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    SARS-CoV-2 comprehensive receptor profiling: mechanistic insight to drive new therapeutic strategies

    Authors: Sarah MV Brockbank; Raquel Faba-Rodriguez; Lyn Rosenbrier Ribeiro; Catherine Geh; Helen Thomas; Jenni Delight; Lucy Coverley; W Mark Abbott; Jo Soden; Jim Freeth

    doi:10.1101/2021.03.11.434937 Date: 2021-03-11 Source: bioRxiv

    Here we describe a hypothesis free approach to screen for interactions of SARS-CoV-2 spike MESHD SARS-CoV-2 spike PROTEIN ( S) protein PROTEIN with human cell surface receptors. We used a library screening approach to detect binding interactions across one of the largest known panels of membrane-bound and soluble receptors, comprising 5845 targets, expressed recombinantly in human cells. We were able confirm and replicate SARS-CoV-2 binding to ACE2 HGNC and other putative coreceptors such as CD209 HGNC and CLEC4M HGNC. More significantly, we identified interactions with a number of novel SARS-CoV-2 S binding proteins. Three of these novel receptors, NID1 HGNC, CNTN1 HGNC and APOA4 HGNC were specific to SARS-CoV-2, and not SARS-COV MESHD, with APOA4 HGNC binding the S-protein HGNC S-protein PROTEIN with equal affinity as ACE2 HGNC. With this knowledge we may further understand the disease pathogenesis of COVID-19 MESHD patients and how infection by SARS-CoV-2 may lead to differences in pathology in specific organs or indeed the virulence observed in different ethnicities. Importantly we illustrate a methodology which can be used for rapid, unbiassed identification of cell surface receptors, to support drug screening and drug repurposing approaches for this and future pandemics.

    SARS-CoV-2 Spike PROTEIN SARS-CoV-2 Spike MESHD Protein Impairs Endothelial Function via Downregulation of ACE2

    Authors: Cara R. Schiavon; Ming He; Hui Shen; Yichi Zhang; Yoshitake Cho; Leonardo Andrade; Gerry S. Shadel; Mark Hepokoski; Jin Zhang; Jason X.-J. Yuan; Atul Malhotra; Uri Manor; John Y-J. Shyy; Daniel Batlle; Thomas J Hope; Yang Shen; Yuan Luo; Young Chae; Hui Zhang; Suchitra Swaminathan; Glenn C. Randall; Alexis R Demonbreun; Michael G Ison; Deyu Fang; Huiping Liu; Nicholas C. Morano; Gregory J. Krause; Joseph M. Sweeney; Kelsie Cowman; Stephanie Allen; Jayabhargav Annam; Ariella Applebaum; Daniel Barboto; Ahmed Khokhar; Brianna J. Lally; Audrey Lee; Max Lee; Avinash Malaviya; Reise Sample; Xiuyi A. Yang; Yang Li; Rafael Ruiz; Raja Thota; Jason Barnhill; Doctor Y. Goldstein; Joan Uehlinger; Scott J. Garforth; Steven C. Almo; Jonathan R. Lai; Morayma Reyes Gil; Amy S. Fox; Kartik Chandran; Tao Wang; Johanna P. Daily; Liise-anne Pirofski

    doi:10.1101/2020.12.04.409144 Date: 2020-12-04 Source: bioRxiv

    Coronavirus disease 2019 MESHD ( COVID-19 MESHD) includes the cardiovascular complications in addition to respiratory disease MESHD. SARS-CoV-2 infection MESHD impairs endothelial function and induces vascular inflammation MESHD, leading to endotheliitis. SARS-CoV-2 infection MESHD relies on the binding of Spike glycoprotein PROTEIN ( S protein PROTEIN S protein HGNC) to angiotensin converting enzyme 2 HGNC ( ACE2 HGNC) in the host cells. We show here that S protein HGNC S protein PROTEIN alone can damage vascular endothelial cells (ECs) in vitro and in vivo, manifested by impaired mitochondrial function, decreased ACE2 HGNC expression and eNOS activity, and increased glycolysis. The underlying mechanism involves S protein PROTEIN S protein HGNC downregulation of AMPK HGNC and upregulation of MDM2 HGNC, causing ACE2 HGNC destabilization. Thus, the S protein PROTEIN S protein HGNC-exerted vascular endothelial damage via ACE2 HGNC downregulation overrides the decreased virus infectivity.

