Corpus overview


Overview

MeSH Disease

HGNC Genes

SARS-CoV-2 proteins

ProteinS (100)

ProteinN (5)

ProteinE (2)

ORF8 (1)

ProteinS1 (1)


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SARS-CoV-2 Proteins
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    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.

    Coagulation factors directly cleave SARS-CoV-2 spike PROTEIN and enhance viral entry MESHD

    Authors: Edward R Kastenhuber; Javier A. Jaimes; Jared L. Johnson; Marisa Mercadante; Frauke Muecksch; Yiska Weisblum; Yaron Bram; Robert E. Schwartz; Gary R. Whittaker; Lewis C. Cantley

    doi:10.1101/2021.03.31.437960 Date: 2021-04-01 Source: bioRxiv

    Coagulopathy is recognized as a significant aspect of morbidity in COVID-19 MESHD patients. The clotting cascade is propagated by a series of proteases, including factor Xa HGNC and thrombin HGNC. Other host proteases, including TMPRSS2 HGNC, are recognized to be important for cleavage activation of SARS-CoV-2 spike PROTEIN to promote viral entry. Using biochemical and cell-based assays, we demonstrate that factor Xa HGNC and thrombin HGNC can also directly cleave SARS-CoV-2 spike PROTEIN, enhancing viral entry. A drug-repurposing screen identified a subset of protease inhibitors that promiscuously inhibited spike cleavage by both transmembrane serine proteases as well as coagulation factors. The mechanism of the protease inhibitors nafamostat and camostat extend beyond inhibition of TMPRSS2 HGNC to coagulation-induced spike cleavage. Anticoagulation is critical in the management of COVID-19 MESHD, and early intervention could provide collateral benefit by suppressing SARS-CoV-2 viral entry. We propose a model of positive feedback whereby infection-induced hypercoagulation MESHD exacerbates SARS-CoV-2 infectivity MESHD.

    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.

    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.

    The inhibitory effects of toothpaste and mouthwash ingredients on the interaction between the SARS-CoV-2 spike PROTEIN protein and ACE2 HGNC, and the protease activity of TMPRSS2 HGNC, in vitro

    Authors: Riho Tateyama-Makino; Mari Abe-Yutori; Taku Iwamoto; Kota Tsutsumi; Motonori Tsuji; Satoru Morishita; Kei Kurita; Yukio Yamamoto; Eiji Nishinaga; Keiichi Tsukinoki

    doi:10.1101/2021.03.19.435740 Date: 2021-03-19 Source: bioRxiv

    Severe acute respiratory syndrome coronavirus 2 MESHD (SARS-CoV-2) enters host cells when the viral spike protein PROTEIN is cleaved by transmembrane protease serine 2 HGNC ( TMPRSS2 HGNC) after binding to the host angiotensin-converting enzyme 2 HGNC ( ACE2 HGNC). Since ACE2 HGNC and TMPRSS2 HGNC are expressed in the mucosa of the tongue and gingiva, the oral cavity seems like it is an entry point for SARS-CoV-2. Daily oral care using mouthwash seems to play an important role in preventing SARS-CoV-2 infection MESHD. However, the relationship between daily oral care and the mechanisms of virus entry into host cells is unclear. In this study, we evaluated the inhibitory effects of ingredients that are generally contained in toothpaste and mouthwash on the interaction between the spike protein PROTEIN and ACE2 HGNC and on the serine protease HGNC activity of TMPRSS2 HGNC using an enzyme-linked immunosorbent assay and in vitro enzyme assay, respectively. Both assays detected inhibitory effects of sodium tetradecene sulfonate, sodium N-lauroyl-N-methyltaurate, sodium N-lauroylsarcosinate MESHD, sodium dodecyl sulfate, and copper gluconate. Molecular docking simulations suggested that these ingredients could bind to the inhibitor-binding site of ACE2 HGNC. In addition, tranexamic acid and 6-aminohexanoic acid, which act as serine protease HGNC inhibitors, exerted inhibitory effects on TMPRSS2 HGNC protease activity. Further experimental and clinical studies are needed to further elucidate these mechanisms. Our findings support the possibility that toothpaste and mouthwash contain ingredients that inhibit SARS-CoV-2 infection MESHD.

