 at the neurovascular interface, outlining their possible implication in microvasculature injury MESHD in COVID-19 MESHD. Yet, pericyte responses to SARS-CoV-2 is still to be fully elucidated. Using cell-based assays, we report that ACE2 HGNC expression in human brain vascular pericytes is highly dynamic and is increased upon S protein PROTEIN stimulation. Pericytes exposed to S protein PROTEIN underwent profound phenotypic changes translated by increased expression of contractile and myofibrogenic proteins, namely -smooth muscle actin (- SMA HGNC), fibronectin HGNC, collagen I, and neurogenic locus notch homolog protein-3 HGNC ( NOTCH3 HGNC). These changes were associated to an altered intracellular calcium (Ca2+) dynamic. Furthermore, S protein PROTEIN induced lipid peroxidation, oxidative and nitrosative stress in pericytes as well as triggered an immune reaction translated by activation of nuclear factor-kappa-B ( NF-{kappa}B HGNC) signalling pathway, which was potentiated by hypoxia MESHD, a condition associated to vascular comorbidities, which exacerbate COVID-19 MESHD pathogenesis. S protein PROTEIN exposure combined to hypoxia MESHD enhanced the production of pro-inflammatory cytokines involved in immune cell activation and trafficking, namely interleukin-8 HGNC ( IL-8 HGNC), IL-18 HGNC, macrophage migration inhibitory factor HGNC ( MIF HGNC), and stromal cell-derived factor-1 HGNC ( SDF-1 HGNC). Finally, we found that S protein PROTEIN could reach the mouse brain via the intranasal route and that reactive ACE2-expressing pericytes are recruited to the damaged tissue undergoing fibrotic scarring in a mouse model of cerebral multifocal micro-occlusions, a main reported vascular-mediated neurological condition associated to COVID-19 MESHD. Our data demonstrate that the released S protein PROTEIN is sufficient to mediate pericyte immunoreactivity, which may contribute to microvasculature injury MESHD in absence of a productive viral infection MESHD. Our study provides a better understanding for the possible mechanisms underlying cerebrovascular disorders MESHD in COVID-19 MESHD, paving the way to develop new therapeutic interventions.

    Original antigenic sin responses to heterologous Betacoronavirus spike proteins PROTEIN are observed in mice following intramuscular administration, but are not apparent in children following SARS-CoV-2 infection MESHD

    Authors: Stacey A. Lapp; Venkata Viswanadh Edara; Austin Lu; Lilin Lai; Laila Hussaini; Ann Chahroudi; Larry J. Anderson; Mehul S. Suthar; Evan J. Anderson; Christina A. Rostad

