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MeSH Disease

HGNC Genes

SARS-CoV-2 proteins

ProteinS (239)

ProteinN (22)

NSP5 (12)

ORF1ab (6)

ProteinE (4)


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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.

    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.

    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.

    Convergent evolution of SARS-CoV-2 spike PROTEIN mutations, L452R, E484Q and P681R, in the second wave of COVID-19 MESHD in Maharashtra, India

    Authors: Sarah Cherian; Varsha Potdar; Santosh Jadhav; Pragya Yadav; Nivedita Gupta; Mousmi Das; Soumitra Das; Anurag Agarwal; Sujeet Singh; Priya Abraham; Samiran Panda; Shekhar Mande; Renu Swarup; Balram Bhargava; Rajesh Bhushan; - NIC team; - INSACOG Consortium

    doi:10.1101/2021.04.22.440932 Date: 2021-04-24 Source: bioRxiv

    As the global severe acute respiratory syndrome coronavirus 2 MESHD (SARS-CoV-2) pandemic expands, genomic epidemiology and whole genome sequencing are being constantly used to investigate its transmissions and evolution. In the backdrop of the global emergence of variants of concern (VOCs) during December 2020 and an upsurge in a state in the western part of India since January 2021, whole genome sequencing and analysis of spike protein PROTEIN mutations using sequence and structural approaches was undertaken to identify possible new variants and gauge the fitness of current circulating strains. Phylogenetic analysis revealed that the predominant clade in circulation was a distinct newly identified lineage B.1.617 possessing common signature mutations D111D, G142D, L452R, E484Q, D614G and P681R, in the spike protein PROTEIN including within the receptor binding domain (RBD). Of these, the mutations at residue positions 452, 484 and 681 have been reported in other globally circulating lineages. The structural analysis of RBD mutations L452R and E484Q along with P681R in the furin cleavage site, may possibly result in increased ACE2 HGNC binding and rate of S1-S2 cleavage resulting in better transmissibility. The same two RBD mutations indicated decreased binding to selected monoclonal antibodies (mAbs) and may affect their neutralization potential. Experimental validation is warranted for accessing both ACE2 HGNC binding and the effectiveness of commonly elicited neutralizing mAbs for the strains of lineage B.1.617. The emergence of such local variants through the accumulation of convergent mutations during the COVID-19 MESHD second wave needs to be further investigated for their public health impact in the rest of the country and its possibility of becoming a VOC.

    SARS-CoV-2 natural antibody response persists up to 12 months in a nationwide study from the Faroe Islands

    Authors: Maria Skaalum Petersen; Cecilie Bo Hansen; Marnar Fridheim Kristiansen; Jogvan Pall Fjallsbak; Solrun Larsen; Johanna Ljosa Hansen; Ida Jarlhelt; Laura Perez Alos; Bjarni a Steig; Debes Hammershaimb Christiansen; Lars Fodgaard Moller; Marin Strom; Gudrid Andorsdottir; Shahin Gaini; Pal Weihe; Peter Garred

    doi:10.1101/2021.04.19.21255720 Date: 2021-04-22 Source: medRxiv

    Only a few studies have assessed the long-term duration of the humoral immune response against severe acute respiratory syndrome coronavirus 2 MESHD (SARS-CoV-2). In this nationwide longitudinal study from the Faroe Islands with close to full participation of all individuals on the Islands with PCR confirmed COVID-19 MESHD during the two waves of infections in the spring and autumn 2020 (n=172 & n=233), samples were drawn at three longitudinal time points (3, 7 and 12 months and 1, 3 and 7 months after disease onset, respectively). Serum was analyzed with a direct quantitative IgG antibody binding ELISA to detect anti- SARS-CoV-2 spike PROTEIN RBD antibodies and a commercially available qualitative sandwich RBD ELISA kit measuring total antibody binding. The seropositive rate in the convalescent individuals was above 95 % at all sampling time points for both assays. There was an overall decline in IgG titers over time in both waves (p < 0.001). Pairwise comparison showed that IgG declined significantly from the first sample until approximately 7 months in both waves (p < 0.001). After that, the antibody level still declined significantly (p < 0.001), but decelerated with an altered slope remaining fairly stable from 7 months to 12 months after infection. Interestingly, the IgG titers followed a U-shaped curve with higher antibody levels among the oldest (67+) and the youngest (0-17) age groups compared to intermediate groups (p < 0.001). Our results indicate that COVID-19 MESHD convalescent individuals are likely to be protected from reinfection at least 12 months after symptom onset and maybe even longer. We believe our results can add to the understanding of natural immunity and the expected durability of SARS-CoV-2 vaccine immune responses.

    Structural basis for enhanced infectivity and immune evasion of SARS-CoV-2 variants

    Authors: Christy L. Lavine; Shaun Rawson; Haisun Zhu; Krishna Anand; Pei Tong; Avneesh Gautam; Shen Lu; Sarah Sterling; Richard M Walsh Jr.; Jianming Lu; Wei Yang; Michael S Seaman

    doi:10.1101/2021.04.13.439709 Date: 2021-04-14 Source: bioRxiv

    Several fast-spreading variants of severe acute respiratory syndrome coronavirus 2 MESHD (SARS-CoV-2) have become the dominant circulating strains that continue to fuel the COVID-19 pandemic MESHD despite intensive vaccination efforts throughout the world. We report here cryo-EM structures of the full-length spike (S) trimers of the B.1.1.7 and B.1.351 variants, as well as their biochemical and antigenic properties. Mutations in the B.1.1.7 protein increase the accessibility of its receptor binding domain and also the binding affinity for receptor angiotensin-converting enzyme 2 HGNC ( ACE2 HGNC). The enhanced receptor engagement can account for the increased transmissibility and risk of mortality as the variant may begin to infect efficiently infect MESHD additional cell types expressing low levels of ACE2 HGNC. The B.1.351 variant has evolved to reshape antigenic surfaces of the major neutralizing sites on the S protein PROTEIN, rendering complete resistance to some potent neutralizing antibodies. These findings provide structural details on how the wide spread of SARS-CoV-2 enables rapid evolution to enhance viral fitness MESHD and immune evasion. They may guide intervention strategies to control the pandemic.

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MeSH Disease
HGNC Genes
SARS-CoV-2 Proteins


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