    Common dandelion (Taraxacum officinale) efficiently blocks the interaction between ACE2 cell surface receptor and SARS-CoV-2 spike PROTEIN protein D614, mutants D614G, N501Y, K417N and E484K in vitro

    Authors: Hoai Thi Thu Tran; Nguyen Phan Khoi Le; Michael Gigl; Corinna Dawid; Evelyn Lamy

    doi:10.1101/2021.03.19.435959 Date: 2021-03-19 Source: bioRxiv

    On 11th March 2020, coronavirus disease 2019 MESHD ( COVID-19 MESHD), caused by the SARS-CoV-2 virus, was declared as a global pandemic by the World Health Organization (WHO). To date, there are rapidly spreading new "variants of concern" of SARS-CoV-2, the United Kingdom (B.1.1.7), the South African (B.1.351) or Brasilian (P.1) variant. All of them contain multiple mutations in the ACE2 HGNC receptor recognition site of the spike protein PROTEIN, compared to the original Wuhan sequence, which is of great concern, because of their potential for immune escape. Here we report on the efficacy of dandelion (Taraxacum officinale) to block protein-protein interaction of spike S1 to the human ACE2 cell surface receptor. This could be shown for the original spike D614, but also for its mutant forms (D614G, N501Y, and mix of K417N, E484K, N501Y) in human HEK293- hACE2 HGNC kidney and A549- hACE2 HGNC- TMPRSS2 HGNC lung cells. High molecular weight compounds in the water-based extract account for this effect. Infection of lung cells using SARS-CoV-2 spike PROTEIN pseudotyped lentivirus particles was efficiently prevented by the extract and so was virus-triggered pro-inflammatory interleukin 6 secretion. Modern herbal monographs consider the usage of this medicinal plant as safe. Thus, the in vitro results reported here should encourage further research on the clinical relevance and applicability of the extract as prevention strategy for SARS-CoV-2 infection MESHD.

    Clomipramine suppresses ACE2 HGNC-mediated SARS-CoV-2 entry MESHD

    Authors: Yuri Kato; Shigeru Yamada; Kazuhiro Nishiyama; Ayano Satsuka; Suyong Re; Daiki Tomokiyo; Jae Man Lee; Tomohiro Tanaka; Akiyuki Nishimura; Kenzo Yonemitsu; Hiroshi Asakura; Yuko Ibuki; Yumiko Imai; Noriho Kamiya; Kenji Mizuguchi; Takahiro Kusakabe; Yasunari Kanda; Motohiro Nishida

    doi:10.1101/2021.03.13.435221 Date: 2021-03-14 Source: bioRxiv

    Myocardial damage caused by the newly emerged coronavirus ( SARS-CoV-2) infection MESHD is one of key determinants of COVID-19 MESHD severity and mortality. SARS-CoV-2 entry to host cells are initiated by binding with its receptor, angiotensin converting enzyme (ACE) 2 HGNC, and the ACE2 HGNC abundance is thought to reflect the susceptibility to infection. Here, we found that clomipramine, a tricyclic antidepressant, potently inhibits SARS-CoV-2 infection MESHD and metabolic disorder MESHD in human iPS-derived cardiomyocytes. Among 13 approved drugs that we have previously identified as potential inhibitor of doxorubicin-induced cardiotoxicity MESHD, clomipramine showed the best potency to inhibit SARS-CoV-2 spike PROTEIN glycoprotein pseudovirus-stimulated ACE2 HGNC internalization. Indeed, SARS-CoV-2 infection MESHD to human iPS-derived cardiomyocytes (iPS-CMs) and TMPRSS2 HGNC-expressing VeroE6 cells were dramatically suppressed even after treatment with clomipramine. Furthermore, the combined use of clomipramine and remdesivir was revealed to synergistically suppress SARS-CoV-2 infection MESHD. Our results will provide the potentiality of clomipramine for the breakthrough treatment of severe COVID-19 MESHD.

    A simplified SARS-CoV-2 pseudovirus neutralization assay

    Authors: Gaetano Donofrio; Valentina Franceschi; Francesca Macchi; Luca Russo; Anna Rocci; Valentina Marchica; Federica Costa; Nicola Giuliani; Carlo Ferrari; Gabriele Missale

    doi:10.1101/2021.03.12.21253435 Date: 2021-03-12 Source: medRxiv

    COVID-19 MESHD is an ongoing pandemic caused by the highly infectious coronavirus SARS-CoV-2 that is engaging worldwide scientific research to find a timely and effective eradication strategy. Great efforts have been put into anti- COVID-19 MESHD vaccine generation in an effort to protect the world population and block SARS-CoV-2 spread. To validate the protective efficacy of the vaccination campaign and effectively control the pandemy, it is necessary to quantify the neutralizing antibodies induction by vaccination, since they have been established to be a correlate of protection. In this work a SARS-CoV-2 pseudovirus neutralization assay, based on a replication incompetent lentivirus expressing an adapted form of CoV-2 S protein PROTEIN and an ACE2 HGNC/ TMPRSS2 HGNC stably expressing cell line, have been minimized in term of protocol steps without loss of accuracy. The goal of the present simplified neutralization system is to improve SARS-CoV-2 vaccination campaign by means of an easy and accessible approach to be performed in any medical laboratory, maintaining the sensitivity and quantitative reliability of classical serum neutralization assays. Further this assay can be easily adapted to different coronaviruses variants by simply modifying the pseudotyping vector.

