Corpus overview


Overview

MeSH Disease

HGNC Genes

SARS-CoV-2 proteins

ProteinS (728)

NSP5 (34)

ProteinN (30)

ProteinS1 (28)

ComplexRdRp (23)


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SARS-CoV-2 Proteins
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    Prefusion conformation of SARS-CoV-2 receptor-binding domain favors interactions with human receptor ACE2

    Authors: Nitesh Kumawat; Andrejs Tucs; Soumen Bera; Gennady N. Chuev; Marina V. Fedotova; Koji Tsuda; Sergey E. Kruchinin; Adnan Sljoka; AMIT CHAKRABORTY

    doi:10.1101/2021.04.22.441041 Date: 2021-04-23 Source: bioRxiv

    A new coronavirus epidemic COVID-19 MESHD caused by Severe Acute Respiratory Syndrome coronavirus (SARS-CoV-2 MESHD) poses serious threat across continents, leading to the World Health Organization declaration of a Public Health Emergence of International Concern. In order to stop the entry of the virus into human host cell, major therapeutic and vaccine design efforts are now targeting interactions between the SARS-CoV-2 spike PROTEIN ( S) glycoprotein PROTEIN and the human cellular membrane receptor angiotensin-converting enzyme, hACE2 HGNC. By analysing cryo-EM structures of SARS-CoV-2 and SARS-CoV-1, we report here that the homotrimer SARS-CoV-2 S receptor-binding domain (RBD) that bind with hACE2 HGNC has expanded in size with a large conformational change of its AA residues relative to SARS-CoV-1 S protein PROTEIN. Protomer with the up-conformational form RBD that only can bind with hACE2 HGNC showed higher intermolecular interactions at the interface, with differential distributions and the inclusion of two specific H-bonds in the CoV-2 complex. However, these interactions are resulted in significant reductions in structural rigidity MESHD, favouring proteolytic processing of S protein PROTEIN for the fusion of the viral and cellular membrane. Further conformational dynamics analysis of the RBD motions of SARS-CoV-2 and SARS-CoV-1 point to the role in modification in the RBD conformational dynamics and their likely impact on infectivity.

    Novel Human Lung Tissue Model for the Study of SARS-CoV-2 Entry, Inflammation MESHD and New Therapeutics

    Authors: Javier Garcia-Perez; Jose Alcami

    doi:10.1101/2021.04.21.440731 Date: 2021-04-23 Source: bioRxiv

    The development of physiological models that reproduce SARS-CoV-2 infection MESHD in primary human cells will be instrumental to identify host-pathogen interactions and potential therapeutics. Here, using cell suspensions from primary human lung tissues (HLT), we have developed a platform for the identification of viral targets and the expression of viral entry factors, as well as for the screening of viral entry inhibitors and anti-inflammatory compounds. We show that the HLT MESHD model preserves its main cell populations, maintains the expression of proteins required for SARS-CoV-2 infection MESHD, and identifies alveolar type II MESHD ( AT-II MESHD) cells as the most susceptible cell targets for SARS-CoV-2 in the human lung. Antiviral testing of 39 drug candidates revealed a highly reproducible system, and provided the identification of new compounds missed by conventional systems such as VeroE6. Using this model, we also show that interferons do not modulate ACE2 HGNC expression, and that stimulation of local inflammatory responses can be modulated by different compounds with antiviral activity. Overall, we present a novel and relevant physiological model for the study of SARS-CoV-2.

    Topical TMPRSS2 HGNC inhibition prevents SARS-CoV-2 infection MESHD in differentiated primary human airway cells

