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MeSH Disease

HGNC Genes

SARS-CoV-2 proteins

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SARS-CoV-2 Proteins
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    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.

    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.

    Genomics-guided identification of potential modulators of SARS-CoV-2 entry proteases, TMPRSS2 HGNC and Cathepsins B/L

    Authors: Kartikay Prasad; Vijay Kumar

    doi:10.21203/rs.3.rs-138273/v1 Date: 2020-12-30 Source: ResearchSquare

    The entry of SARS-CoV-2 into host cells requires the activation of its spike protein PROTEIN by host cell proteases. The serine protease HGNC, transmembrane serine protease 2 ( TMPRSS2 HGNC) and cysteine proteases, cathepsins B, L ( CTSB HGNC/L) activate spike protein PROTEIN and enabling SARS-CoV-2 entry to the host cell through two completely different and independent pathways. Given that the uncertainty of how SARS-CoV-2 infects MESHD and kills, the need for a deep understanding of SARS-CoV-2 biology is imperative. Herein, we performed genomic-guided meta-analysis to identify upstream regulatory elements altering the expression of TMPRSS2 HGNC and CTSB HGNC/L genes. Further, drugs and medicinal compounds were identified based on their effects on gene expression signatures of the modulators of TMPRSS2 HGNC and CTSB HGNC/L genes. Using this strategy, estradiol and retinoic acid have been identified as putative SARS-CoV-2 alleviation agents. Further, we analysed drug-gene and gene-gene interaction network using 332 human targets of SARS-CoV-2 proteins. The network results indicate that out of 332 human proteins, estradiol interacts with 135 (41%) and retinoic acid interacts with 40 (12%) proteins. Interestingly, a combination of both estradiol and retinoic acid interacts with 153 (46%) of human proteins acting as SARS-CoV-2 targets and affect the functions of nearly all of the SARS-CoV-2 viral proteins, indicating the therapeutic benefits of drug combination therapy. Finally, molecular docking analysis suggest that both the drugs binds to TMPRSS2 HGNC and CTSL HGNC with the nanomolar to low micromolar affinity. This study, for the first time, reports the molecules like estradiol and retinoic acid as candidate drugs against both the host proteases, TMPRSS2 HGNC and CTSB HGNC/L. We here thus suggest that these antiviral drugs alone or in combination can simultaneously target both the entry pathways and thus can be considered as a potential treatment option for COVID-19 MESHD.

    Prognostic value of thrombin HGNC generation parameters in hospitalized COVID-19 MESHD patients 

    Authors: María Eugenia de la Morena-Barrio; Carlos Bravo-Pérez; Antonia Miñano; Belén de la Morena-Barrio; María Piedad Fernandez-Perez; Enrique Bernal; José Miguel Gómez-Verdu; María Teresa Herranz; Vicente Vicente; Javier Corral; María Luisa Lozano

    doi:10.21203/rs.3.rs-115220/v1 Date: 2020-11-24 Source: ResearchSquare

    Background. SARS-CoV-2 infection MESHD ARS-CoV-2 infection increases MESHDthe risk of t hrombosis MESHDby different mechanisms not fully characterized. Although still debated, an increase in D-dimer has been proposed as a first-line hemostasis test associated with t hromboembolic MESHDrisk and unfavorable prognosis. Objective. We aim to systematically and comprehensively evaluate the association between t hrombin HGNCgeneration parameters and the inflammatory and hypercoagulable state, as well as their prognostic value in COVID-19 MESHD patientsMethods. A total of 127 hospitalized patients with confirmed COVID-19 MESHD, 24 hospitalized patients with SARS-CoV-2-negative p neumonia MESHDand 12 healthy subjects were included. Clinical characteristics, t hrombin HGNCgeneration triggered by tissue factor with and without soluble thrombomodulin, and also by silica, as well as other biochemical parameters were assessed.Results. Despite the frequent use of heparin, COVID-19 MESHD patients had similar t hrombin HGNCgeneration than healthy controls. In COVID-19 MESHD patients, the t hrombin HGNCgeneration lag-time positively correlated with markers of cell lysis (LDH), i nflammation MESHD(CRP, I L-6) HGNC and coagulation (D-dimer), while the endogenous t hrombin HGNCpotential (ETP) inversely correlated with D-dimer and LDH, and positively correlated with f ibrinogen HGNClevels. Patients with more prolonged lag-time and decreased ETP presented with increased ISTH-DIC scores, and had more severe disease (vascular events and d eath) MESHD. The ROC curve and Kaplan Meier estimate indicated that the D-dimer/ETP ratio was associated with in-hospital mortality (HR 2.5; p=0.006), and with the occurrence of major adverse events (composite end-point of vascular events and d eath) MESHD (HR 2.38; p=0.004).Conclusions. The t hrombin HGNCgeneration ETP and lag-time variables correlate with thromboinflammatory markers, and the D-dimer/ETP ratio can predict major adverse events in COVID-19 MESHD.

