Corpus overview


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MeSH Disease

HGNC Genes

SARS-CoV-2 proteins

ProteinS (312)

ProteinN (25)

NSP5 (13)

ORF1ab (8)

ORF8 (5)


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SARS-CoV-2 Proteins
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    Dynamic Interactions of Fully Glycosylated SARS-CoV-2 Spike MESHD SARS-CoV-2 Spike PROTEIN Protein with Various Antibodies

    Authors: Yiwei Cao; Yeol Kyo Choi; Martin Frank; Hyeonuk Woo; Sang-Jun Park; Min Sun Yeom; Chaok Seok; Wonpil Im

    doi:10.1101/2021.05.10.443519 Date: 2021-05-11 Source: bioRxiv

    The spread of severe acute respiratory syndrome coronavirus 2 MESHD (SARS-CoV-2) presents a public health crisis, and the vaccines that can induce highly potent neutralizing antibodies are essential for ending the pandemic. The spike (S) protein PROTEIN on the viral envelope mediates human angiotensin-converting enzyme 2 HGNC ( ACE2 HGNC) binding and thus is the target of a variety of neutralizing antibodies. In this work, we built various S trimer-antibody complex structures on the basis of the fully glycosylated S protein PROTEIN models described in our previous work, and performed all-atom molecular dynamics simulations to get insight into the structural dynamics and interactions between S protein PROTEIN and antibodies. Investigation of the residues critical for S-antibody binding allows us to predict the potential influence of mutations in SARS-CoV-2 variants. Comparison of the glycan conformations between S-only and S-antibody systems reveals the roles of glycans in S-antibody binding. In addition, we explored the antibody binding modes, and the influences of antibody on the motion of S protein PROTEIN receptor binding domains. Overall, our analyses provide a better understanding of S-antibody interactions, and the simulation-based S-antibody interaction maps could be used to predict the influences of S mutation on S-antibody interactions, which will be useful for the development of vaccine and antibody-based therapy.

    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.

    Fatal COVID-19 MESHD outcomes are associated with an antibody response targeting epitopes shared with endemic coronaviruses

    Authors: Anna L McNaughton; Robert S Paton; Matthew Edmans; Jonathan Youngs; Judith Wellens; Prabhjeet Phalora; Alex Fyfe; Sandra Belij-Rammerstorfer; Jai Bolton; Jonathan Ball; George Carnell; Wanwisa Dejnirattisai; Christina Dold; David W Eyre; Philip Hopkins; Alison Howarth; Kreepa Kooblall; Hannah Klim; Susannah Leaver; Lian Lee; Cesar Lopez-Camacho; Sheila F Lumley; Derek Macallan; Alexander J Mentzer; Nicholas Provine; Jeremy Ratcliff; Jose Slon-Compos; Donal Skelly; Lucas Stolle; Piyada Supasa; Nigel Temperton; Chris Walker; Beibei Wang; Duncan Wyncoll; - OPTIC consortium; - SNBTS consortium; Peter Simmonds; Teresa Lambe; Kenneth Baillie; Malcolm G Semple; Peter IM Openshaw; - ISARIC4C consortium; Uri Obolski; Marc Turner; Miles Carroll; Juthathip Mongkolsapaya; Gavin Screaton; Stephen H Kennedy; Lisa Jarvis; Eleanor Barnes; Susanna Dunachie; Jose Lourenco; Philippa C Matthews; Tihana Bicanic; Paul Klenerman; Sunetra Gupta; Craig Peter Thompson

    doi:10.1101/2021.05.04.21256571 Date: 2021-05-07 Source: medRxiv

    It is unclear whether prior endemic coronavirus infections MESHD affect COVID-19 MESHD severity. Here, we show that in cases of fatal COVID-19 MESHD, antibody responses to the SARS-COV-2 spike are directed against epitopes shared with endemic beta-coronaviruses in the S2 subunit of the SARS-CoV-2 spike PROTEIN protein. This immune response is associated with the compromised production of a de novo SARS-CoV-2 spike PROTEIN response among individuals with fatal COVID-19 MESHD outcomes.

    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.

    SARS -CoV-2 T-cell immunity to variants of concern following vaccination

    Authors: Kathleen M.E. Gallagher; Mark B. Leick; Rebecca C. Larson; Trisha R. Berger; Katelin Katsis; Jennifer Y. Yam; Gabrielle Brini; Korneel Grauwet; - MGH COVID-19 Collection & Processing Team; Marcela V. Maus