    Long-Term Persistence of Spike Antibody and Predictive Modeling of Antibody Dynamics Following Infection with SARS-CoV-2

    Authors: Louis Grandjean; Anja Saso; Arturo Torres Ortiz; Tanya Lam; James Hatcher; Rosie Thistlethwaite; Mark Harris; Timothy Best; Marina Johnson; Helen Wagstaffe; Elizabeth Ralph; Annabelle Mai; Caroline Colijn; Judith Breuer; Matthew Buckland; Kimberly Gilmour; David Goldblatt; - The Co-Stars Study Team

    doi:10.1101/2020.11.20.20235697 Date: 2020-11-23 Source: medRxiv

    Background: Antibodies to Severe Acute Respiratory Syndrome Coronavirus-2 MESHD (SARS-CoV-2) have been shown to neutralize the virus in-vitro. Similarly, animal challenge models suggest that neutralizing antibodies isolated from SARS-CoV-2 infected MESHD individuals prevent against disease upon re-exposure to the virus. Understanding the nature and duration of the antibody response following SARS-CoV-2 infection MESHD is therefore critically important. Methods: Between April and October 2020 we undertook a prospective cohort study of 3555 healthcare workers in order to elucidate the duration and dynamics of antibody responses following infection with SARS-CoV-2. After a formal performance evaluation against 169 PCR confirmed cases and negative controls, the Meso-Scale Discovery assay was used to quantify in parallel, antibody titers to the SARS-CoV-2 nucleoprotein (N PROTEIN), spike (S) protein PROTEIN and the receptor-binding-domain (RBD) of the S-protein HGNC S-protein PROTEIN. All seropositive participants were followed up monthly for a maximum of 7 months; those participants that were symptomatic, with known dates of symptom-onset, seropositive by the MSD assay and who provided 2 or more monthly samples were included in the analysis. Survival analysis was used to determine the proportion of sero-reversion (switching from positive to negative) from the raw data. In order to predict long-term antibody dynamics, two hierarchical longitudinal Gamma models were implemented to provide predictions for the lower bound (continuous antibody decay to zero, 'Gamma-decay') and upper bound (decay-to-plateau due to long lived plasma cells, 'Gamma-plateau') long-term antibody titers. Results: A total of 1163 samples were provided from 349 of 3555 recruited participants who were symptomatic, seropositive by the MSD assay, and were followed up with 2 or more monthly samples. At 200 days post symptom onset, 99% of participants had detectable S-antibody whereas only 75% of participants had detectable N-antibody. Even under our most pessimistic assumption of persistent negative exponential decay, the S-antibody was predicted to remain detectable in 95% of participants until 465 days [95% CI 370-575] after symptom onset. Under the Gamma-plateau model, the entire posterior distribution of S-antibody titers at plateau remained above the threshold for detection indefinitely. Surrogate neutralization assays demonstrated a strong positive correlation between antibody titers to the S-protein PROTEIN S-protein HGNC and blocking of the ACE-2 HGNC receptor in-vitro [R2=0.72, p<0.001]. By contrast, the N-antibody waned rapidly with a half-life of 60 days [95% CI 52-68]. Discussion: This study has demonstrated persistence of the spike antibody in 99% of participants at 200 days following SARS-CoV-2 symptoms MESHD and rapid decay of the nucleoprotein PROTEIN antibody. Diagnostic tests or studies that rely on the N-antibody as a measure of seroprevalence must be interpreted with caution. Our lowest bound prediction for duration of the spike antibody was 465 days and our upper bound predicted spike antibody to remain indefinitely in line with the long-term seropositivity reported for SARS-CoV infection MESHD. The long-term persistence of the S-antibody, together with the strong positive correlation between the S-antibody and viral surrogate neutralization in-vitro, has important implications for the duration of functional immunity following SARS-CoV-2 infection MESHD.

    A new proposed mechanism of some known drugs targeting the SARS-CoV-2 spike PROTEIN glycoprotein using molecular docking

