Corpus overview


MeSH Disease

HGNC Genes

SARS-CoV-2 proteins

ProteinS (732)

ProteinN (18)

ProteinS1 (17)

NSP5 (10)

ComplexRdRp (9)


SARS-CoV-2 Proteins
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    Analysis of the Role of N-glycosylation in Cell-surface expression, Function and Binding Properties of SARS-CoV-2 receptor ACE2

    Authors: Alberto Brandariz-Nuñez; Raymond R Rowland

    doi:10.1101/2021.05.10.443532 Date: 2021-05-12 Source: bioRxiv

    Human angiotensin I-converting enzyme 2 HGNC ( hACE2 HGNC) is a type-I transmembrane glycoprotein that serves as the major cell entry receptor for SARS-CoV and SARS-CoV-2 MESHD. The viral spike (S) protein PROTEIN is required for attachment to ACE2 HGNC and subsequent virus-host cell membrane fusion. Previous work has demonstrated the presence of N-linked glycans in ACE2 HGNC. N-glycosylation is implicated in many biological activities, including protein folding, protein activity, and cell surface expression of biomolecules. However, the contribution of N-glycosylation to ACE2 HGNC function is poorly understood. Here, we examined the role of N-glycosylation in the activity and localization of two species with different susceptibility to SARS-CoV-2 infection MESHD, porcine ACE2 HGNC (pACE2) and hACE2 HGNC. The elimination of N-glycosylation by tunicamycin (TM) treatment or mutagenesis, showed that N-glycosylation is critical for the proper cell surface expression of ACE2 HGNC but not for its carboxiprotease activity. Furthermore, nonglycosylable ACE2 HGNC localized predominantly in the endoplasmic reticulum (ER) and not at the cell surface. Our data also revealed that binding of SARS-CoV and SARS-CoV-2 S MESHD S protein PROTEIN to porcine or human ACE2 HGNC was not affected by deglycosylation of ACE2 HGNC or S proteins PROTEIN, suggesting that N-glycosylation plays no role in the interaction between SARS coronaviruses and the ACE2 HGNC receptor. Impairment of hACE2 HGNC N-glycosylation decreased cell to cell fusion mediated by SARS-CoV S MESHD S protein PROTEIN but not SARS-CoV-2 S protein PROTEIN. Finally, we found that hACE2 HGNC N-glycosylation is required for an efficient viral entry of SARS-CoV/SARS-CoV-2 S MESHD pseudotyped viruses, which could be the result of low cell surface expression of the deglycosylated ACE2 HGNC receptor.

    Impacts on the structure-function relationship of SARS-CoV-2 spike PROTEIN by B.1.1.7 mutations

    Authors: Tzu-Jing Yang; Pei-Yu Yu; Yuan-Chih Chang; Kang-Hao Liang; Hsian-Cheng Tso; Meng-Ru Ho; Wan-Yu Chen; Hsiu-Ting Lin; Han-Chung Wu; Shang-Te Danny Hsu

    doi:10.1101/2021.05.11.443686 Date: 2021-05-12 Source: bioRxiv

    The UK variant of the severe acute respiratory syndrome coronavirus (SARS-CoV-2) MESHD, known as B.1.1.7, harbors several point mutations and deletions on the spike (s) protein PROTEIN, which potentially alter its structural epitopes to evade host immunity while enhancing host receptor binding. Here we report the cryo-EM structures of the S protein PROTEIN of B.1.1.7 in its apo form and in the receptor ACE2 HGNC-bound form. One or two of the three receptor binding domains (RBDs) were in the open conformation but no fully closed form was observed. In the ACE-bound form, all three RBDs were engaged in receptor binding. The B.1.1.7-specific A570D mutation introduced a salt bridge switch that could modulate the opening and closing of the RBD. Furthermore, the N501Y mutation in the RBD introduced a favorable {pi}-{pi} interaction manifested in enhanced ACE2 HGNC binding affinity. The N501Y mutation abolished the neutralization activity of one of the three potent neutralizing antibodies (nAbs). Cryo-EM showed that the cocktail of other two nAbs simultaneously bound to all three RBDs. Furthermore, the nAb cocktail synergistically neutralized different SARS-CoV-2 pseudovirus strains, including the B.1.1.7.

