Corpus overview


Overview

MeSH Disease

HGNC Genes

SARS-CoV-2 proteins

ProteinS (689)

NSP5 (33)

ProteinN (29)

ProteinS1 (26)

ComplexRdRp (23)


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SARS-CoV-2 Proteins
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    Weak humoral immune reactivity among residents of long-term care facilities following one dose of the BNT162b2 mRNA COVID-19 MESHD vaccine

    Authors: Mark A Brockman; Francis Mwimanzi; Yurous Sang; Kurtis Ng; Olga Agafitei; Siobhan Ennis; Hope Lapointe; Landon Young; Gisele Umviligihozo; Laura Burns; Chanson J Brumme; Victor Leung; Julio S G Montaner; Daniel Holmes; Mari DeMarco; Janet Simons; Masahiro Niikura; Ralph Pantophlet; Marc G Romney; Zabrina L Brumme

    doi:10.1101/2021.03.17.21253773 Date: 2021-03-24 Source: medRxiv

    Background. Several Canadian provinces are extending the interval between COVID-19 MESHD vaccine doses to increase population vaccine coverage more rapidly. However, immunogenicity of these vaccines after one dose is incompletely characterized, particularly among the elderly, who are at greatest risk of severe COVID-19 MESHD. Methods. We assessed SARS-CoV-2 humoral responses pre-vaccine and one month following the first dose of BNT162b2 mRNA vaccine, in 12 COVID-19 MESHD seronegative residents of long-term care facilities (median age, 82 years), 18 seronegative healthcare workers (HCW; median age, 36 years) and 4 convalescent HCW. Total antibody responses to SARS-CoV-2 nucleocapsid (N PROTEIN) and spike protein PROTEIN receptor binding domain (S/RBD) were assessed using commercial immunoassays. We quantified IgG and IgM responses to S/RBD and determined the ability of antibodies to block S/RBD binding to ACE2 HGNC receptor using ELISA. Neutralizing antibody activity was also assessed using pseudovirus and live SARS-CoV-2. Results. After one vaccine dose, binding antibodies against S/RBD were ~4-fold lower in residents compared to HCW (p<0.001). Inhibition of ACE2 HGNC binding was 3-fold lower in residents compared to HCW (p=0.01) and pseudovirus neutralizing activity was 2-fold lower (p=0.003). While six (33%) seronegative HCW neutralized live SARS-CoV-2, only one (8%) resident did (p=0.19). In contrast, convalescent HCW displayed 7- to 20-fold higher levels of binding antibodies and substantial ability to neutralize live virus after one dose. Interpretation. Extending the interval between COVID-19 MESHD vaccine doses may pose a risk to the elderly due to lower vaccine immunogenicity in this group. We recommend that second doses not be delayed in elderly individuals.

    Isolation and Characterization of Cross-Neutralizing Coronavirus Antibodies from COVID-19 MESHD+ Subjects

    Authors: Madelein Jennewein; Anna MacCamey; Nicholas Akins; Junli Feng; Leah Homad; Nicholas Hurlburt; Emily Seydoux; Yu-Hsin Wang; Andrew B Stuart; Venkata Vishwanadh Edara; Katharine Floyd; Abigail Vanderheiden; John R. Mascola; Nicole Doria-Rose; Lingshu Wang; Eun Yang; Helen Chu; Jonathan Torres; Gabriel Ozorowski; Andrew Ward; Rachael Whaley; Kristen Cohen; Marie Pancera; Juliana McElrath; Janet A Englund; Andres Finzi; Mehul Suthar; Andrew McGuire; Leonidas Stamatatos