    A common TMPRSS2 HGNC variant protects against severe COVID-19 MESHD

    Authors: Alessia David; Nicholas Parkinson; Thomas P Peacock; Erola Pairo-Castineira; Tarun Khanna; Aurelie Cobat; Albert Tenesa; Vanessa Sancho-Shimizu; - GenOMICC Investigators, ISARIC4C Investigators; Jean-Laurent Casanova; Laurent Abel; Wendy S Barclay; J Kenneth Baillie; Michael J.E. Sternberg

    doi:10.1101/2021.03.04.21252931 Date: 2021-03-08 Source: medRxiv

    Infection with SARS-CoV-2 has a wide range of clinical presentations, from asymptomatic to life-threatening. Old age is the strongest factor associated with increased COVID19 MESHD-related mortality, followed by sex and pre-existing conditions. The importance of genetic and immunological factors on COVID19 MESHD outcome is also starting to emerge, as demonstrated by population studies and the discovery of damaging variants in genes controlling type I IFN immunity and of autoantibodies that neutralize type I IFNs. The human protein transmembrane protease serine type 2 ( TMPRSS2 HGNC) plays a key role in SARS-CoV-2 infection MESHD, as it is required to activate the virus spike protein PROTEIN, facilitating entry into target cells. We focused on the only common TMPRSS2 HGNC non-synonymous variant predicted to be damaging (rs12329760), which has a minor allele frequency of [~]25% in the population. In a large population of SARS-CoV-2 positive patients, we show that this variant is associated with a reduced likelihood of developing severe COVID19 MESHD (OR 0.87, 95%CI:0.79-0.97, p=0.01). This association was stronger in homozygous individuals when compared to the general population (OR 0.65, 95%CI:0.50-0.84, p=1.3x10-3). We demonstrate in vitro that this variant, which causes the amino acid substitution valine to methionine, impacts the catalytic activity of TMPRSS2 HGNC and is less able to support SARS-CoV-2 spike PROTEIN-mediated entry into cells. TMPRSS2 HGNC rs12329760 is a common variant associated with a significantly decreased risk of severe COVID19 MESHD. Further studies are needed to assess the expression of the TMPRSS2 HGNC across different age groups. Moreover, our results identify TMPRSS2 HGNC as a promising drug target, with a potential role for camostat mesilate, a drug approved for the treatment of chronic pancreatitis MESHD and postoperative reflux esophagitis MESHD, in the treatment of COVID19 MESHD. Clinical trials are needed to confirm this.

    Membrane-Mediated Sars-cov-2 Host Cell Entry: Potential Inhibitory Roles of Terpenoids in Silico

    Authors: Gideon Ampoma Gyebi; Oludare Ogunyemi; Ibrahim M. Ibrahim; Olalekan B. Ogunro; Adegbenro P. Adegunloye; Saheed Afolabi

    doi:10.21203/rs.3.rs-259624/v1 Date: 2021-02-20 Source: ResearchSquare

    Targeting viral cell entry proteins is an emerging therapeutic strategy for inhibiting the first stage of SARS-CoV-2 infection MESHD. In this study, 106 bioactive terpenoids from African medicinal plants were screened through molecular docking analysis against human angiotensin-converting enzyme 2 HGNC ( hACE2 HGNC), human transmembrane protease serine 2 HGNC ( TMPRSS2 HGNC) and the S proteins PROTEIN of SARS-CoV-2, SARS-CoV MESHD and MERS-CoV. In silico ADMET and drug-likeness prediction, molecular dynamics simulation ( MDS MESHD), binding free energy calculations and clustering analysis of MDS trajectories were performed on the top docked compounds to respective targets. The results revealed eight terpenoids with high binding tendencies to the catalytic residues of different targets. Pentacyclic terpenoids: 24-methylene cycloartenol and isoiguesterin interacted with the hACE2 HGNC binding hotspots for the SARS-CoV-2 Spike MESHD SARS-CoV-2 Spike PROTEIN protein. 11-hydroxy-2 - (3,4-dihydroxybenzoyloxy) abieta -5,7,9 (11),13-tetraene-12-one, 11-hydroxy-2 -(4-hydroxybenzoyloxy)-abieta- 5,7,9(11),13-tetraene-12-one and other abietane diterpenes interacted strongly with the S1-specificy pocket of TMPRSS2 HGNC. 3-benzoylhosloppone and cucurbitacin interacted with the RBD and S2 subunit of SARS-CoV-2 spike PROTEIN protein respectively. The predicted druggable and ADMET favourable terpenoids formed structurally stable complexes in the simulated dynamics environment. These terpenoids provides core structure that can be exploited for further lead optimization to design drugs against SARS-CoV-2 cell mediated entry, subject to further in vitro and in vivo studies. 

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MeSH Disease
HGNC Genes
SARS-CoV-2 Proteins


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