    The SARS-CoV-2 multibasic cleavage site facilitates early serine protease HGNC-mediated entry into organoid-derived human airway cells

    Authors: Anna Z Mykytyn; Tim I Breugem; Samra Riesebosch; Debby Schipper; Petra B van den Doel; Robbert Rottier; Mart M Lamers; Bart L Haagmans; Hao-Yuan Cheng; Ta-Chou Ng; Hsien-Ho Lin; Rob Hinch; Joanna Masel; A. Marm Kilpatrick; Christophe Fraser; Raquel Gonzalez Seoane; Clara Martinez Diago; Esther Canedo Carballeira; Macarena Alferez Alvarez Mallo; Cristina Casanova Pedraz; Onofre Alomar Mateu; Cristina Lesmes Heredia; Juan Carlos Wizner de Alva; Ruth Bernardo Vega; Montserrat Macia Badia; Cristina Alvarez Colomo; Antonio Sanchez Munoz; Laia Pratcorona Alicart; Ruben Alonso Saiz; Monica Lopez Rodriguez; Maria Carmen Barbancho Lopez; Marta Meca Casbas; Oscar Vaquerizo Ruiz; Eva Moran Antolin; Maria Jose Nunez Valera; Camino Fernandez Fernandez; Albert Tubau Navarra; Alejandra M Cano Garcia; Carmen Baena Luque; Susana Soldevilla Perez; Irene Gastaca Abasolo; Jose Adanez Garcia; Maria Teulon Gonzalez; Alberto Puertas Prieto; Rosa Ostos; Maria del Pilar Guadix Martin; Monica Catalina Coello; Maria Luisa De la Cruz Conti; Africa Cano Aguilar; Jose A Sainz Bueno

    doi:10.1101/2020.09.07.286120 Date: 2020-09-07 Source: bioRxiv

    After the SARS-CoV outbreak in 2003, a second zoonotic coronavirus named SARS-CoV-2, emerged late 2019 in China and rapidly caused the COVID-19 pandemic MESHD COVID-19 pandemic MESHD leading to a public health crisis of an unprecedented scale. Despite the fact that SARS-CoV-2 uses the same receptor as SARS-CoV, transmission and pathogenesis of both viruses seem to be quite distinct. A remarkable feature of the SARS-CoV-2 spike PROTEIN is the presence of a multibasic cleavage site, which is absent in the SARS-CoV spike MESHD. The viral spike protein PROTEIN not only attaches to the entry receptor, but also mediates fusion after cleavage by host proteases. Here, we report that the SARS-CoV-2 spike PROTEIN multibasic cleavage site increases infectivity on differentiated organoid-derived human airway cells. Compared with SARS-CoV, SARS-CoV-2 MESHD entered faster into the lung cell line Calu-3, and more frequently formed syncytial cells in differentiated organoid-derived human airway cells. Moreover, the multibasic cleavage site increased entry speed and plasma membrane serine protease HGNC usage relative to endosomal entry using cathepsins. Blocking serine protease HGNC activity using the clinically approved drug camostat mesylate effectively inhibited SARS-CoV-2 entry and replication in differentiated organoid-derived human airway cells. Our findings provide novel information on how SARS-CoV-2 enters relevant airway cells and highlight serine proteases as an attractive antiviral target.