    doi:10.1101/2021.03.23.436684 Date: 2021-03-24 Source: bioRxiv

    SARS-CoV-2 is one of three coronaviruses that have crossed the animal-to-human barrier in the past two decades. The development of a universal human coronavirus vaccine could prevent future pandemics. We characterized 198 antibodies isolated from four COVID19 MESHD+ subjects and identified 14 SARS-CoV-2 neutralizing antibodies. One targeted the NTD HGNC, one recognized an epitope in S2 and twelve bound the RBD. Three anti-RBD neutralizing antibodies cross-neutralized SARS-CoV-1 by effectively blocking binding of both the SARS-CoV-1 and SARS-CoV-2 RBDs MESHD to the ACE2 HGNC receptor. Using the K18-hACE transgenic mouse model, we demonstrate that the neutralization potency rather than the antibody epitope specificity regulates the in vivo protective potential of anti-SARS-CoV-2 antibodies. The anti-S2 antibody also neutralized SARS-CoV-1 and all four cross-neutralizing antibodies neutralized the B.1.351 mutant strain. Thus, our study reveals that epitopes in S2 can serve as blueprints for the design of immunogens capable of eliciting cross-neutralizing coronavirus antibodies.

    The SARS-CoV-2 Spike PROTEIN SARS-CoV-2 Spike MESHD Protein is vulnerable to moderate electric fields

    Authors: Claudia R. Arbeitman; Pablo Rojas; Pedro Ojeda-May; Martin E. Garcia

    id:2103.12733v1 Date: 2021-03-23 Source: arXiv

    Most of the ongoing projects aimed at the development of specific therapies and vaccines against COVID-19 MESHD use the SARS-CoV-2 spike PROTEIN ( S) protein PROTEIN as the main target [1-3]. The binding of the spike protein PROTEIN with the ACE2 receptor ( ACE2 HGNC) of the host cell constitutes the first and key step for virus entry. During this process, the receptor binding domain (RBD) of the S protein PROTEIN plays an essential role, since it contains the receptor binding motif (RBM), responsible for the docking to the receptor. So far, mostly biochemical methods are being tested in order to prevent binding of the virus to ACE2 HGNC [4]. Here we show, with the help of atomistic simulations, that external electric fields of easily achievable and moderate strengths can dramatically destabilise the S protein PROTEIN, inducing long-lasting structural damage. One striking field-induced conformational change occurs at the level of the recognition loop L3 of the RBD where two parallel beta sheets, believed to be responsible for a high affinity to ACE2 HGNC [5], undergo a change into an unstructured coil, which exhibits almost no binding possibilities to the ACE2 HGNC receptor (Figure 1a). Remarkably, while the structural flexibility of S allows the virus to improve its probability of entering the cell, it is also the origin of the surprising vulnerability of S upon application of electric fields of strengths at least two orders of magnitude smaller than those required for damaging most proteins. Our findings suggest the existence of a clean physical method to weaken the SARS-CoV-2 virus without further biochemical processing. Moreover, the effect could be used for infection prevention purposes and also to develop technologies for in-vitro structural manipulation of S. Since the method is largely unspecific, it can be suitable for application to mutations in S, to other proteins of SARS-CoV-2 and in general to membrane proteins of other virus types.

    Antidepressant and antipsychotic drugs reduce viral infection MESHD by SARS-CoV-2 and fluoxetine show antiviral activity against the novel variants in vitro

    Authors: Merve Senem Fred; Suvi Kuivanen; Hasan Ugurlu; Plinio Cabrera Casarotto; Lev Levanov; Kalle Saksela; Olli Vapalahti; Eero Castren

