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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.

    Spontaneous Binding of Potential COVID-19 MESHD Drugs to Human Serine Protease HGNC TMPRSS2

    Authors: Haixia Zhu; Wenhao Du; Menghua Song; Qing Liu; Andreas Herrmann; Qiang Huang

    doi:10.26434/chemrxiv.13049663.v1 Date: 2020-10-06 Source: ChemRxiv

    Effective treatment or vaccine is not yet available for combating SARS coronavirus 2 (SARSCoV-2) that caused the COVID-19 pandemic MESHD COVID-19 pandemic MESHD. Recent studies showed that two drugs, Camostat and Nafamostat, might be repurposed to treat COVID-19 MESHD by inhibiting human TMPRSS2 HGNC required for proteolytic activation of viral spike ( S) glycoprotein PROTEIN. However, their molecular mechanisms of pharmacological action remain unclear. Here, we perform molecular dynamics simulations to investigate their native binding sites on TMPRSS2 HGNC. We revealed that both drugs could spontaneously and stably bind to the TMPRSS2 HGNC catalytic center, and thereby inhibit its proteolytic processing of the S protein PROTEIN. Also, we found that Nafamostat is more specific than Camostat for binding to the catalytic center, consistent with reported observation that Nafamostat blocks the SARS-CoV-2 infection MESHD at a lower concentration. Thus, this study provides mechanistic insights into the Camostat and Nafamostat inhibition of the SARS-CoV-2 infection MESHD, and offers useful information for COVID-19 MESHD drug development.

    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

    Repurposed Single Inhibitor for Serine Protease HGNC and Spike Glycoproteins PROTEIN of SAR-CoV-2

    Authors: Hamdullah Khadim Sheikh; Tanzila Arshad; Zainab Sher Mohammad; Iqra Arshad; Mohtasheemul Hassan

    doi:10.26434/chemrxiv.12192660.v1 Date: 2020-04-27 Source: ChemRxiv

    In this research, structure of SARS-CoV-2 spike PROTEIN glycoprotein S1 and S2 along with TMPRSS2 HGNC, TMPRSS4 HGNC, TMPRSS11A HGNC, TMPRSS11D HGNC and TMPRSS11E serine protease (which activates S1 and S2) are used for docking with repurposed inhibitor drug molecules. We searched for a universally active drug molecule which binds with glycoproteins and serine protease HGNC with binding energy above a pre-set threshold value, thus single handedly inhibits the virus glycoprotein interaction with ACE-II receptor on human cell preventing the virus RNA transfer to human cell. Through data analysis performed on binding energies of the selected repurposed inhibitors, we found out five molecules to have high binding energies on both spike glycoproteins PROTEIN and serine protease HGNC, while showing less variance in their binding energies. Among these five, Edoxaban is an FDA approved commercially available drug molecule. Hence, high binding molecular inhibitors for spike glycoprotein PROTEIN and serine protease for treatment of SARS-CoV-2 were identified.

    TMPRSS2 HGNC and TMPRSS4 HGNC mediate SARS-CoV-2 infection MESHD of human small intestinal enterocytes

    Authors: Ruochen Zang; Maria F.G. Castro; Broc T. McCune; Qiru Zeng; Paul W. Rothlauf; Naomi M. Sonnek; Zhuoming Liu; Kevin F. Brulois; Xin Wang; Harry B. Greenberg; Michael S. Diamond; Matthew A. Ciorba; Sean P.J. Whelan; Siyuan Ding

    doi:10.1101/2020.04.21.054015 Date: 2020-04-23 Source: bioRxiv

    Both gastrointestinal symptoms MESHD and fecal shedding of SARS-CoV-2 RNA have been frequently observed in COVID-19 MESHD patients. However, whether SARS-CoV-2 replicate in the human intestine and its clinical relevance to potential fecal-oral transmission remain unclear. Here, we demonstrate productive infection of SARS-CoV-2 in ACE2 HGNC+ mature enterocytes in human small intestinal enteroids. In addition to TMPRSS2 HGNC, another mucosa-specific serine protease HGNC, TMPRSS4 HGNC, also enhanced SARS-CoV-2 spike PROTEIN fusogenic activity and mediated viral entry into host cells. However, newly synthesized viruses released into the intestinal lumen were rapidly inactivated by human colonic fluids and no infectious virus was recovered from the stool specimens of COVID-19 MESHD patients. Our results highlight the intestine as a potential site of SARS-CoV-2 replication, which may contribute to local and systemic illness MESHD and overall disease progression.