    Authors: Wenrui Guo; Linsey M Porter; Thomas WM Crozier; Matthew Coates; Akhilesh Jha; Mikel McKie; James A Nathan; Paul J Lehner; Edward JD Greenwood; Frank McCaughan

    doi:10.1101/2021.04.23.440619 Date: 2021-04-23 Source: bioRxiv

    Background: There are no effective prophylactic treatments for SARS-CoV-2 infection MESHD, and limited early treatment options. Viral cell entry requires spike protein PROTEIN binding to the ACE2 HGNC receptor and spike cleavage by TMPRSS2 HGNC, a cell surface serine protease. Targeting of TMPRSS2 HGNC by either androgen blockade or direct inhibition is already in clinical trials in early SARS-CoV-2 infection MESHD. Methods: The likely initial cells of SARS-CoV-2 entry are the ciliated cells of the upper airway. We therefore used differentiated primary human airway epithelial cells maintained at the air-liquid interface (ALI) to test the impact of targeting TMPRSS2 HGNC on the prevention of SARS-CoV-2 infection MESHD. Results: We first modelled the systemic delivery of compounds. Enzalutamide, an oral androgen receptor HGNC antagonist, had no impact on SARS-Cov-2 infection MESHD. By contrast, camostat mesylate, an orally available serine protease inhibitor, blocked SARS-CoV-2 entry. However, camostat is rapidly metabolised in the circulation in vivo, and systemic bioavailability after oral dosing is low. We therefore modelled local airway administration by applying camostat to the apical surface of the differentiated ALI cultures. We demonstrated that a brief exposure to topical camostat is effective at restricting SARS-CoV-2 viral infection MESHD. Conclusion: These experiments demonstrate a potential therapeutic role for topical camostat for pre- or post-exposure prophylaxis of SARS-CoV-2, which can now be evaluated in a clinical trial.

    Genome-wide, bidirectional CRISPR screens identify mucins as critical host factors modulating SARS-CoV-2 infection MESHD

    Authors: Scott B Biering; Sylvia A Sarnik; Eleanor Wang; James R Zengel; Varun Sathyan; Xammy Nguyenla; Erik Van Dis; Carmelle Catamura; Livia H Yamashiro; Adam Begeman; Jessica C Stark; D. Judy Shon; Douglas M Fox; Andreas S Puschnik; Carolyn R Bertozzi; Jan E Carette; Sarah A Stanley; Eva Harris; Silvana Konermann; Patrick D Hsu

    doi:10.1101/2021.04.22.440848 Date: 2021-04-23 Source: bioRxiv

    SARS-CoV-2 can cause a range of symptoms in infected individuals, from mild respiratory illness MESHD to acute respiratory distress syndrome MESHD. A systematic understanding of the host factors mediating viral infection MESHD or restriction is critical to elucidate SARS-CoV-2 host-pathogen interactions and the progression of COVID-19 MESHD. To this end, we conducted genome-wide CRISPR knockout and activation screens in human lung epithelial cells with endogenous expression of the SARS-CoV-2 entry factors ACE2 HGNC and TMPRSS2 HGNC. These screens uncovered proviral and antiviral host factors across highly interconnected host pathways, including components implicated in clathrin transport, inflammatory signaling, cell cycle regulation, and transcriptional and epigenetic regulation. Mucins, a family of high-molecular weight glycoproteins and the main constituent of mucus, are central components of a prominent viral restriction pathway that we identified. We demonstrate that multiple membrane-anchored mucins are critical inhibitors of SARS-CoV-2 entry MESHD and are upregulated in response to viral infection MESHD. This functional landscape of SARS-CoV-2 host factors provides a physiologically relevant starting point for new host-directed therapeutics and suggests interactions between SARS-CoV-2 and airway mucins of COVID-19 MESHD patients as a host defense mechanism.

    Amino acids 484 and 494 of SARS-CoV-2 spike PROTEIN SARS-CoV-2 spike MESHD are hotspots of immune evasion affecting antibody but not ACE2 HGNC binding