    doi:10.1101/2021.03.22.436379 Date: 2021-03-23 Source: bioRxiv

    Background and Purpose: Repurposing of currently available drugs is a valuable strategy to tackle the consequences of COVID-19 MESHD. Recently, several studies have investigated the effect of psychoactive drugs on SARS-CoV-2 in cell culture models as well as in clinical practice. Our aim was to expand these studies and test some of these compounds against newly emerged variants. Experimental Approach: Several antidepressant drugs and antipsychotic drugs with different primary mechanisms of action were tested in ACE2 HGNC/ TMPRSS2 HGNC-expressing human embryonic kidney cells against the infection by SARS-CoV-2 spike PROTEIN protein-dependent pseudoviruses. Some of these compounds were also tested in human lung epithelial cell line, Calu-1, against the first wave (B.1) lineage of SARS-CoV-2 and the variants of concern, B.1.1.7 and B.1.351. Key Results: Several clinically used antidepressants, including fluoxetine, citalopram, reboxetine, imipramine, as well as antipsychotic compounds chlorpromazine, flupenthixol, and pimozide inhibited the infection by pseudotyped viruses with minimal effects on cell viability. The antiviral action of several of these drugs was verified in Calu-1 cells against the (B.1) lineage of SARS-CoV-2. By contrast, the anticonvulsant carbamazepine, and novel antidepressants ketamine and its derivatives as well as MAO and phosphodiesterase inhibitors phenelzine and rolipram, respectively, showed no activity in the pseudovirus model. Furthermore, fluoxetine remained effective against pseudo viruses with N501Y, K417N, and E484K spike mutations, and the VoC-1 (B.1.1.7) and VoC-2 (B.1.351) variants of SARS-CoV-2. Conclusion and Implications: Our study confirms previous data and extends information on the repurposing of these drugs to counteract SARS-CoV-2 infection MESHD including different variants of concern.

    Structural modeling of the SARS-CoV-2 Spike PROTEIN/human ACE2 HGNC complex interface can identify high-affinity variants associated with increased transmissibility

    Authors: Hin Hark Gan; Alan Twaddle; Benoit Marchand; Kris Gunsalus

    doi:10.1101/2021.03.22.436454 Date: 2021-03-22 Source: bioRxiv

    The COVID-19 pandemic MESHD has triggered concerns about the emergence of more infectious and pathogenic viral strains. As a public health measure, efficient screening methods are needed to determine the functional effects of new sequence variants. Here we show that structural modeling of SARS-CoV-2 Spike PROTEIN SARS-CoV-2 Spike MESHD protein binding to the human ACE2 receptor, the first step in host-cell entry, predicts many novel variant combinations with enhanced binding affinities. By focusing on natural variants at the Spike- hACE2 HGNC interface and assessing over 700 mutant complexes, our analysis reveals that high-affinity Spike mutations (including N440K, S443A, G476S, E484R, G502P) tend to cluster near known human ACE2 HGNC recognition sites (K31 and K353). These Spike regions are conformationally flexible, allowing certain mutations to optimize interface interaction energies. Although most human ACE2 HGNC variants tend to weaken binding affinity, they can interact with Spike mutations to generate high-affinity double mutant complexes, suggesting variation in individual susceptibility to infection. Applying structural analysis to highly transmissible variants, we find that circulating point mutations S447N, E484K and N501Y form high-affinity complexes (~40% more than wild-type). By combining predicted affinities and available antibody escape data, we show that fast-spreading viral variants exploit combinatorial mutations possessing both enhanced affinity and antibody resistance, including S447N/E484K, E484K/N501Y and K417T/E484K/N501Y. Thus, three-dimensional modeling of the Spike/ hACE2 HGNC complex predicts changes in structure and binding affinity that correlate with transmissibility and therefore can help inform future intervention strategies.

    CVnCoV protects human ACE2 HGNC transgenic mice from ancestral B BavPat1 and emerging B.1.351 SARS-CoV-2

    Authors: Donata Hoffmann; Bjoern Corleis; Susanne Rauch; Nicole Roth; Janine Muehe; Nico Joel Halwe; Lorenz Ulrich; Charlie Fricke; Jacob Schoen; Anna Kraft; Angele Breithaupt; Kerstin Wernike; Anna Michelitsch; Franziska Sick; Claudia Wylezich; Stefan O. Mueller; Thomas C. Mettenleiter; Benjamin Petsch; Anca Dorhoi; Martin Beer