    Authors: Tarek Moussa; Nevien Sabry

    doi:10.21203/rs.3.rs-105677/v1 Date: 2020-11-10 Source: ResearchSquare

    COVID-19 MESHD is caused by the novel enveloped beta-coronavirus with a genomic RNA closely related to severe acute respiratory syndrome-corona virus MESHD ( SARS-CoV MESHD) and is named coronavirus 2 (SARS-CoV-2). The receptor binding domain (RBD) of the S-protein PROTEIN S-protein HGNC interacts with the human ACE-2 HGNC receptor that enables the initiation of viral entry. Hence, blocking the S-protein PROTEIN S-protein HGNC interactions by means of synthetic compounds mark the pivotal step for targeting SARS-CoV-2. Most of the six compounds were observed to fit nicely with specific noncovalent interactions, including H bonds, electrostatic, Van der Waals and hydrophobic bonds (pi and sigma bonds). Oseltamivir was found to be the most strongly interacting with the RBD, exhibiting high values of full fitness MESHD and low free energy of binding. it formed multiple noncovalent bonds in the region of the active site. Hydroxychloroquine also demonstrated high binding affinity in the solvent accessbility state and fit nicely into the active pocket of the S-protein PROTEIN S-protein HGNC. The results revealed that these compounds could be potent inhibitors of S-protein PROTEIN S-protein HGNC that could, to some extent, block its interaction with ACE-2 HGNC. It is obvious from the 3D structure of SARS-CoV-2 spike PROTEIN protein was changed with the interaction of different drugs, which led to the unsuitability to bind ACE2 HGNC receptor. Hence, laboratory studies elucidating the action of these compounds on SARS-CoV-2 are warranted for clinical assessments. Chloroquine, hydroxychloroquine and oseltamivir interacted well with the receptor binding domain of S-protein PROTEIN S-protein HGNC via noncovalent interactions and recommended as excellent candidates for COVID-19 MESHD

    Temporal patterns in the evolutionary genetic distance of SARS-CoV-2 during the COVID-19 MESHD COVID-19 MESHD pandemic

    Authors: Jingzhi Lou; Shi Zhao; Lirong Cao; Zigui Chen; Renee WY Chan; Marc KC Chong; Benny CY Zee; Paul KS Chan; Maggie H Wang; Marian J Killip; Patricia A Cane; Christine B Bruce; Allen D.G Roberts; Guanghui Tian; Haji A. Aisa; Tianwen Hu; Daibao Wei; Yi Jiang; Gengfu Xiao; Hualiang Jiang; Leike Zhang; Xuekui Yu; Jingshan Shen; Shuyang Zhang; H. Eric Xu

    doi:10.1101/2020.11.01.363739 Date: 2020-11-02 Source: bioRxiv

    Background: During the pandemic of coronavirus disease 2019 MESHD ( COVID-19 MESHD), the genetic mutations occurred in severe acute respiratory syndrome coronavirus 2 MESHD (SARS-CoV-2) cumulatively or sporadically. In this study, we employed a computational approach to identify and trace the emerging patterns of the SARS-CoV-2 mutations, and quantify accumulative genetic distance across different periods and proteins. Methods: Full-length human SARS-CoV-2 strains in United Kingdom were collected. We investigated the temporal variation in the evolutionary genetic distance defined by the Hamming distance since the start of COVID-19 pandemic MESHD. Findings: Our results showed that the SARS-CoV-2 was in the process of continuous evolution, mainly involved in spike protein (S PROTEIN S protein HGNC), the RNA-dependent RNA polymerase PROTEIN ( RdRp PROTEIN) region of open reading frame 1 PROTEIN ( ORF1 PROTEIN) and nucleocapsid protein (N PROTEIN protein). By contrast, mutations in other proteins were sporadic and genetic distance to the initial sequenced strain did not show an increasing trend.

    Immunogenicity of novel mRNA COVID-19 MESHD vaccine MRT5500 in mice and non-human primates

    Authors: Kirill V Kalnin; Timothy Plitnik; Michael Kishko; Jinrong Zhang; Donghui Zhang; Andrien Beauvais; Natalie G Anosova; Timothy Tibbitts; Joshua M DiNapoli; Po-Wei D Huang; James Huleatt; Deanne Vincent; Katherine Fries; Shrirang Karve; Rebecca Goldman; Hardip Gopani; Anusha Dias; Khang Tran; Minnie Zacharia; Xiaobo Gu; Lianne Boeglin; Sudha Chivukula; Ron Swearingen; Victoria Landolfi; Tong-Ming Fu; Frank DeRosa; Danilo Casimiro