    Authors: Marta Alenquer; Filipe Ferreira; Diana Lousa; Mariana Valerio; Monica Medina-Lopes; Marie-Louise Bergman; Juliana Goncalves; Jocelyne Demengeot; Ricardo B. Leite; Jingtao Lilue; Zemin Ning; Carlos Penha-Goncalves; Helena Soares; Claudio Soares; Maria Joao Amorim

    doi:10.1101/2021.04.22.441007 Date: 2021-04-22 Source: bioRxiv

    Understanding SARS-CoV-2 evolution and host immunity is critical to control COVID-19 pandemic MESHDs. At the core is an arms-race between SARS-CoV-2 antibody and angiotensin-converting enzyme 2 HGNC ( ACE2 HGNC) recognition, a function of the viral protein spike PROTEIN and, predominantly, of its receptor-binding-domain (RBD). Mutations in spike impacting antibody or ACE2 HGNC binding are known, but the effect of mutation synergy is less explored. We engineered 22 spike-pseudotyped lentiviruses containing individual and combined mutations, and confirmed that E484K evades antibody neutralization elicited by infection or vaccination, a capacity augmented when complemented by K417N and N501Y mutations. In silico analysis provided an explanation for E484K immune evasion. E484 frequently engages in interactions with antibodies but not with ACE2 HGNC. Importantly, we identified a novel amino acid of concern, S494, which shares a similar pattern. Using the already circulating mutation S494P, we found that it reduces antibody neutralization of convalescent sera. This amino acid emerges as an additional hotspot for immune evasion and a target for therapies, vaccines and diagnostics.

    Human Taste Cells Express ACE2 HGNC: A Portal for SARS-CoV-2 Infection MESHD

    Authors: Maire Doyle; Ashley Appleton; Qing-Rong Liu; Qin Yao; Caio Henrique Mazucanti; Josephine M Egan

    doi:10.1101/2021.04.21.440680 Date: 2021-04-21 Source: bioRxiv

    Loss and changes in taste and smell are well-reported symptoms of SARS-CoV-2 infection MESHD. The virus targets cells for entry by high affinity binding of its spike protein PROTEIN to cell-surface angiotensin-converting enzyme- 2 ( ACE2 HGNC). It was not known whether ACE2 HGNC is expressed on taste receptor cells (TRCs) nor if TRCs are infected directly. Using an in-situ hybridization ( ISH MESHD) probe and an antibody specific to ACE2 HGNC, it seems evident that ACE2 HGNC is present on a subpopulation of specialized TRCs, namely, PLC{beta}2 HGNC positive, Type II cells in taste buds in taste papillae MESHD. Fungiform papillae (FP) of a SARS-CoV-2+ patient exhibiting symptoms of COVID-19 MESHD, including taste changes, were biopsied. Based on ISH, replicating SARS-CoV-2 was present in Type II cells of this patient. Therefore, taste Type II cells provide a portal for viral entry that predicts vulnerabilities to SARS-CoV-2 in the oral cavity. The continuity and cell turnover of the FP taste stem cell layer of the patient were disrupted during infection and had not fully recovered 6 weeks post symptom onset. Another patient suffering post- COVID-19 MESHD taste disturbances also had disrupted stem cells. These results indicate that a COVID-19 MESHD patient who experienced taste changes had replicating virus in their taste buds and that SARS-CoV-2 infection MESHD results in deficient stem cell turnover MESHD needed for differentiation into TRCs.

    Ultrapotent SARS-CoV-2 neutralizing antibodies with protective efficacy against newly emerged mutational variants

    Authors: Tingting Li; XiaoJian Han; Chenjian Gu; Hangtian Guo; Huajun Zhang; Yingming Wang; Chao Hu; Kai Wang; Fangjiang Liu; Feiyang Luo; Yanan Zhang; Jie Hu; Wang wang; Shenglong Li; Yanan Hao; Meiying Shen; Jingjing Huang; Yingyi Long; Shuyi Song; Ruixin Wu; Song Mu; Qian Chen; Fengxia Gao; Jianwei Wang; Shunhua Long; Luo Li; Yang Wu; Yan Gao; Wei Xu; Xia Cai; Di Qu; Zherui Zhang; Hongqing Zhang; Na Li; Qingzhu Gao; guiji Zhang; Changlong He; Wei Wang; Xiaoyun Ji; Ni Tang; Zhenghong Yuan; Youhua Xie; Bo Zhang; Haitao Yang; Ailong Huang; Aishun Jin