    doi:10.1101/2021.03.22.435960 Date: 2021-03-22 Source: bioRxiv

    The ongoing severe acute respiratory syndrome coronavirus-2 MESHD (SARS-CoV-2) pandemic necessitates the fast development of vaccines as the primary control option. Recently, viral mutants termed "variants of concern" (VOC) have emerged with the potential to escape host immunity. VOC B.1.351 was first discovered in South Africa in late 2020, and causes global concern due to poor neutralization with propensity to evade preexisting immunity from ancestral strains. We tested the efficacy of a spike encoding mRNA vaccine (CVnCoV) against the ancestral strain BavPat1 and the novel VOC B.1.351 in a K18- hACE2 HGNC transgenic mouse model. Naive mice and mice immunized with formalin-inactivated SARS-CoV-2 preparation were used as controls. mRNA-immunized mice developed elevated SARS-CoV-2 RBD-specific antibody as well as neutralization titers against the ancestral strain BavPat1. Neutralization titers against VOC B.1.351 were readily detectable but significantly reduced compared to BavPat1. VOC B.1.351-infected control animals experienced a delayed course of disease, yet nearly all SARS-CoV-2 challenged naive mice succumbed with virus dissemination and high viral loads. CVnCoV vaccine completely protected the animals from disease and mortality caused by either viral strain. Moreover, SARS-CoV-2 was not detected in oral swabs, lung, or brain in these groups. Only partial protection was observed in mice receiving the formalin-inactivated virus preparation. Despite lower neutralizing antibody titers compared to the ancestral strain BavPat1, CVnCoV shows complete disease protection against the novel VOC B.1.351 in our studies.

    Live imaging of SARS-CoV-2 infection MESHD in mice reveals neutralizing antibodies require Fc function for optimal efficacy

    Authors: Irfan Ullah; Jeremie Prevost; Mark S. Ladinsky; Helen Stone; Maolin Lu; Sai Priya Anand; Guillaume Beaudoin-Bussieres; Mehdi Benlarbi; Shilei Ding; Romain Gasser; Corby Fink; Yaozong Chen; Alexandra Tauzin; Guillaume Goyette; Catherine Bourassa; Halima Medjahed; Matthias Mack; Kunho Chung; Craig B Wilen; Gregory A Dekaban; Jimmy D Dikeakos; Emily A Bruce; Daniel E Kaufmann; Leonidas Stamatatos; Andrew McGuire; Jonathan Richard; Marzena Pazgier; Pamela Bjorkman; Walther Mothes; Andres Finzi; Priti Kumar; Pradeep D Uchil

    doi:10.1101/2021.03.22.436337 Date: 2021-03-22 Source: bioRxiv

    Neutralizing antibodies (NAbs) are effective in treating COVID-19 MESHD but the mechanism of immune protection is not fully understood. Here, we applied live bioluminescence imaging (BLI) to monitor the real-time effects of NAb treatment in prophylaxis and therapy of K18- hACE2 HGNC mice intranasally infected with SARS-CoV-2-nanoluciferase. We visualized sequential spread of virus from the nasal cavity to the lungs followed by systemic spread to various organs including the brain, culminating in death MESHD. Highly potent NAbs from a COVID-19 MESHD convalescent subject prevented, and also effectively resolved, established infection when administered within three days of infection. In addition to direct neutralization, in vivo efficacy required Fc effector functions of NAbs, with contributions from monocytes, neutrophils and natural killer cells, to dampen inflammatory responses and limit immunopathology. Thus, our study highlights the requirement of both Fab and Fc effector functions for an optimal in vivo efficacy afforded by NAbs against SARS-CoV-2.

    TMPRSS2 HGNC inhibitor discovery facilitated through an in silico and biochemical screening platform

    Authors: Amanda L Peiffer; Julie M Garlick; Yujin Wu; Matthew B Soellner; Charles L Brooks III; Anna K Mapp

    doi:10.1101/2021.03.22.436465 Date: 2021-03-22 Source: bioRxiv

    The COVID-19 pandemic MESHD has highlighted the need for new antiviral targets, as many of the currently approved drugs have proven ineffective against mitigating SARS-CoV-2 infections MESHD. The host transmembrane serine protease HGNC TMPRSS2 HGNC is a highly promising antiviral target, as it plays a direct role in priming the spike protein PROTEIN before viral entry occurs. Further, unlike other targets such as ACE2 HGNC, TMPRSS2 HGNC has no known biological role. Here we utilize virtual screening to curate large libraries into a focused collection of potential inhibitors. Optimization of a recombinant expression and purification protocol for the TMPRSS2 HGNC peptidase domain facilitates subsequent biochemical screening and characterization of selected compounds from the curated collection in a kinetic assay. In doing so, we demonstrate that serine protease HGNC inhibitors camostat, nafamostat, and gabexate inhibit through a covalent mechanism. We further identify new non-covalent compounds as TMPRSS2 HGNC protease inhibitors, demonstrating the utility of a combined virtual and experimental screening campaign in rapid drug discovery efforts.