    doi:10.1101/2020.10.14.337535 Date: 2020-10-14 Source: bioRxiv

    An effective vaccine to address the global pandemic of coronavirus disease 2019 MESHD ( COVID-19 MESHD) is an urgent public health priority. Novel synthetic mRNA and vector-based vaccine technologies offer an expeditious development path alternative to traditional vaccine approaches. Here we describe the efforts to utilize an mRNA platform for rational design and evaluations of mRNA vaccine candidates based on Spike ( S) glycoprotein PROTEIN of Severe Acute Respiratory Syndrome Coronavirus 2 MESHD (SARS-CoV-2), the virus causing COVID-19 MESHD. Several mRNA constructs expressing various structural conformations of S-protein HGNC S-protein PROTEIN, including wild type (WT), a pre-fusion stabilized mutant (2P), a furin cleavage-site mutant (GSAS) and a double mutant form (2P/GSAS), were tested in a preclinical animal model for their capacity to elicit neutralizing antibodies (nAbs). The lead 2P/GSAS candidate was further assessed in dose-ranging studies in mice and Cynomolgus macaques. The selected 2P/GSAS vaccine formulation, now designated MRT5500, elicited potent nAbs as measured in two types of neutralization assays. In addition, MRT5500 elicited TH1-biased responses in both mouse and non-human primate species, a result that helps to address a hypothetical concern regarding potential vaccine-associated enhanced respiratory diseases MESHD associated with TH2-biased responses. These data position MRT5500 as a viable vaccine candidate for clinical development against COVID-19 MESHD.

    Spike conformation transition in SARS-CoV-2 infection MESHD

    Authors: Liaofu Luo; Yongchun Zuo

    id:2009.11288v1 Date: 2020-09-23 Source: arXiv

    A theory on the conformation transition for SARS-CoV-2 spike PROTEIN SARS-CoV-2 spike MESHD protein (S PROTEIN) is established. The conformation equilibrium between open (up) and closed (down) conformations of receptor binding domain (RBD) is studied from the first-principle. The free energy change in conformation transition of S protein HGNC S protein PROTEIN is introduced and we demonstrated that it includes two parts, one from the difference of conformation potential and another from the variation of structural elasticity. The latter is dependent of amino acid mutation. When the amino acid mutation of S protein HGNC S protein PROTEIN causes a substantial reduction of elastic energy the equilibrium is biased to the open conformation. Only then can the virus infection process continue. That both the D614G mutation and the K986P mutation increase the COVID-19 MESHD infectivity and why a large number of mutations, including those at interface residues, have not been selected in current SARS-CoV-2 pandemic are interpreted from the presented theory. The evolution of coronavirus dependent on the alteration of conformation equilibrium is indicated. Finally, introduction of electric field to change the conformation potential barrier and how the conformation equilibrium depends on temperature and humidity are briefly discussed.

    Neutralizing antibody response in non-hospitalized SARS-CoV-2 patients

    Authors: Natalia Ruetalo; Ramona Businger; Karina Althaus; Simon Fink; Felix Ruoff; Klaus Hamprecht; Bertram Flehmig; Tamam Bakchoul; Markus F Templin; Michael Schindler

    doi:10.1101/2020.08.07.20169961 Date: 2020-08-07 Source: medRxiv

    The majority of infections with SARS-CoV-2 ( SCoV2 MESHD) are asymptomatic or mild without the necessity of hospitalization. It is of outmost importance to reveal if these patients develop an antibody response against SCoV2 MESHD and to define which antibodies confer virus neutralization. We hence conducted a comprehensive serological survey of 49 patients with a mild course of disease and quantified neutralizing antibody responses against authentic SCoV2 MESHD employing human cells as targets. Four patients (8%), even though symptomatic, did not develop antibodies against SCoV2 MESHD and two other sera (4%) were only positive in one of the serological assays employed. For the remainder, antibody response against the S-protein PROTEIN S-protein HGNC correlated with serum neutralization whereas antibodies against the nucleocapsid were poor predictors of virus neutralization. Only six sera (12%) could be classified as highly neutralizing. Furthermore, sera from several individuals with fairly high antibody levels had only poor neutralizing activity. In addition, our data suggest that antibodies against the seasonal coronavirus 229E contribute to SCoV2 MESHD neutralization. Altogether, we show that there is a wide breadth of antibody responses against SCoV2 MESHD in patients that differentially correlate with virus neutralization. This highlights the difficulty to define reliable surrogate markers for immunity against SCoV2 MESHD.

    N-glycosylation network construction and analysis to modify glycans on the spike S glycoprotein PROTEIN of SARS-CoV-2.

