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MeSH Disease

HGNC Genes

SARS-CoV-2 proteins

ProteinS (665)

ProteinN (69)

ProteinS1 (16)

ProteinE (15)

ORF8 (12)


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SARS-CoV-2 Proteins
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    Dynamic Profiling of Binding and Allosteric Propensities of the SARS-CoV-2 Spike MESHD SARS-CoV-2 Spike PROTEIN Protein with Different Classes of Antibodies: Mutational and Perturbation-Based Scanning Reveal Allosteric Duality of Functionally Adaptable Hotspots

    Authors: Gennady M Verkhivker; Steve Agajanian; Deniz Yazar Oztas; Grace Gupta

    doi:10.1101/2021.04.13.439743 Date: 2021-04-14 Source: bioRxiv

    Structural and biochemical studies of the SARS-CoV-2 spike PROTEIN complexes with highly potent antibodies have revealed multiple conformation-dependent epitopes and a broad range of recognition modes linked to different neutralization responses In this study, we combined atomistic simulations with mutational and perturbation-based scanning approaches to perform in silico profiling of binding and allosteric propensities of the SARS-CoV-2 spike PROTEIN protein residues in complexes with B38, P2B-2F6, EY6A and S304 antibodies representing three different classes. Conformational dynamics analysis revealed that binding-induced modulation of soft modes can elicit the unique protein response to different classes of antibodies. Mutational scanning heatmaps and sensitivity analysis revealed the binding energy hotspots for different classes of antibodies that are consistent with the experimental deep mutagenesis, showing that differences in the binding affinity caused by global circulating variants in spike positions K417, E484 and N501 are relatively moderate and may not fully account for the observed antibody resistance effects. Through functional dynamics analysis and perturbation-response scanning of the SARS-CoV-2 spike PROTEIN protein residues in the unbound form and antibody-bound forms, we examine how antibody binding can modulate allosteric propensities of spike protein PROTEIN residues and determine allosteric hotspots that control signal transmission and global conformational changes. These results show that residues K417, E484, and N501 targeted by circulating mutations correspond to a group of versatile allosteric centers in which small perturbations can modulate collective motions, alter the global allosteric response and elicit binding resistance. We suggest that SARS-CoV-2 S protein PROTEIN may exploit plasticity of specific allosteric hotspots to generate escape mutants that alter response to antibody binding without compromising activity of the spike protein PROTEIN.

    Epitope classification and RBD binding properties of neutralizing antibodies against SARS-CoV-2 variants of concern

    Authors: Ashlesha Deshpande; Bethany D. Harris; Luis Martinez-Sobrido; James J. Kobie; Mark R Walter

    doi:10.1101/2021.04.13.439681 Date: 2021-04-13 Source: bioRxiv

    Severe acute respiratory syndrome coronavirus-2 MESHD (SAR-CoV-2) causes coronavirus disease 2019 MESHD ( COVID19 MESHD) that is responsible for short and long-term disease, as well as death, in susceptible hosts. The receptor binding domain (RBD) of the SARS-CoV-2 Spike MESHD SARS-CoV-2 Spike PROTEIN ( S) protein PROTEIN binds to cell surface angiotensin converting enzyme type-II ( ACE2 HGNC) to initiate viral attachment and ultimately viral pathogenesis. The SARS-CoV-2 S RBD MESHD is a major target of neutralizing antibodies (NAbs) that block RBD - ACE2 HGNC interactions. In this report, NAb-RBD binding epitopes in the protein databank were classified as C1, C1D, C2, C3, or C4 HGNC, using a RBD binding profile (BP), based on NAb-specific RBD buried surface area and used to predict the binding epitopes of a series of uncharacterized NAbs. Naturally occurring SARS-CoV-2 RBD sequence variation was also quantified to predict NAb binding sensitivities to the RBD-variants. NAb and ACE2 HGNC binding studies confirmed the NAb classifications and determined whether the RBD variants enhanced ACE2 HGNC binding to promote viral infectivity, and/or disrupted NAb binding to evade the host immune response. Of 9 single RBD mutants evaluated, K417T, E484K, and N501Y disrupted binding of 65% of the NAbs evaluated, consistent with the assignment of the SARS-CoV-2 P.1 Japan/Brazil strain as a variant of concern (VoC). RBD variants E484K and N501Y exhibited ACE2 HGNC binding equivalent to a Wuhan-1 reference SARS-CoV-2 RBD. While slightly less disruptive to NAb binding, L452R enhanced ACE2 HGNC binding affinity. Thus, the L452R mutant, associated with the SARS-CoV-2 California VoC MESHD (B.1.427/B.1.429-California), has evolved to enhance ACE2 HGNC binding, while simultaneously disrupting C1 and C2 NAb classes. The analysis also identified a non-overlapping antibody pair (1213H7 and 1215D1) that bound to all SARS-CoV-2 RBD variants evaluated, representing an excellent therapeutic option for treatment of SARS-CoV-2 WT MESHD and VoC strains.