    Characterisation of B.1.1.7 and Pangolin coronavirus spike provides insights on the evolutionary trajectory of SARS-CoV-2

    Authors: Samuel J Dicken; Matthew J Murray; Lucy G Thorne; Ann-Kathrin Reuschl; Calum Forrest; Maaroothen Ganeshalingham; Luke Muir; Mphatso D Kalemera; Machaela Palor; Laura E McCoy; Clare Jolly; Greg J Towers; Matthew Reeves; Joe Grove

    doi:10.1101/2021.03.22.436468 Date: 2021-03-22 Source: bioRxiv

    The recent emergence of SARS-CoV-2 variants with increased transmission, pathogenesis and immune resistance has jeopardised the global response to the COVID-19 pandemic MESHD. Determining the fundamental biology of viral variants and understanding their evolutionary trajectories will guide current mitigation measures, future genetic surveillance and vaccination strategies. Here we examine virus entry by the B.1.1.7 lineage, commonly referred to as the UK/Kent variant. Pseudovirus infection of model cell lines demonstrate that B.1.1.7 entry is enhanced relative to the Wuhan-Hu-1 reference strain, particularly under low expression of receptor ACE2 HGNC. Moreover, the entry characteristics of B.1.1.7 were distinct from that of its predecessor strain containing the D614G mutation. These data suggest evolutionary tuning of spike protein PROTEIN function. Additionally, we found that amino acid deletions within the N-terminal domain ( NTD HGNC) of spike were important for efficient entry by B.1.1.7. The NTD HGNC is a hotspot of diversity across sarbecoviruses, therefore, we further investigated this region by examining the entry of closely related CoVs. Surprisingly, Pangolin CoV spike entry was 50-100 fold enhanced relative to SARS-CoV-2; suggesting there may be evolutionary pathways by which SARS-CoV-2 may further optimise entry. Swapping the NTD HGNC between Pangolin CoV and SARS-CoV-2 demonstrates that changes in this region alone have the capacity to enhance virus entry. Thus, the NTD HGNC plays a hitherto unrecognised role in modulating spike activity, warranting further investigation and surveillance of NTD HGNC mutations.

    Critical interactions for SARS-CoV-2 spike PROTEIN protein binding to ACE2 HGNC identified by machine learning

    Authors: Anna Pavlova; Zijian Zhang; Atanu Acharya; Diane L Lynch; Yui Tik Pang; Zhongyu Mou; Jerry M Parks; Chris Chipot; James C. Gumbart

    doi:10.1101/2021.03.19.436231 Date: 2021-03-21 Source: bioRxiv

    Both SARS-CoV MESHD and SARS-CoV-2 bind to the human ACE2 HGNC receptor. Based on high-resolution structures, the two viruses bind in practically identical conformations, although several residues of the receptor-binding domain (RBD) differ between them. Here we have used molecular dynamics ( MD MESHD) simulations, machine learning (ML), and free energy perturbation (FEP) calculations to elucidate the differences in RBD binding by the two viruses. Although only subtle differences were observed from the initial MD simulations of the two RBD- ACE2 HGNC complexes, ML identified the individual residues with the most distinctive ACE2 HGNC interactions, many of which have been highlighted in previous experimental studies. FEP calculations quantified the corresponding differences in binding free energies to ACE2 HGNC, and examination of MD trajectories provided structural explanations for these differences. Lastly, the energetics of emerging SARS-CoV-2 mutations were studied, showing that the affinity of the RBD for ACE2 HGNC is increased by N501Y and E484K mutations but is slightly decreased by K417N.

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MeSH Disease
HGNC Genes
SARS-CoV-2 Proteins


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