    Energy Landscape of the SARS-CoV-2 Reveals Extensive Conformational Heterogeneity

    Authors: Ghoncheh Mashayekhi; John Vant; Abhishek Singharoy; Abbas Ourmazd

    doi:10.1101/2021.05.11.443708 Date: 2021-05-12 Source: bioRxiv

    Cryo-electron microscopy (cryo-EM) has produced a number of structural models of the SARS-CoV-2 spike PROTEIN, already prompting biomedical outcomes. However, these reported models and their associated electrostatic potential maps represent an unknown admixture of conformations stemming from the underlying energy landscape of the spike protein PROTEIN. As for any protein, some of the spike's PROTEIN conformational motions are expected to be biophysically relevant, but cannot be interpreted only by static models. Using experimental cryo-EM images, we present the energy landscape of the spike protein PROTEIN conformations, and identify molecular rearrangements along the most-likely conformational path in the vicinity of the open (so called 1RBD-up) state. The resulting global and local atomic refinements reveal larger movements than those expected by comparing the reported 1RBD-up and 1RBD-down cryo-EM models. Here we report greater degrees of "openness MESHD" in global conformations of the 1RBD-up state, not revealed in the single-model interpretations of the density maps, together with conformations that overlap with the reported models. We discover how the glycan shield contributes to the stability of these conformations along the minimum free-energy pathway. A local analysis of seven key binding pockets reveals that six out them, including those for engaging ACE2 HGNC, therapeutic mini-proteins, linoleic acid, two different kinds of antibodies, and protein-glycan interaction sites, switch conformations between their known apo- and holo-conformations, even when the global spike conformation is 1RBD-up. This is reminiscent of a conformational pre-equilibrium. We found only one binding pocket, namely antibody AB-C135 to remain closed along the entire minimum free energy path, suggesting an induced fit mechanism for this enzyme.

    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.

    Structure and mechanism of SARS-CoV-2 Spike PROTEIN SARS-CoV-2 Spike MESHD N679-V687 deletion variant elucidate cell-type specific evolution of viral fitness

    Authors: Kapil Gupta; Christine Toelzer; Maia Kavanagh Williamson; Deborah Shoemark; A. Sofia F. Oliveira; David A Matthews; Abdulaziz Almuqrin; Oskar Staufer; Sathish K.N. Yadav; Ufuk Borucu; Frederic Garzoni; Daniel Fitzgerald; Joachim Spatz; Adrian J Mulholland; Andrew D. Davidson; Christiane Schaffitzel; Imre Berger

    doi:10.1101/2021.05.11.443384 Date: 2021-05-11 Source: bioRxiv

    As the global burden of SARS-CoV-2 infections escalates MESHD, so does the evolution of viral variants which is of particular concern due to their potential for increased transmissibility and pathology. In addition to this entrenched variant diversity in circulation, RNA viruses can also display genetic diversity within single infected hosts with co-existing viral variants evolving differently in distinct cell types. The BriS{Delta} variant, originally identified as a viral subpopulation by passaging SARS-CoV-2 isolate hCoV-19/England/02/2020, comprises in the spike glycoprotein PROTEIN an eight amino-acid deletion encompassing the furin recognition motif and S1/S2 cleavage site. Here, we analyzed the structure, function and molecular dynamics of this variant spike, providing mechanistic insight into how the deletion correlates to viral cell tropism, ACE2 HGNC receptor binding and infectivity, allowing the virus to probe diverse trajectories in distinct cell types to evolve viral fitness MESHD. TeaserSARS-CoV-2 can exploit different cell types to diversify and evolve virus variants distinct in infectivity and structure.