    doi:10.1101/2021.04.29.21256344 Date: 2021-04-30 Source: medRxiv

    Background: The effects of pre-existing endemic human coronavirus (HCoV) immunity on SARS-CoV-2 serologic and clinical responses are incompletely understood. Objectives: We sought to determine the effects of prior exposure to HCoV Betacoronavirus HKU1 spike MESHD spike protein PROTEIN on serologic responses to SARS-CoV-2 spike PROTEIN protein after intramuscular administration in mice. We also sought to understand the baseline seroprevalence of HKU1 spike antibodies in healthy children and to measure their correlation with SARS-CoV-2 binding and neutralizing antibodies in children hospitalized with acute coronavirus disease MESHD coronavirus disease 2019 MESHD ( COVID-19 MESHD) or multisystem inflammatory syndrome MESHD ( MIS-C MESHD). Methods: Groups of 5 mice were injected intramuscularly with two doses of alum-adjuvanted HKU1 spike followed by SARS-CoV-2 spike PROTEIN; or the reciprocal regimen of SARS-Cov-2 spike followed by HKU1 spike. Sera collected 21 days following each injection was analyzed for IgG antibodies to HKU1 spike, SARS-CoV-2 PROTEIN SARS-CoV-2 spike MESHD spike, and SARS-CoV-2 PROTEIN neutralization. Sera from children hospitalized with acute COVID-19 MESHD, MIS-C or healthy controls (n=14 per group) were analyzed for these same antibodies. Results: Mice primed with SARS-CoV-2 spike PROTEIN SARS-CoV-2 spike MESHD and boosted with HKU1 spike developed high titers of SARS-CoV-2 binding and neutralizing antibodies; however, mice primed with HKU1 spike and boosted with SARS-CoV-2 spike PROTEIN were unable to mount neutralizing antibodies to SARS-CoV-2. HKU1 spike antibodies were detected in all children with acute COVID-19 MESHD, MIS-C, and healthy controls. Although children with MIS-C had significantly higher HKU1 spike titers than healthy children (GMT 37239 vs. 7551, P=0.012), these titers correlated positively with both SARS-CoV-2 binding (r=0.7577, P<0.001) and neutralizing (r=0.6201, P=0.001) antibodies. Conclusions: Prior murine exposure to HKU1 spike protein PROTEIN completely impeded the development of neutralizing antibodies to SARS-CoV-2, consistent with original antigenic sin. In contrast, the presence of HKU1 spike IgG antibodies in children with acute COVID-19 MESHD or MIS-C was not associated with diminished neutralizing antibody responses to SARS-CoV-2.

    Local emergence and decline of a SARS-CoV-2 variant with mutations L452R and N501Y in the spike protein PROTEIN

    Authors: Jan-Philipp Mallm; Christian Bundschuh; Heeyoung Kim; Niklas Weidner; Simon Steiger; Isabelle Lander; Kathleen Börner; Katharina Bauer; Daniel Hübschmann; Vladimir Benes; Tobias Rausch; Nayara Trevisan Doimo de Azevedo; Anja Telzerow; Katharina Laurence Jost; Sylvia Parthé; Paul Schnitzler; Michael Boutros; Barbara Müller; Ralf Bartenschlager; Hans-Georg Kräusslich; Karsten Rippe

    doi:10.1101/2021.04.27.21254849 Date: 2021-04-29 Source: medRxiv

    Variants of severe acute respiratory syndrome coronavirus 2 MESHD (SARS-CoV-2) are replacing the initial wild-type strain, jeopardizing current efforts to contain the pandemic. Amino acid exchanges in the spike protein PROTEIN are of particular concern as they can render the virus more transmissible or reduce vaccine efficacy. Here, we conducted whole genome sequencing of SARS-CoV MESHD 2 positive samples from the Rhine-Neckar district in Germany during January-March 2021. We detected a total of 166 samples positive for a variant with a distinct mutational pattern in the spike gene comprising L18F, L452R, N501Y, A653V, H655Y, D796Y and G1219V with a later gain of A222V. This variant was designated A.27.RN according to its phylogenetic clade classification. It emerged in parallel with the B.1.1.7 variant, increased to >50% of all SARS-CoV-2 variants by week five. Subsequently it decreased to <10% of all variants by calendar week eight when B.1.1.7 had become the dominant strain. Antibodies induced by BNT162b2 vaccination neutralized A.27.RN but with a two-to-threefold reduced efficacy as compared to the wild-type and B.1.1.7 strains. These observations strongly argue for continuous and comprehensive monitoring of SARS CoV MESHD 2 evolution on a population level.

    Predicted structural mimicry of spike receptor-binding motifs from highly pathogenic human coronaviruses