    doi:10.1101/2021.04.19.440481 Date: 2021-04-20 Source: bioRxiv

    Accumulating mutations in the SARS-CoV-2 Spike MESHD SARS-CoV-2 Spike PROTEIN ( S) protein PROTEIN can increase the possibility of immune escape, challenging the present COVID-19 MESHD prophylaxis and clinical interventions. Here, 3 receptor binding domain (RBD) specific monoclonal antibodies (mAbs), 58G6, 510A5 and 13G9, with high neutralizing potency blocking authentic SARS-CoV-2 virus displayed remarkable efficacy against authentic B.1.351 virus. Each of these 3 mAbs in combination with one neutralizing Ab recognizing non-competing epitope exhibited synergistic effect against authentic SARS-CoV-2 virus. Surprisingly, structural analysis revealed that 58G6 and 13G9, encoded by the IGHV1-58 HGNC and the IGKV3-20 germline genes, both recognized the steric region S470-495 on the RBD, overlapping the E484K mutation presented in B.1.351. Also, 58G6 directly bound to another region S450-458 in the RBD. Significantly, 58G6 and 510A5 both demonstrated prophylactic efficacy against authentic SARS-CoV-2 and B.1.351 viruses in the transgenic mice expressing human ACE2 HGNC ( hACE2 HGNC), protecting weight loss MESHD and reducing virus loads. These 2 ultrapotent neutralizing Abs can be promising candidates to fulfill the urgent needs for the prolonged COVID-19 pandemic MESHD.

    SARS-CoV-2 receptor binding domain fusion protein efficiently neutralizes virus infection MESHD

    Authors: Abigael Eva Chaouat; Hagit Achdout; Inbal Kol; Orit Berhani; Gil Roi; Einat B Vitner; Sharon Melamed; Boaz Politi; Eran Zahavi; Ilija Brizic; Tihana Lenac Rovis; Or B. Alfi; Dana Wolf; Stipan Jonjic; Tomer Israely; Ofer Mandelboim

    doi:10.1101/2021.04.18.440302 Date: 2021-04-19 Source: bioRxiv

    Severe acute respiratory syndrome coronavirus (SARS-CoV-2) is responsible for the COVID-19 pandemic MESHD, causing health and economic problems. Currently, as dangerous mutations emerge there is an increased demand for specific treatments for SARS-CoV-2 infected MESHD patients. The spike glycoprotein PROTEIN on the virus membrane binds to the angiotensin converting enzyme 2 HGNC ( ACE2 HGNC) receptor on host cells through its receptor binding domain (RBD) to mediate virus entry. Thus, blocking this interaction may inhibit viral entry and consequently stop infection. Here, we generated fusion proteins composed of the extracellular portions of ACE2 HGNC and RBD fused to the Fc portion of human IgG1 ( ACE2 HGNC-Ig and RBD-Ig, respectively). We demonstrate that ACE2 HGNC-Ig is enzymatically active and that it can be recognized by the SARS-CoV-2 RBD, independently of its enzymatic activity. We further show that RBD-Ig efficiently inhibits in vitro and in vivo SARS-CoV-2 infection MESHD, better than ACE2 HGNC-Ig. Mechanistically we show that anti-spike antibodies generation, ACE2 HGNC enzymatic activity and ACE2 HGNC surface expression were not affected by RBD-Ig. Finally, we show that RBD-Ig is more efficient than ACE2 HGNC-Ig at neutralizing high virus concentration infection. We thus propose that RBD-Ig physically blocks virus infection MESHD by binding to ACE2 HGNC and that RBD-Ig should be used for the treatment of SARS-CoV-2-infected MESHD patients.