    Antibody Responses After a Single Dose of ChAdOx1 nCoV-19 Vaccine in Healthcare Workers Previously Infected with SARS-CoV-2

    Authors: Sebastian Havervall; Ulrika Marking; Nina Greilert-Norin; Henry Ng; Ann-Christin Salomonsson; Cecilia Hellstrom; Elisa Pin; Kim Blom; Sara Mangsbo; Mia Phillipson; Jonas Klingstrom; Mikael Aberg; Sophia Hober; Peter Nilsson; Charlotte Thalin

    doi:10.1101/2021.05.08.21256866 Date: 2021-05-11 Source: medRxiv

    Background Recent reports demonstrate robust serological responses to a single dose of messenger RNA (mRNA) vaccines in individuals previously infected with SARS-CoV-2. Data on immune responses following a single-dose adenovirus-vectored vaccine expressing the SARS-CoV-2 spike PROTEIN protein (ChAdOx1 nCoV-19) in individuals with previous SARS-CoV-2 infection MESHD are however limited, and current guidelines recommend a two-dose regime regardless of preexisting immunity. Methods We compared spike-specific IgG and pseudo-neutralizing spike- ACE2 HGNC blocking antibodies against SARS-CoV-2 wild type and variants B.1.1.7, B.1.351, and P1 following two doses of the mRNA vaccine BNT162b2 and a single dose of the adenovector vaccine ChAdOx1 nCoV-19 in 232 healthcare workers with and without previous COVID-19 MESHD. Findings The post-vaccine levels of spike-specific IgG and neutralizing antibodies against the SARS-CoV-2 wild type and all three variants of concern were similar or higher in participants receiving a single dose of ChAdOx1 nCoV-19 vaccine post SARS-CoV-2 infection MESHD (both < 11 months post infection (n=37) and [≥] 11 months infection (n=46)) compared to participants who received two doses of BNT162b2 vaccine (n=149). Interpretation Our data support that a single dose ChAdOx1 nCoV-19 vaccine serves as an effective immune booster after priming with natural SARS-CoV-2 infection MESHD up to at least 11 months post infection.

    In-vivo Protection from SARS-CoV-2 infection MESHD by ATN-161 in k18- hACE2 HGNC transgenic mice


    doi:10.1101/2021.05.08.443275 Date: 2021-05-09 Source: bioRxiv

    Severe acute respiratory syndrome coronavirus 2 MESHD (SARS-CoV-2) is an infectious disease MESHD that has spread worldwide. Current treatments are limited in both availability and efficacy, such that improving our understanding of the factors that facilitate infection is urgently needed to more effectively treat infected individuals and to curb the pandemic. We and others have previously demonstrated the significance of interactions between the SARS-CoV-2 spike PROTEIN protein, integrin alpha5beta1 and human ACE2 HGNC to facilitate viral entry into host cells in vitro. We previously found that inhibition of integrin alpha5beta1 by the clinically validated small peptide ATN-161 inhibits these spike protein PROTEIN interactions and cell infection in vitro. In continuation with our previous findings, here we have further evaluated the therapeutic potential of ATN-161 on SARS-CoV-2 infection MESHD in k18- hACE2 HGNC transgenic (SARS-CoV-2 susceptible) mice in vivo. We discovered that treatment with single- or repeated intravenous doses of ATN-161 (1 mg/kg) within 48 hours after intranasal inoculation with SARS-CoV-2 lead to a reduction of lung viral load, viral immunofluorescence and improved lung histology in a majority of mice 72 hours post-infection. Furthermore, ATN-161 reduced SARS-CoV-2-induced increased expression of lung integrin alpha 5 and alpha v (an alpha 5-related integrin that has also been implicated in SARS-CoV-2 interactions) as well as the C-X-C motif chemokine ligand 10 (Cxcl10), further supporting the potential involvement of these integrins, and the anti-inflammatory potential of ATN-161, respectively, in SARS-CoV-2 infection MESHD. To the best of our knowledge, this is the first study demonstrating the potential therapeutic efficacy of targeting integrin alpha5beta1 in SARS-CoV-2 infection MESHD in vivo and supports the development of ATN-161 as a novel SARS-CoV-2 therapy.

    The role of host cell glycans on virus infectivity: The SARS-CoV-2 case


    doi:10.1101/2021.05.08.443212 Date: 2021-05-09 Source: bioRxiv

    Long and complex chains of sugars, called glycans, often coat both the cell and protein surface. Glycans both modulate specific interactions and protect cells. On the cell surface, these sugars form a cushion known as the glycocalyx. Here, we show that Heparan Sulfate (HS) chains - part of the glycocalyx - and other glycans - expressed on the surface of both host and virus proteins - have a critical role in modulating both attractive and repulsive potentials during viral infection. We analyse the SARS-CoV-2 virus, modelling its spike proteins PROTEIN binding to HS chains and two key entry receptors, ACE2 HGNC and TMPRSS2 HGNC. We include the volume exclusion effect imposed on the HS chains impose during virus insertion into glycocalyx and the steric repulsion caused by changes in the conformation of the ACE2 HGNC glycans involved in binding to the spike. We then combine all these interactions, showing that the interplay of all these components is critical to the behaviour of the virus. We show that the virus tropism depends on the combinatorial expression of both HS chains and receptors. Finally, we demonstrate that when both HS chains and entry receptors express at high density, steric effects dominate the interaction, preventing infection.

