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    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.

    A first-in-human evaluation of the safety and immunogenicity of SCB-2019, an adjuvanted, recombinant SARS-CoV-2 trimeric S-protein PROTEIN S-protein HGNC subunit vaccine for COVID-19 MESHD in healthy adults; a phase 1, randomised, double-blind, placebo-controlled trial

    Authors: Peter Richmond; Lara Hetchual; Min Dong; Brenda Ma; Branda Hu; Igor Smolenov; Ping Li; Peng Liang; Htay Htay Han; Joshua Liang; Ralf Clemens

    doi:10.1101/2020.12.03.20243709 Date: 2020-12-04 Source: medRxiv

    BackgroundAs part of the accelerated development of prophylactic vaccines against severe acute respiratory syndrome coronavirus 2 MESHD (SARS-CoV-2) we report a first-in-human dose-finding and adjuvant justification study of SCB-2019, a novel protein subunit vaccine candidate composed of a stabilised trimeric form of the spike (S)-protein PROTEIN produced in CHO-cells, combined with two different adjuvants. MethodsThis phase 1 study was done in one centre in Western Australia in 151 healthy adult volunteers in two age groups (18-54 and 55-75 years), allocated to 15 groups (nine young and six older adults) to receive two doses, 21 days apart, of placebo, or 3 g, 9 g or 30 g SCB-2019, alone or adjuvanted with AS03 or CpG/Alum. Reactogenicity was assessed for 7 days after each vaccination. Humoral responses were measured as SCB-2019 binding and ACE2-competitive binding IgG antibodies by ELISA, and as neutralising antibodies by wild-type SARS-CoV-2 microneutralisation assay; cellular responses to pooled S-protein HGNC S-protein PROTEIN peptides were measured by flow-cytometric intracellular cytokine staining. FindingsWe report on 148 participants with at least 4 weeks follow-up post dose 2. Three participants withdrew, two for personal reasons and one with an unrelated SAE (pituitary adenoma MESHD). Vaccination was well tolerated, with few Grade 3 solicited adverse events (AE). Most local AEs MESHD were mild injection site pain MESHD, which were more frequent with formulations containing AS03 than CpG/Alum or unadjuvanted SCB-2019. Systemic AEs MESHD, mostly transient headache MESHD, fatigue MESHD or myalgia MESHD, were more frequent in young adults than older adults after the first dose, but similar after second doses. Unadjuvanted SCB-2019 elicited minimal immune responses, but SCB-2019 with fixed doses of AS03 or CpG/Alum induced high titres and seroconversion rates of binding and neutralising antibodies in both young and older adults. Titres were higher than those observed in a panel of COVID-19 MESHD convalescent sera in all AS03 groups and high dose CpG/Alum groups. Both adjuvanted formulations elicited Th1-biased CD4+ T cell responses. InterpretationSCB-2019 trimeric protein formulated with AS03 or CpG/Alum adjuvants elicited robust humoral and cellular immune responses against SARS-CoV-2 with high viral neutralising activity. Both adjuvanted formulations were well tolerated and are suitable for further clinical development. Clinical trial registrationClinicalTrials.gov identifier NCT04405908.

    The N-glycosylation sites and Glycan-binding ability of S-protein HGNC S-protein PROTEIN in SARS-CoV-2 Coronavirus

    Authors: Wentian Chen; Ziye Hui; Xiameng Ren; Yijie Luo; Jian Shu; Hanjie Yu; Zheng Li