    Inferring the stabilization effects of SARS-CoV-2 variants on the binding with ACE2 HGNC receptor

    Authors: Mattia Miotto; Lorenzo Di Rienzo; Giorgio Gosti; Leonardo Bo; Giacomo Parisi; Roberta Piacentini; Alberto Boffi; Giancarlo Ruocco; Edoardo Milanetti

    doi:10.1101/2021.04.18.440345 Date: 2021-04-19 Source: bioRxiv

    With the progression of the SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2 MESHD) pandemic, several variants of the virus are emerging with mutations distributed all over the viral sequence. While most of them are expected to have little to no effects at the phenotype level, some of these variants presenting specific mutations on the Spike protein PROTEIN are rapidly spreading, making urgent the need of characterizing their effects on phenotype features like contagiousness and antigenicity. With this aim, we performed extensive molecular dynamics simulations on a selected set of possible Spike variants in order to assess the stabilizing effect of particular amino acid substitutions, with a special focus on the mutations that are both characteristic of the top three most worrying variants at the moment, i.e the English, South African and Amazonian ones, and that occur at the molecular interface between SARS-CoV-2 Spike PROTEIN SARS-CoV-2 Spike MESHD protein and its human ACE2 receptor. We characterize these variants' effect in terms of (i) residues mobility, (ii) compactness, studying the network of interactions at the interface, and (iii) variation of shape complementarity via expanding the molecular surfaces in the Zernike basis. Overall, our analyses highlighted greater stability of the three variant complexes with respect to both the wild type and two negative control systems, especially for the English and Amazonian variants. In addition, in the three variants, we investigate the effects a not-yet observed mutation in position 501 could provoke on complex stability. We found that a phenylalanine mutation behaves similarly to the English variant and may cooperate in further increasing the stability of the South African one, hinting at the need for careful surveillance for the emergence of such kind of mutations in the population. Ultimately, we show that the observables we propose describe key features for the stability of the ACE2 HGNC-spike complex and can help to monitor further possible spike variants.

    A point-of-care lateral flow assay for neutralising antibodies against SARS-CoV-2

    Authors: Thomas S. Fulford; Huy Van; Nicholas A. Gherardin; Shuning Zheng; Marcin Ciula; Heidi E. Drummer; Samuel Redmond; Hyon-Xhi Tan; Rob J. Center; Fan Li; Samantha L. Grimley; Bruce D. Wines; Thi HO Nguyen; Francesca L. Mordant; Louise C. Rowntree; Allen C. Cheng; Denise L. Doola; Katherine Bond; P. Mark Hogarth; Zoe McQuilten; Kanta Subbarao; Katherine Kedzierska; Jennifer A. Juno; Adam K. Wheatley; Stephen J. Kent; Deborah A. Williamson; Damian F.J. Purcell; David A. Anderson; Dale I. Godfrey

    doi:10.1101/2021.04.12.21255368 Date: 2021-04-19 Source: medRxiv

    As vaccines against SARS-CoV-2 are now being rolled out, a better understanding of immunity to the virus; whether through infection, or passive or active immunisation, and the durability of this protection is required. This will benefit from the ability to measure SARS-CoV-2 immunity, ideally with rapid turnaround and without the need for laboratory-based testing. Current rapid point-of-care (POC) tests measure antibodies (Ab) against the SARS-CoV-2 virus, however, these tests provide no information on whether the antibodies can neutralise virus infectivity and are potentially protective, especially against newly emerging variants of the virus. Neutralising Antibodies (NAb) are emerging as a strong correlate of protection, but most current NAb assays require many hours or days, samples of venous blood, and access to laboratory facilities, which is especially problematic in resource-limited settings. We have developed a lateral flow POC test that can measure levels of RBD- ACE2 HGNC neutralising antibodies from whole blood, with a result that can be determined by eye (semi-quantitative) or on a small instrument (quantitative), and results show high correlation with microneutralisation assays. This assay also provides a measure of total anti-RBD antibody, thereby providing evidence of exposure to SARS-CoV-2, regardless of whether NAb are present in the sample. By testing samples from immunised macaques, we demonstrate that this test is equally applicable for use with animal samples, and we show that this assay is readily adaptable to test for immunity to newly emerging SARS-CoV-2 variants. Accordingly, the COVID-19 MESHD NAb-testTM test described here can provide a rapid readout of immunity to SARS-CoV-2 at the point of care.

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MeSH Disease
HGNC Genes
SARS-CoV-2 Proteins


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