    SARS-CoV-2 B.1.617 emergence and sensitivity to vaccine-elicited antibodies


    doi:10.1101/2021.05.08.443253 Date: 2021-05-09 Source: bioRxiv

    The B.1.617 variant emerged in the Indian state of Maharashtra in late 2020 and has spread throughout India and to at least 40 countries. There have been fears that two key mutations seen in the receptor binding domain L452R and E484Q would have additive effects on evasion of neutralising antibodies. Here we delineate the phylogenetics of B.1.617 and spike mutation frequencies, in the context of others bearing L452R. The defining mutations in B.1.617.1 spike are L452R and E484Q in the RBD that interacts with ACE2 HGNC and is the target of neutralising antibodies. All B.1.617 viruses have the P681R mutation in the polybasic cleavage site region in spike. We report that B.1.617.1 spike bearing L452R, E484Q and P681R mediates entry into cells with slightly reduced efficiency compared to Wuhan-1. This spike confers modestly reduced sensitivity to BNT162b2 mRNA vaccine-elicited antibodies that is similar in magnitude to the loss of sensitivity conferred by L452R or E484Q alone. Furthermore we show that the P681R mutation significantly augments syncytium formation upon the B.1.617.1 spike protein PROTEIN, potentially contributing to increased pathogenesis observed in hamsters and infection growth MESHD rates observed in humans.

    Evaluation of a multi-species SARS-CoV-2 surrogate virus neutralization test

    Authors: Carmen W.E. Embregts; Babs Verstrepen; Jan A.M. Langermans; Kinga P Boszormenyi; Reina S. Sikkema; Rory D. de Vries; Donata Hoffmann; Kerstin Wernike; Lidwien A.M. Smit; Shan Zhao; Barry Rockx; Marion Koopmans; Bart L. Haagmans; Thijs Kuiken; Corine GeurtsvanKessel

    doi:10.1101/2021.05.07.21252267 Date: 2021-05-07 Source: medRxiv

    Assays to measure SARS-CoV-2-specific neutralizing antibodies are important to monitor seroprevalence, to study asymptomatic infections and to reveal (intermediate) hosts. A recently developed assay, the surrogate virus-neutralization test (sVNT) is a quick and commercially available alternative to the 'gold standard' virus neutralization assay using authentic virus, and does not require processing at BSL-3 level. The assay relies on the inhibition of binding of the receptor binding domain (RBD) on the spike (S) protein PROTEIN to human angiotensin-converting enzyme 2 HGNC ( hACE2 HGNC) by antibodies present in sera. As the sVNT does not require species- or isotype-specific conjugates, it can be similarly used for antibody detection in human and animal sera. In this study, we used 298 sera from PCR-confirmed COVID-19 MESHD patients and 151 sera from patients confirmed with other coronavirus or other (respiratory) infections, to evaluate the performance of the sVNT. To analyze the use of the assay in a One Health setting, we studied the presence of RBD-binding antibodies in 154 sera from nine animal species (cynomolgus and rhesus macaques, ferrets, rabbits, hamsters, cats, cattle, mink and dromedary camels). The sVNT showed a moderate to high sensitivity and a high specificity using sera from confirmed COVID-19 MESHD patients (91.3% and 100%, respectively) and animal sera (93.9% and 100%), however it lacked sensitivity to detect low titers. Significant correlations were found between the sVNT outcomes and PRNT50 and the Wantai total Ig and IgM ELISAs. While species-specific validation will be essential, our results show that the sVNT holds promise in detecting RBD-binding antibodies in multiple species.

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MeSH Disease
HGNC Genes
SARS-CoV-2 Proteins

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