    Haematological factors of SARS-CoV-2 infection MESHD aggravation: a COVID'HEMOS study

    Authors: Paul Billoir; Kevin Alexandre; Thomas Duflot; Maxime Roger; Sebastien Miranda; Odile Goria; Luc Marie Joly; Mathieu Demeyere; Guillaume Feugray; Manuel Etienne; Veronique Le Cam Duchez

    doi:10.21203/rs.3.rs-64302/v1 Date: 2020-08-23 Source: ResearchSquare

    Since December 2019, a pandemic caused by a new coronavirus has spread to more than 170 countries around the world. Worsening infected MESHD patients requiring intensive care unit (ICU) admission, associated with 30% of mortality. A part of worsening is mediated by haemostasis deregulation. The primary aim of this study was to determine if haematological biomarkers, in addition to clinical risk factors on hospital admission, predict worsening (defined by ICU admission and/or death MESHD) in Covid-19 MESHD infected MESHD patients, and secondary, if they could predict the occurrence of thrombotic MESHD events. Thirty-five of the 99 patients got clinically worse and 8 developed pulmonary embolism MESHD ( PE MESHD). Final model of the logistic regression analysis revealed that oxygenodependence (RR=7.27[1.50-19.31]), fibrinogen HGNC levels (RR=1.45[1.17-1.82]), thrombin HGNC peak (RR=1.28[1.03-1.59]), monocytes counts below 0.2 G/L (RR=2.88[1.67-3.19]) and prothrombin fragment 1+2 ( F1+2 HGNC) higher than 290 pM (RR=2.39[1.20-3.30]) were associated with clinical worsening. Fibrinogen HGNC level threshold of 5.5 g/L, thrombin HGNC peak measurement threshold of 99 pM and oxygenodepence allowed prediction of clinical outcome in near than 80% of our cohort. Moreover, using ROC curves, thrombin HGNC peak and F1+2 HGNC on admission with a threshold of 204 nM and 393 pM were sensitive and specific to predict PE MESHD (AUC: 85.7% Se: 70.8% Sp: 100% and AUC: 81.5% Se: 75.0% Sp: 86.8% respectively). In conclusion, we described a rapid decision tree to predict outcome of SARS-CoV-2 infected MESHD patients based on fibrinogen HGNC, TGA HGNC peak and oxygen dependence. Furthermore, thrombin HGNC peak and F1+2 HGNC seem to be specific haematological marker to predict PE MESHD, even in patients with thromboprophylaxis.

    Generation of human bronchial organoids for SARS-CoV-2 research

    Authors: Tatsuya Suzuki; Yumi Ito; Yusuke Sakai; Akatsuki Saito; Daisuke Okuzaki; Daisuke Motooka; Shohei Minami; Takeshi Kobayashi; Takuya Yamamoto; Toru Okamoto; Kazuo Takayama

    doi:10.1101/2020.05.25.115600 Date: 2020-05-26 Source: bioRxiv

    Coronavirus disease 2019 MESHD ( COVID-19 MESHD) is a disease that causes fatal disorders MESHD including severe pneumonia MESHD. To develop a therapeutic drug for COVID-19 MESHD, a model that can reproduce the viral life cycle and evaluate the drug efficacy of anti-viral drugs is essential. In this study, we established a method to generate human bronchial organoids (hBO) from commercially available cryopreserved human bronchial epithelial cells and examined whether they could be used as a model for severe acute respiratory syndrome coronavirus 2 MESHD (SARS-CoV-2) research. Our hBO contain basal, club, ciliated, and goblet cells. Angiotensin-converting enzyme 2 HGNC ( ACE2 HGNC), which is a receptor for SARS-CoV-2, and transmembrane serine proteinase 2 ( TMPRSS2 HGNC), which is an essential serine protease HGNC for priming spike (S) protein PROTEIN of SARS-CoV-2, were highly expressed. After SARS-CoV-2 infection MESHD, not only the intracellular viral genome, but also progeny virus, cytotoxicity MESHD, pyknotic cells, and moderate increases of the type I interferon signal could be observed. Treatment with camostat, an inhibitor of TMPRSS2 HGNC, reduced the viral copy number to 2% of the control group. Furthermore, the gene expression profile in SARS-CoV-2-infected MESHD hBO was obtained by performing RNA-seq analysis. In conclusion, we succeeded in generating hBO that can be used for SARS-CoV-2 research and COVID-19 MESHD drug discovery. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/115600v2_ufig1.gif" ALT="Figure 1"> View larger version (99K): org.highwire.dtl.DTLVardef@13a6908org.highwire.dtl.DTLVardef@1c59300org.highwire.dtl.DTLVardef@362167org.highwire.dtl.DTLVardef@1cb31ed_HPS_FORMAT_FIGEXP M_FIG C_FIG

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MeSH Disease
HGNC Genes
SARS-CoV-2 Proteins


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