    Variant SARS-CoV-2 mRNA vaccines confer broad neutralization as primary or booster series in mice

    Authors: Kai Wu; Angela Choi; Matthew Koch; Sayda Elbashir; LingZhi Ma; Diana Lee; Angela Woods; Carole Henry; Charis Palandjian; Anna Hill; Julian Quinones; Naveen Nunna; Adrian B McDermott; Samantha Falcone; Elisabeth Narayanan; Tonya Colpitts; Hamilton Bennett; Kizzmekia Corbett; Robert Seder; Barney S Graham; Guillaume BE Stewart-Jones; Andrea Carfi; Darin K Edwards

    doi:10.1101/2021.04.13.439482 Date: 2021-04-13 Source: bioRxiv

    Severe acute respiratory syndrome coronavirus 2 MESHD (SARS-CoV-2) is the causative agent of a global pandemic that has led to more than 2.8 million deaths worldwide. Safe and effective vaccines are now available, including Moderna's COVID-19 MESHD vaccine (mRNA-1273) that showed 94% efficacy in prevention of symptomatic COVID-19 MESHD disease in a phase 3 clinical study. mRNA-1273 encodes for a prefusion stabilized full length spike (S) protein PROTEIN of the Wuhan-Hu-1 isolate. However, the emergence of SARS-CoV-2 variants has led to concerns of viral escape from vaccine-induced immunity. Several emerging variants have shown decreased susceptibility to neutralization by vaccine induced immunity, most notably the B.1.351 variant, although the overall impact on vaccine efficacy remains to be determined. Here, we present the initial evaluation in mice of two updated COVID-19 MESHD mRNA vaccines designed to target emerging SARS-CoV-2 variants: (1) monovalent mRNA-1273.351 encodes for the S protein PROTEIN found in the B.1.351 lineage and (2) mRNA-1273.211 comprising a 1:1 mix of mRNA-1273 and mRNA-1273.351. Both vaccines were evaluated as a 2-dose primary series in mice; mRNA-1273.351 was also evaluated as a booster dose in animals previously vaccinated with 2-doses of mRNA-1273. The results demonstrated that a primary vaccination series of mRNA-1273.351 was effective at increasing neutralizing antibody titers against the B.1.351 lineage, while mRNA-1273.211 was most effective at providing broad cross-variant neutralization in mice. In addition, these results demonstrated a third dose of mRNA-1273.351 significantly increased both wild-type and B.1.351-specific neutralization titers. Both mRNA-1273.351 and mRNA-1273.211 are currently being evaluated in additional pre-clinical challenge models and in phase 1/2 clinical studies.

    A multiplexed high-throughput neutralization assay reveals a lack of activity against multiple variants after SARS-CoV-2 infection MESHD

    Authors: Craig Fenwick; Priscilla Turelli; Celine Pellaton; Alex Farina; Jeremy Campos; Charlene Raclot; Florence Pojer; Valeria Cagno; Giuseppe Pantaleo; Didier Trono