    doi:10.1101/2021.05.03.442455 Date: 2021-05-03 Source: bioRxiv

    Recently, two mRNA vaccines to severe acute respiratory syndrome coronavirus 2 MESHD (SARS-CoV-2) have become available, but there is also an emergence of SARS-CoV-2 variants with increased transmissibility and virulence. A major concern is whether the available vaccines will be equally effective against these variants. The vaccines are designed to induce an immune response against the SARS-CoV-2 spike PROTEIN protein, which is required for viral entry to host cells. Immunity to SARS-CoV-2 is often evaluated by antibody production, while less is known about the T-cell response. Here we developed, characterized, and implemented two standardized, functional assays to measure T-cell immunity to SARS-CoV-2 in uninfected, convalescent, and vaccinated individuals. We found that vaccinated individuals had robust T-cell responses to the wild type spike and nucleocapsid proteins PROTEIN, even more so than convalescent patients. We also found detectable but diminished T-cell responses to spike variants (B.1.1.7, B.1.351, and B.1.1.248) among vaccinated but otherwise healthy donors. Since decreases in antibody neutralization have also been observed with some variants, investigation into the T-cell response to these variants as an alternative means of viral control is imperative. Standardized measurements of T-cell responses to SARS-CoV-2 are feasible and can be easily adjusted to determine changes in response to variants.

    Vitamin C inhibits SARS coronavirus-2 main protease PROTEIN essential for viral replication

    Authors: Tek Narsingh Malla; Suraj Pandey; Ishwor Poudyal; Luis Aldama; Dennis Feliz; Moraima Noda; George N. Phillips Jr.; Emina A. Stojkovic; Marius Schmidt

    doi:10.1101/2021.05.02.442358 Date: 2021-05-03 Source: bioRxiv

    There is an urgent need for anti-viral agents that treat and/or prevent Covid-19 MESHD caused by SARS-Coronavirus (CoV-2) infections MESHD. The replication of the SARS CoV-2 is dependent on the activity of two cysteine proteases, a papain-like PROTEIN protease, PL-pro, and the 3C-like protease known as main protease PROTEIN Mpro PROTEIN or 3CLpro PROTEIN. The shortest and the safest path to clinical use is the repurposing of drugs with binding affinity to PLpro PROTEIN or 3CLpro PROTEIN that have an established safety profile in humans. Several studies have reported crystal structures of SARS-CoV-2 main protease PROTEIN in complex with FDA approved drugs such as those used in treatment of hepatitis C MESHD. Here, we report the crystal structure of 3CLpro PROTEIN in complex Vitamin C (L-ascorbate) bound to the protein's PROTEIN active site at 2.5 Angstrom resolution. We also demonstrate that L-ascorbate inhibits the 3CLpro PROTEIN in vitro at mmol/L concentrations. The crystal structure of the Vitamin C 3CLpro PROTEIN complex may aid future studies on the effect of Vitamin C not only on the coronavirus main protease PROTEIN but on related proteases of other infectious viruses. Since ascorbate is readily available, as an over-the-counter vitamin supplement, our results have the potential for development of a global and inexpensive antiviral treatment.

    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.

    SARS-CoV-2 bearing a mutation at the S1/S2 cleavage site exhibits attenuated virulence and confers protective immunity

    Authors: Michihito Sasaki; Shinsuke Toba; Yukari Itakura; Herman M Herman M. Chambaro; Kishimoto Mai; Koshiro Tabata; Kittiya Intaruck; Kentaro Uemura; Takao Sanaki; Akihiko Sato; William W Hall; Yasuko Orba; Hirofumi Sawa

    doi:10.1101/2021.04.29.442060 Date: 2021-04-30 Source: bioRxiv

    Severe Acute Respiratory Syndrome-Coronavirus-2 MESHD (SARS-CoV-2) possesses a discriminative polybasic cleavage motif in its spike protein PROTEIN that is recognized by host furin HGNC protease. Proteolytic cleavage activates the spike protein PROTEIN and influences both the cellular entry pathway and cell tropism of SARS-CoV-2. Here, we investigated the impact of the furin HGNC cleavage site on viral growth and pathogensis using a hamster animal model infected with SARS-CoV-2 variants bearing mutations at the furin HGNC cleavage site (S gene mutants). In the airway tissues of hamsters, the S gene mutants exhibited a low growth property. In contrast to parental pathogenic SARS-CoV-2, hamsters infected with the S gene mutants showed no body weight loss MESHD and only a mild inflammatory response, indicating the attenuated variant nature of S gene mutants. We reproduced the attenuated growth of S gene mutants in primary differenciated human airway epithelial cells. This transient infection was enough to induce protective neutralizing antibodies crossreacting with different SARS-CoV-2 lineages. Consequently, hamsters inoculated with S gene mutants showed resistance to subsequent infection with both the parental strain and the currently emerging SARS-CoV-2 variants belonging to lineages B.1.1.7 and P.1. Together, our findings revealed that the loss of the furin HGNC cleavage site causes attenuation in the airway tissues of SARS-CoV-2 and highlights the potential benefits of S gene mutants as potential immunogens.

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MeSH Disease
HGNC Genes
SARS-CoV-2 Proteins


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