    doi:10.1101/2020.12.01.406025 Date: 2020-12-01 Source: bioRxiv

    The emerging acute respiratory disease MESHD, COVID-19 MESHD, caused by SARS-CoV-2 Coronavirus (SARS2 CoV) has spread fastly all over the word. As a member of RNA viruses, the glycosylation of envelope glycoprotein plays the crucial role in protein folding, evasing host immune system, invading host cell membrane, even affecting host preference. Therefore, detail glyco-related researches have been adopted in the Spike protein (S PROTEIN S-protein HGNC) of SARS2 CoV from the bioinformatic perspective. Phylogenic analysis of S-protein HGNC S-protein PROTEIN sequences revealed the evolutionary relationship of N-glycosylation sites in different CoVs. Structural comparation of S-proteins PROTEIN indicated their similarity and distributions of N-glycosylation sites. Further potential sialic acid or galactose affinity domains have been described in the S-protein HGNC S-protein PROTEIN by docking analysis. Molecular dynamic simulation for the glycosylated complexus of S-protein HGNC S-protein PROTEIN- ACE2 HGNC implied that the complicate viral binding of receptor-binding domain may be influenced by peripheric N-glycans from own and adjacent monoers. These works will contribute to investigate the N-glycosylation in S-protein HGNC S-protein PROTEIN and explain the highly contagious of COVID-19 MESHD.

    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.

    Computational analyses of the G476S variant of SARS-CoV-2: A focus on the interaction with human ACE-2 HGNC and neutralizing antibodies

    Authors: Alexander Kwarteng; Ebenezer Asiedu; Augustina Angelina Sylverken

    doi:10.21203/rs.3.rs-98463/v1 Date: 2020-10-26 Source: ResearchSquare

    Recently, several mutations in the SARS-CoV-2 genome have been identified and reported. However, little is currently known about the influence of these mutations on the infectivity, transmissibility and antigenicity of the virus. Here, using an integrative computational approach, we characterized the G476S variant of SARS-CoV-2 focusing on interactions with ACE-2 HGNC and neutralizing antibodies. The substitution of Gly-476 to Ser-476 in the SARS-CoV-2 Receptor-binding domain (RBD) largely affected the structural dynamics of the S-protein HGNC S-protein PROTEIN leading to significant influence on the interactions with ACE-2 HGNC and neutralizing antibodies. Structural properties of the S-protein PROTEIN S-protein HGNC such as conformation changes, residual fluctuations and residue surface area largely varied between the wild-type and G476S variant, especially in the RBD. Analyses of the interaction energies between S-protein PROTEIN S-protein HGNC and ACE-2 HGNC suggest that the G476S variant may have enhanced interactions with ACE-2 HGNC compared to the wild-type. The G476S variant was found to have weaker interactions with the neutralizing antibody H014 compared to the wild-type. Collectively, our findings have implications for the infectivity and antigenicity of the G476S variant of SARS-CoV-2. 

    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.

    Prediction and mitigation of mutation threats to COVID-19 MESHD vaccines and antibody therapies

    Authors: Jiahui Chen; Kaifu Gao; Rui Wang; Guowei Wei

    id:2010.06357v1 Date: 2020-10-13 Source: arXiv

    Antibody therapeutics and vaccines are among our last resort to end the raging COVID-19 MESHD COVID-19 MESHD pandemic.They, however, are prone to over 1,800 mutations uncovered by a Mutation Tracker. It is urgent to understand how vaccines and antibodies in the development would be impacted by mutations. In this work, we first study the mechanism, frequency, and ratio of mutations on the spike (S) protein PROTEIN S) protein HGNC, which is the common target of most COVID-19 MESHD vaccines and antibody therapies. Additionally, we build a library of antibody structures and analyze their 2D and 3D characteristics. Moreover, we predict the mutation-induced binding free energy (BFE) changes for the complexes of S protein PROTEIN and antibodies or ACE2 HGNC. By integrating genetics, biophysics, deep learning MESHD, and algebraic topology, we deduce that some of the mutations such as M153I, S254F, and S255F may weaken the binding of S protein PROTEIN and antibodies, and potentially disrupt the efficacy and reliability of antibody therapies and vaccines in the development. We provide a strategy to prioritize the selection of mutations for designing vaccines or antibody cocktails.

    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.

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MeSH Disease
HGNC Genes
SARS-CoV-2 Proteins

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