    doi:10.1101/2021.04.08.21255150 Date: 2021-04-13 Source: medRxiv

    The detection of SARS-CoV-2-specific antibodies in the serum of an individual indicates prior infection or vaccination. However, it provides limited insight into the protective nature of this immune response. Neutralizing antibodies recognizing the viral Spike are far more revealing, yet their measurement traditionally requires virus- and cell-based systems that are costly, time-consuming, poorly flexible and potentially biohazardous. Here we present a cell-free quantitative neutralization assay based on the competitive inhibition of trimeric SARS-CoV-2 Spike PROTEIN SARS-CoV-2 Spike MESHD protein binding to the angiotensin converting enzyme 2 HGNC ( ACE2 HGNC) viral receptor. This high-throughput method matches the performance of the gold standard live virus infectious assay, as verified with a panel of 206 seropositive donors with varying degrees of infection severity and virus-specific IgG titers, achieving 96.7% sensitivity and 100% specificity. Furthermore, it allows for the parallel assessment of neutralizing activities against multiple SARS-CoV-2 Spike PROTEIN variants of concern (VOC), which is otherwise unpredictable even in individuals displaying robust neutralizing antibody responses. Profiling serum samples from 59 hospitalized COVID-19 MESHD patients, we found that although most had high activity against the 2019-nCoV Spike and to a lesser extent the B.1.1.7 variant, only 58% could efficiently neutralize a Spike derivative containing mutations present in the B.1.351 variant. In conclusion, we have developed an assay that has proven its clinical relevance in the large-scale evaluation of effective neutralizing antibody responses to VOC after natural infection and that can be applied to the characterization of vaccine-induced antibody responses and of the potency of human monoclonal antibodies.

    Antibody and T-cell responses to a single dose of the AZD1222/Covishield vaccine in previously SARS-CoV-2 infected MESHD and naive health care workers in Sri HGNC Lanka

    Authors: Chandima Jeewandara; Achala Kamaladasa; Pradeep D Pushpakumara; Deshni Jayathilaka; Inoka Sepali; Saubhagyagya Danasekara; Dinuka Guruge; Thushali Ranasinghe; Shashika Dayaratne; Thilagaraj T Padmanadan; Gayasha Somathilaka; Deshan Madusanka; Shyrar Tanussiya; Tibutius Jayadas; Heshan Kuruppu; Ayesha Wijesinghe; Nimasha Thashmi; Dushantha Milroy; Achini Nandasena; Nilanka Sanjeewani; Ruwan Wijayamuni; Sudath Samaraweera; Lisa Schimanski; Tiong Tan; Tao Dong; Graham Ogg; Alain Townsend; Gathsaurie Neelika Malavige

    doi:10.1101/2021.04.09.21255194 Date: 2021-04-13 Source: medRxiv

    Background: In order to determine the immunogenicity of a single dose of the AZD1222/Covishield vaccine in a real-world situation, we assessed the immunogenicity, in a large cohort of health care workers in Sri HGNC Lanka. Methods: SARS-CoV-2 antibodies was carried out in 607 naive and 26 previously infected health care workers (HCWs) 28 to 32 days following a single dose of the vaccine. Haemagglutination test (HAT) for antibodies to the receptor binding domain (RBD) of the wild type virus, B.1.1.7, B.1.351 and the surrogate neutralization assay (sVNT) was carried out in 69 naive and 26 previously infected individuals. Spike protein PROTEIN (pools S1 and S2) specific T cell responses were measured by ex vivo ELISpot IFNg HGNC; assays in 76 individuals. Results: 92.9% of previously naive HCWs seroconverted to a single dose of the vaccine, irrespective of age and gender; and ACE2 HGNC blocking antibodies were detected in 67/69 (97.1%) previously naive vaccine recipients. Although high levels of antibodies were found to the RBD of the wild type virus, the titres for B.1.1.7 and B.1.351 were lower in previously naive HCWs. Ex vivo T cell responses were observed to S1 in 63.9% HCWs and S2 in 31.9%. The ACE2 HGNC blocking titres measured by the sVNT significantly increased (p<0.0001) from a median of 54.1 to 97.9 % of inhibition, in previously infected HCWs and antibodies to the RBD for the variants B.1.1.7 and B.1.351 also significantly increased. Discussion: a single dose of the AZD1222/Covishield vaccine was shown to be highly immunogenic in previously naive individuals inducing antibody levels greater than following natural infection. In infected individuals, a single dose induced very high levels of ACE2 HGNC blocking antibodies and antibodies to RBDs of SARS-CoV-2 variants of concern.