    Authors: Christopher A Beaudoin; Arian Rokkum Jamasb; Ali Alsulami; Liviu Copoiu; Andries J van Tonder; Sharif Hala; Bridget P Bannerman; Sherine E Thomas; Sundeep Chaitanya Vedithi; Pedro H M Torres; Tom L Blundell

    doi:10.1101/2021.04.23.441187 Date: 2021-04-26 Source: bioRxiv

    Viruses often encode proteins that mimic host proteins in order to facilitate infection. Little work has been done to understand the potential mimicry of the SARS-CoV-2, SARS-CoV MESHD, and MERS-CoV spike proteins MESHD spike proteins PROTEIN, particularly the receptor-binding motifs, which could be important in determining tropism of the virus. Here, we use structural bioinformatics software to characterize potential mimicry of the three coronavirus spike protein PROTEIN receptor-binding motifs. We utilize sequence-independent alignment tools to compare structurally known or predicted three-dimensional protein models with the receptor-binding motifs and verify potential mimicry with protein docking simulations. Both human and non-human proteins were found to be similar to all three receptor-binding motifs. Similarity to human proteins may reveal which pathways the spike protein PROTEIN is co-opting, while analogous non-human proteins may indicate shared host interaction partners and overlapping antibody cross-reactivity. These findings can help guide experimental efforts to further understand potential interactions between human and coronavirus proteins.

    Inferring the stabilization effects of SARS-CoV-2 variants on the binding with ACE2 HGNC receptor

    Authors: Mattia Miotto; Lorenzo Di Rienzo; Giorgio Gosti; Leonardo Bo; Giacomo Parisi; Roberta Piacentini; Alberto Boffi; Giancarlo Ruocco; Edoardo Milanetti

    doi:10.1101/2021.04.18.440345 Date: 2021-04-19 Source: bioRxiv

    With the progression of the SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2 MESHD) pandemic, several variants of the virus are emerging with mutations distributed all over the viral sequence. While most of them are expected to have little to no effects at the phenotype level, some of these variants presenting specific mutations on the Spike protein PROTEIN are rapidly spreading, making urgent the need of characterizing their effects on phenotype features like contagiousness and antigenicity. With this aim, we performed extensive molecular dynamics simulations on a selected set of possible Spike variants in order to assess the stabilizing effect of particular amino acid substitutions, with a special focus on the mutations that are both characteristic of the top three most worrying variants at the moment, i.e the English, South African and Amazonian ones, and that occur at the molecular interface between SARS-CoV-2 Spike PROTEIN SARS-CoV-2 Spike MESHD protein and its human ACE2 receptor. We characterize these variants' effect in terms of (i) residues mobility, (ii) compactness, studying the network of interactions at the interface, and (iii) variation of shape complementarity via expanding the molecular surfaces in the Zernike basis. Overall, our analyses highlighted greater stability of the three variant complexes with respect to both the wild type and two negative control systems, especially for the English and Amazonian variants. In addition, in the three variants, we investigate the effects a not-yet observed mutation in position 501 could provoke on complex stability. We found that a phenylalanine mutation behaves similarly to the English variant and may cooperate in further increasing the stability of the South African one, hinting at the need for careful surveillance for the emergence of such kind of mutations in the population. Ultimately, we show that the observables we propose describe key features for the stability of the ACE2 HGNC-spike complex and can help to monitor further possible spike variants.

    Epitope classification and RBD binding properties of neutralizing antibodies against SARS-CoV-2 variants of concern

    Authors: Ashlesha Deshpande; Bethany D. Harris; Luis Martinez-Sobrido; James J. Kobie; Mark R Walter