    Structural Basis of SARS-CoV-2 Spike PROTEIN Protein Priming by TMPRSS2

    Authors: Mushtaq Hussain; Nusrat Jabeen; Anusha Amanullah; Ayesha Ashraf Baig; Basma Aziz; Sanya Shabbir; Fozia Raza

    doi:10.1101/2020.04.21.052639 Date: 2020-04-22 Source: bioRxiv

    Entry of SARS-CoV-2, etiological agent of COVID-19 MESHD, in the host cell is driven by the interaction of its spike protein PROTEIN with human ACE2 receptor and a serine protease HGNC, TMPRSS2 HGNC. Although complex between SARS-CoV-2 spike PROTEIN protein and ACE2 HGNC has been structurally resolved, the molecular details of the SARS-CoV-2 and TMPRSS2 HGNC complex are still elusive. TMPRSS2 HGNC is responsible for priming of the viral spike protein PROTEIN that entails cleavage of the spike protein PROTEIN at two potential sites, Arg685/Ser686 and Arg815/Ser816. The present study aims to investigate the conformational details of complex between TMPRSS2 HGNC and SARS-CoV-2 spike PROTEIN protein, in order to discern the finer details of the priming of viral spike and to point candidate drug targets. Briefly, full length structural model of TMPRSS2 HGNC was developed and docked against the resolved structure of SARS-CoV-2 spike PROTEIN protein with directional restraints of both cleavage sites. The docking simulations showed that TMPRSS2 HGNC interacts with the two different loops of SARS-CoV-2 spike PROTEIN protein, each containing different cleavage sites. Key functional residues of TMPRSS2 HGNC (His296, Ser441 and Ser460) were found to interact with immediate flanking residues of cleavage sites of SARS-CoV-2 spike PROTEIN protein. Compared to the N-terminal cleavage site (Arg685/Ser686), TMPRSS2 HGNC region that interact with C-terminal cleavage site (Arg815/Ser816) of the SARS-CoV-2 spike PROTEIN protein was predicted as relatively more druggable. In summary, the present study provide structural characteristics of molecular complex between human TMPRSS2 HGNC and SARS-CoV-2 spike PROTEIN protein and points to the candidate drug targets that could further be exploited to direct structure base drug designing.

    scRNA-seq reveals ACE2 HGNC and TMPRSS2 HGNC expression in TROP2 HGNC+ Liver Progenitor Cells: Implications in COVID-19 MESHD associated Liver Dysfunction

    Authors: Justine Jia Wen Seow; Rhea Pai; Archita Mishra; Edwin Shepherdson; Tony Kiat Hon Lim; Brian K P Goh; Jerry KY Chan; Pierce KH Chow; Florent Ginhoux; Ramanuj DasGupta; Ankur Sharma

    doi:10.1101/2020.03.23.002832 Date: 2020-03-25 Source: bioRxiv

    The recent pandemic of coronavirus disease 2019 MESHD ( COVID-19 MESHD) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). COVID-19 MESHD was first reported in China (December 2019) and now prevalent in [~]170 countries across the globe. Entry of SARS-CoV-2 into mammalian cells require the binding of viral Spike (S) proteins PROTEIN to the ACE2 HGNC (angiotensin converting enzyme 2) receptor. Once entered the S protein PROTEIN is primed by a specialised serine protease HGNC, TMPRSS2 HGNC (Transmembrane Serine Protease 2) in the host cell. Importantly, beside respiratory symptoms, consistent with other common respiratory virus infection MESHD when patients become viraemic, a significant number of COVID-19 MESHD patients also develop liver comorbidities. We explored if specific target cell-type in the mammalian liver, could be implicated in disease pathophysiology other than the general deleterious response to cytokine storms. Here we employed single-cell RNA-seq (scRNA-seq) to survey the human liver and identified potentially implicated liver cell-type for viral ingress. We report the co-expression of ACE2 HGNC and TMPRSS2 HGNC in a TROP2 HGNC+ liver progenitor population. Importantly, we fail to detect the expression of ACE2 HGNC in hepatocyte or any other liver (immune and stromal) cell types. These results indicated that in COVID-19 MESHD associated liver dysfunction MESHD and cell death, viral infection of TROP2 HGNC+ progenitors in liver may significantly impaired liver regeneration and could lead to pathology. Highlights- EPCAM HGNC+ Liver progenitors co-express ACE2 HGNC and TMPRSS2 HGNC - ACE2 HGNC and TMPRSS2 HGNC expression is highest in TROP2 HGNChigh progenitors - ACE2 HGNC and TMPRSS2 HGNC cells express cholangiocyte biased fate markers - ACE2 HGNC and TMPRSS2 HGNC positive cells are absent in human fetal liver

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MeSH Disease
HGNC Genes
SARS-CoV-2 Proteins


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