    Impairment of SARS-CoV-2 spike PROTEIN glycoprotein maturation and fusion activity by the broad-spectrum anti-infective drug nitazoxanide

    Authors: Anna Riccio; Silvia Santopolo; Antonio Rossi; Sara Piacentini; Jean-Francois Rossignol; Maria Gabriella Santoro

    doi:10.1101/2021.04.12.439201 Date: 2021-04-12 Source: bioRxiv

    The emergence of the highly-pathogenic severe acute respiratory syndrome coronavirus-2 MESHD (SARS-CoV-2), the causative agent of COVID-19 MESHD (coronavirus disease-2019), has caused an unprecedented global health crisis, as well as societal and economic disruption. The SARS-CoV-2 spike MESHD SARS-CoV-2 spike PROTEIN (S), a surface-anchored trimeric class-I fusion glycoprotein essential for entry into host cells, represents a key target for developing vaccines and therapeutics capable of blocking virus invasion. The emergence of several SARS-CoV-2 spike PROTEIN variants that facilitate virus spread and may affect the efficacy of recently developed vaccines, creates great concern and highlights the importance of identifying antiviral drugs to reduce SARS-CoV-2-related morbidity and mortality. Nitazoxanide, a thiazolide originally developed as an antiprotozoal agent with recognized broad-spectrum antiviral activity in-vitro and in clinical studies, was recently shown to be effective against several coronaviruses, including SARS-CoV-2. Using biochemical and pseudovirus entry assays, we now demonstrate that nitazoxanide interferes with the SARS-CoV-2 spike PROTEIN biogenesis, hampering its maturation at an endoglycosidase H-sensitive stage, and hindering its fusion activity in human cells. Besides membrane fusion during virus entry, SARS-CoV-2 S-proteins MESHD S-proteins PROTEIN in infected cells can also trigger receptor-dependent formation of syncytia, observed in-vitro and in COVID-19 MESHD patients tissues, facilitating viral dissemination between cells and possibly promoting immune evasion. Utilizing two different quantitative cell-cell fusion assays, we show that nitazoxanide is effective in inhibiting syncytia formation mediated by different SARS-CoV-2 spike PROTEIN variants in human lung, liver and intestinal cells. The results suggest that nitazoxanide may represent a useful tool in the fight against COVID-19 MESHD infections, inhibiting SARS-CoV-2 replication and preventing spike-mediated syncytia formation.

    Prediction and evolution of the molecular fitness of SARS-CoV-2 variants: Introducing SpikePro

    Authors: Fabrizio Pucci; Marianne Rooman

    doi:10.1101/2021.04.11.439322 Date: 2021-04-12 Source: bioRxiv

    The understanding of the molecular mechanisms driving the fitness of the SARS-CoV-2 MESHD virus and its mutational evolution is still a critical issue. We built a simplified computational model, called SpikePro, to predict the SARS-CoV-2 fitness MESHD from the amino acid sequence and structure of the spike protein PROTEIN. It contains three contributions: the viral transmissibility predicted from the stability of the spike protein PROTEIN, the infectivity computed in terms of the affinity of the spike protein PROTEIN for the ACE2 HGNC receptor, and the ability of the virus to escape from the human immune response based on the binding affinity of the spike protein PROTEIN for a set of neutralizing antibodies. Our model reproduces well the available experimental, epidemiological and clinical data on the impact of variants on the biophysical characteristics of the virus. For example, it is able to identify circulating viral strains that, by increasing their fitness, recently became dominant at the population level. SpikePro is a useful instrument for the genomic surveillance of the SARS-CoV-2 virus, since it predicts in a fast and accurate way the emergence of new viral strains and their dangerousness. It is freely available in the GitHub repository github.com/3BioCompBio/SpikeProSARS-CoV-2.

    Interactions between SARS-CoV-2 N-protein PROTEIN and α-synuclein accelerate amyloid formation

    Authors: Slav Semerdzhiev; Mohammad Amin Abolghassemi Fakhree; Ine Segers-Nolten; Christian Blum; Mireille M.A.E. Claessens

    doi:10.1101/2021.04.12.439549 Date: 2021-04-12 Source: bioRxiv

    First cases that point at a correlation between SARS-CoV-2 infections MESHD and the development of Parkinson's disease MESHD have been reported. Currently it is unclear if there also is a direct causal link between these diseases. To obtain first insights into a possible molecular relation between viral infections and the aggregation of -synuclein protein into amyloid fibrils characteristic for Parkinson's disease MESHD, we investigated the effect of the presence of SARS-CoV-2 proteins on synuclein aggregation. We show, in test tube experiments, that SARS-CoV-2 S-protein PROTEIN has no effect on -synuclein aggregation while SARS-CoV-2 N-protein PROTEIN considerably speeds up the aggregation process. We observe the formation of multi-protein complexes, and eventually amyloid fibrils. Microinjection of N-protein PROTEIN in SHSY-5Y cells disturbed the -synuclein proteostasis MESHD and increased cell death. Our results point toward direct interactions between the N-protein PROTEIN of SARS-CoV-2 and -synuclein as molecular basis for the observed coincidence between SARS-CoV-2 infections and Parkinsonism MESHD.