    Authors: Sridevi Krishnan; Giri P Krishnan

    doi:10.1101/2020.06.23.167791 Date: 2020-06-24 Source: bioRxiv

    Background The spike S-protein PROTEIN S-protein HGNC of SARS-CoV-2 is N-glycosylated. The N-glycan structure and composition of this glycoprotein influence how the virus interacts with host cells.Objective To identify a putative N-glycan biosynthesis pathway of SARS-CoV-2 (HEK293 cell recombinant) from previously published mass spectrometric studies, and to identify what effect blocking some enzymes has on the overall glycoprotein profile. Finally, our goal was to provide the biosynthesis network, and glycans in easy-to-use format for further glycoinformatics work.Methods We reconstructed the glycosylation network based on previously published empirical data using GNAT HGNC, a glycosylation network analysis tool. Our compilation of the network tool had 23 glycosyltransferase and glucosidase enzymes, and could infer the pathway of glycosylation machinery based on glycans identified in the virus spike protein PROTEIN. Once the glycan biosynthesis pathway was generated, we simulated the effect of blocking specific enzymes - Mannosidase-II and alpha-1,6-fucosyltransferase HGNC to see how they would affect the biosynthesis network.Results Of the 23 enzymes, a total of 12 were involved in glycosylation of SARS-CoV-2 - Man-Ia, MGAT1 HGNC, MGAT2 HGNC, MGAT4, MGAT5 HGNC, B4GalT HGNC, B4GalT HGNC, Man II HGNC, SiaT, ST3GalI HGNC, ST3GalVI HGNC and FucT8. Blocking enzymes resulted in a substantially modified glycan profile of the protein.Conclusions A network analysis of N-glycan biosynthesis of SARS-CoV-2 spike PROTEIN SARS-CoV-2 spike MESHD protein shows an elaborate enzymatic pathway with several intermediate glycans, along with the ones identified by mass spectrometric studies. Variations in the final N-glycan profile of the virus, given its site-specific microheterogeneity, could be a factor in the host response to the infection and response to antibodies. Here we provide all the resources generated - the glycans derived from mass spectrometry and intermediate glycans in glycoCT xml format, and the biosynthesis network for future drug and vaccine development work.Competing Interest StatementThe authors have declared no competing interest.View Full Text

    SARS-CoV-2 growth, furin-cleavage-site adaptation and neutralization using serum from acutely infected, hospitalized COVID-19 MESHD patients

    Authors: William B Klimstra; Natasha L Tilston-Lunel; Sham Nambulli; James Boslett; Cynthia M McMillen; Theron Gilliland; Matthew D Dunn; Chengun Sun; Sarah E Wheeler; Alan Wells; Amy L Hartman; Anita K McElroy; Douglas S Reed; Linda J Rennick; W. Paul Duprex

    doi:10.1101/2020.06.19.154930 Date: 2020-06-20 Source: bioRxiv

    SARS-CoV-2, the causative agent of COVID-19 MESHD, emerged at the end of 2019 and by mid-June 2020, the virus has spread to at least 215 countries, caused more than 8,000,000 confirmed infections and over 450,000 deaths, and overwhelmed healthcare systems worldwide. Like SARS-CoV MESHD, which emerged in 2002 and caused a similar disease, SARS-CoV-2 is a betacoronavirus. Both viruses use human angiotensin-converting enzyme 2 HGNC ( hACE2 HGNC) as a receptor to enter cells. However, the SARS-CoV-2 spike PROTEIN ( S) glycoprotein PROTEIN has a novel insertion that generates a putative furin HGNC cleavage signal and this has been postulated to expand the host range. Two low passage (P) strains of SARS-CoV-2 (Wash1: P4 and Munich: P1) were cultured twice in Vero-E6 cells and characterized virologically. Sanger and MinION sequencing demonstrated significant deletions in the furin cleavage signal of Wash1: P6 and minor variants in the Munich: P3 strain. Cleavage of the S glycoprotein PROTEIN in SARS-CoV-2-infected MESHD Vero-E6 cell lysates was inefficient even when an intact furin cleavage signal was present. Indirect immunofluorescence demonstrated the S glycoprotein PROTEIN reached the cell surface. Since the S protein HGNC S protein PROTEIN is a major antigenic target for the development of neutralizing antibodies we investigated the development of neutralizing antibody titers in serial serum samples obtained from COVID-19 MESHD human patients. These were comparable regardless of the presence of an intact or deleted furin HGNC cleavage signal. These studies illustrate the need to characterize virus stocks meticulously prior to performing either in vitro or in vivo pathogenesis studies.

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MeSH Disease
HGNC Genes
SARS-CoV-2 Proteins

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