    doi:10.1101/2021.04.13.439681 Date: 2021-04-13 Source: bioRxiv

    Severe acute respiratory syndrome coronavirus-2 MESHD (SAR-CoV-2) causes coronavirus disease 2019 MESHD ( COVID19 MESHD) that is responsible for short and long-term disease, as well as death, in susceptible hosts. The receptor binding domain (RBD) of the SARS-CoV-2 Spike MESHD SARS-CoV-2 Spike PROTEIN ( S) protein PROTEIN binds to cell surface angiotensin converting enzyme type-II ( ACE2 HGNC) to initiate viral attachment and ultimately viral pathogenesis. The SARS-CoV-2 S RBD MESHD is a major target of neutralizing antibodies (NAbs) that block RBD - ACE2 HGNC interactions. In this report, NAb-RBD binding epitopes in the protein databank were classified as C1, C1D, C2, C3, or C4 HGNC, using a RBD binding profile (BP), based on NAb-specific RBD buried surface area and used to predict the binding epitopes of a series of uncharacterized NAbs. Naturally occurring SARS-CoV-2 RBD sequence variation was also quantified to predict NAb binding sensitivities to the RBD-variants. NAb and ACE2 HGNC binding studies confirmed the NAb classifications and determined whether the RBD variants enhanced ACE2 HGNC binding to promote viral infectivity, and/or disrupted NAb binding to evade the host immune response. Of 9 single RBD mutants evaluated, K417T, E484K, and N501Y disrupted binding of 65% of the NAbs evaluated, consistent with the assignment of the SARS-CoV-2 P.1 Japan/Brazil strain as a variant of concern (VoC). RBD variants E484K and N501Y exhibited ACE2 HGNC binding equivalent to a Wuhan-1 reference SARS-CoV-2 RBD. While slightly less disruptive to NAb binding, L452R enhanced ACE2 HGNC binding affinity. Thus, the L452R mutant, associated with the SARS-CoV-2 California VoC MESHD (B.1.427/B.1.429-California), has evolved to enhance ACE2 HGNC binding, while simultaneously disrupting C1 and C2 NAb classes. The analysis also identified a non-overlapping antibody pair (1213H7 and 1215D1) that bound to all SARS-CoV-2 RBD variants evaluated, representing an excellent therapeutic option for treatment of SARS-CoV-2 WT MESHD and VoC strains.

    Impairment of SARS-CoV-2 spike PROTEIN glycoprotein maturation and fusion activity by the broad-spectrum anti-infective drug nitazoxanide

    Authors: Anna Riccio; Silvia Santopolo; Antonio Rossi; Sara Piacentini; Jean-Francois Rossignol; Maria Gabriella Santoro

    doi:10.1101/2021.04.12.439201 Date: 2021-04-12 Source: bioRxiv

    The emergence of the highly-pathogenic severe acute respiratory syndrome coronavirus-2 MESHD (SARS-CoV-2), the causative agent of COVID-19 MESHD (coronavirus disease-2019), has caused an unprecedented global health crisis, as well as societal and economic disruption. The SARS-CoV-2 spike MESHD SARS-CoV-2 spike PROTEIN (S), a surface-anchored trimeric class-I fusion glycoprotein essential for entry into host cells, represents a key target for developing vaccines and therapeutics capable of blocking virus invasion. The emergence of several SARS-CoV-2 spike PROTEIN variants that facilitate virus spread and may affect the efficacy of recently developed vaccines, creates great concern and highlights the importance of identifying antiviral drugs to reduce SARS-CoV-2-related morbidity and mortality. Nitazoxanide, a thiazolide originally developed as an antiprotozoal agent with recognized broad-spectrum antiviral activity in-vitro and in clinical studies, was recently shown to be effective against several coronaviruses, including SARS-CoV-2. Using biochemical and pseudovirus entry assays, we now demonstrate that nitazoxanide interferes with the SARS-CoV-2 spike PROTEIN biogenesis, hampering its maturation at an endoglycosidase H-sensitive stage, and hindering its fusion activity in human cells. Besides membrane fusion during virus entry, SARS-CoV-2 S-proteins MESHD S-proteins PROTEIN in infected cells can also trigger receptor-dependent formation of syncytia, observed in-vitro and in COVID-19 MESHD patients tissues, facilitating viral dissemination between cells and possibly promoting immune evasion. Utilizing two different quantitative cell-cell fusion assays, we show that nitazoxanide is effective in inhibiting syncytia formation mediated by different SARS-CoV-2 spike PROTEIN variants in human lung, liver and intestinal cells. The results suggest that nitazoxanide may represent a useful tool in the fight against COVID-19 MESHD infections, inhibiting SARS-CoV-2 replication and preventing spike-mediated syncytia formation.

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MeSH Disease
HGNC Genes
SARS-CoV-2 Proteins


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