    Ultrastructural insight into SARS-CoV-2 attachment, entry and budding in human airway epithelium

    Authors: Andreia L Pinto; Ranjit K Rai; Jonathan C Brown; Paul Griffin; James R Edgar; Anand Shah; Aran Singanayagam; Claire Hogg; Wendy S Barclay; Clare E Futter; Thomas Burgoyne

    doi:10.1101/2021.04.10.439279 Date: 2021-04-11 Source: bioRxiv

    Ultrastructural studies of SARS-CoV-2 infected MESHD cells are crucial to better understand the mechanisms of viral entry and budding within host cells. Many studies are limited by the lack of access to appropriate cellular models. As the airway epithelium is the primary site of infection it is essential to study SARS-CoV-2 infection MESHD of these cells. Here, we examined human airway epithelium, grown as highly differentiated air-liquid interface cultures and infected with three different isolates of SARS-CoV-2 including the B.1.1.7 variant (Variant of Concern 202012/01) by transmission electron microscopy and tomography. For all isolates, the virus infected ciliated but not goblet epithelial cells. Two key SARS-CoV-2 entry molecules, ACE2 HGNC and TMPRSS2 HGNC, were found to be localised to the plasma membrane including microvilli but excluded from cilia. Consistent with these observations, extracellular virions were frequently seen associated with microvilli and the apical plasma membrane but rarely with ciliary membranes. Profiles indicative of viral fusion at the apical plasma membrane demonstrate that the plasma membrane is one site of entry where direct fusion releasing the nucleoprotein PROTEIN-encapsidated genome occurs. Intact intracellular virions were found within ciliated cells in compartments with a single membrane bearing S glycoprotein PROTEIN. Profiles strongly suggesting viral budding from the membrane was observed in these compartments and this may explain how virions gain their S glycoprotein PROTEIN containing envelope.

    Quantatitive Analysis of Conserved Sites on the SARS-CoV-2 Receptor-Binding Domain to Promote Development of Universal SARS-Like Coronavirus Vaccines

    Authors: Siling Wang; Dinghui Wu; Hualong Xiong; Juan Wang; Zimin Tang; Zihao Chen; Yizhen Wang; Yali Zhang; Dong Ying; Xue Lin; Chang Liu; Shaoqi Guo; Weikun Tian; Yajie Lin; Xiaoping Zhang; Quan Yuan; Hai Yu; Tianying Zhang; Zizheng Zheng; Ningshao Xia

    doi:10.1101/2021.04.10.439161 Date: 2021-04-11 Source: bioRxiv

    Although vaccines have been successfully developed and approved against SARS-CoV-2, it is still valuable to perform studies on conserved antigenic sites for preventing possible pandemic-risk of other SARS-like coronavirus in the future and prevalent SARS-CoV-2 variants. By antibodies obtained from convalescent COVID-19 MESHD individuals, receptor binding domain ( RBD MESHD) were identified as immunodominant neutralizing domain that efficiently elicits neutralizing antibody response with on-going affinity mature. Moreover, we succeeded to define a quantitative antigenic map of neutralizing sites within SARS-CoV-2 RBD, and found that sites S2, S3 and S4 (new-found site) are conserved sites and determined as subimmunodominant sites, putatively due to their less accessibility than SARS-CoV-2 unique sites. P10-6G3, P07-4D10 and P05-6H7, respectively targeting S2, S3 and S4, are relatively rare antibodies that also potently neutralizes SARS-CoV MESHD, and the last mAbs performing neutralization without blocking S protein PROTEIN binding to receptor. Further, we have tried to design some RBDs to improve the immunogenicity of conserved sites. Our studies, focusing on conserved antigenic sites of SARS-CoV-2 and SARS-CoV MESHD, provide insights for promoting development of universal SARS-like coronavirus vaccines therefore enhancing our pandemic preparedness.

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MeSH Disease
HGNC Genes
SARS-CoV-2 Proteins


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