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MeSH Disease

HGNC Genes

SARS-CoV-2 proteins

ProteinS (87)

ProteinN (5)

NSP5 (2)

ProteinE (2)

NSP3 (1)


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SARS-CoV-2 Proteins
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    The lethal triad: SARS-CoV-2 Spike MESHD SARS-CoV-2 Spike PROTEIN, ACE2 HGNC and TMPRSS2 HGNC. Mutations in host and pathogen may affect the course of pandemic.

    Authors: Matteo Calcagnile; Patricia Forgez; Pietro Alifano; Marco Alifano; Leonardo C Caserta; Patrick K. Mitchell; Eric Cassmann; Alicia Rollins; Nancy C Zylich; Randall Wayne Renshaw; Cassandra Guarino; Bettina Wagner; Kelly Lager; Diego G Diel; Sankar Bhattacharyya; Samreen Siddiqui; Akansha Tyagi; Sujeet Jha; Rajesh Pandey; Somnath Dutta; Rajesh P. Ringe; Raghavan Varadarajan; Louis-Marie Bloyet; Fabio Benigni; Elisabetta Cameroni; Johan Neyts; Agostino Riva; Gyorgy Snell; Amalio Telenti; Sean PJ Whelan; Herbert W Virgin; Davide Corti; Matteo Samuele Pizzuto; David Veesler

    doi:10.1101/2021.01.12.426365 Date: 2021-01-14 Source: bioRxiv

    Variants of SARS-CoV-2 have been identified rapidly after the beginning of pandemic. One of them, involving the spike protein PROTEIN and called D614G, represents a substantial percentage of currently isolated strains. While research on this variant was ongoing worldwide, on December 20th 2020 the European Centre for Disease Prevention and Control reported a Threat Assessment Brief describing the emergence of a new variant of SARS-CoV-2, named B.1.1.7, harboring multiple mutations mostly affecting the Spike protein PROTEIN. This viral variant has been recently associated with a rapid increase in COVID-19 MESHD cases in South East England, with alarming implications for future virus transmission rates. Specifically, of the nine amino acid replacements that characterize the Spike in the emerging variant, four are found in the region between the Fusion Peptide and the RBD domain (namely the already known D614G, together with A570D, P681H, T716I), and one, N501Y, is found in the Spike Receptor Binding Domain - Receptor Binding Motif (RBD- RBM HGNC). In this study, by using in silico biology, we provide evidence that these amino acid replacements have dramatic effects on the interactions between SARS-CoV-2 Spike PROTEIN SARS-CoV-2 Spike MESHD and the host ACE2 receptor or TMPRSS2 HGNC, the protease that induces the fusogenic activity of Spike. Mostly, we show that these effects are strongly dependent on ACE2 HGNC and TMPRSS2 HGNC polymorphism, suggesting that dynamics of pandemics are strongly influenced not only by virus variation but also by host genetic background.

    Comparative Study of Epithelial Entry Gene Expression of SARS-Cov-2 and Other Human Viral Species in Asthma: Differences by Sex, Airway Location Aand Disease MESHD Endotype

    Authors: Mackenzie Coden; Lucas Loffredo; Hiam Abdala-Valencia; Sergejs Berdnikovs

    id:10.20944/preprints202101.0266.v1 Date: 2021-01-14 Source: Preprints.org

    Epithelial characteristics underlying the differential susceptibility of chronic asthma to SARS-CoV-2 MESHD ( COVID-19 MESHD) and other viral infections MESHD are currently unclear. By revisiting transcriptomic data from patients with Th2 low versus Th2 high asthma, as well as mild, moderate and severe asthmatics, we characterized the changes in expression of human coronavirus and influenza viral entry genes relative to sex, airway location and disease endotype. We found sexual dimorphism in expression of COVID-19 MESHD genes ACE2, TMPRSS2 HGNC, TMPRSS4 HGNC, and SLC6A19 HGNC. ACE2 receptor downregulation occurred specifically in females in Th2 high asthma, while proteases broadly assisting coronavirus and influenza viral entry, TMPRSS2 HGNC and TMPRSS4 HGNC, were highly upregulated in both sexes. Overall, changes in COVID-19 MESHD gene expression were specific to Th2 high molecular endotype of asthma MESHD, and different by asthma severity and airway location. The downregulation of ACE2 ( COVID-19 MESHD, SARS) and ANPEP (HCoV-229E) viral receptors correlated with loss of club and ciliated cells in Th2 high asthma, while the increase in DPP4 (MERS-CoV), ST3GAL4, and ST6GAL1 (influenza) associated with an increase in goblet and basal activated cells. Overall, this study elucidates sex, airway location, disease endotype and changes in epithelial heterogeneity as factors underlying asthmatic susceptibility, or lack thereof, to COVID-19 MESHD.

    Comprehensive comparison of transcriptomes in SARS-CoV-2 infection MESHD: alternative entry routes and innate immune responses

    Authors: Yingying Cao; Daniel Hoffmann; Pei Hao; Xintian Xu; Lina Song; Simo Kitanovski; Jun Wang; Matthias Buck; Aaron Weinberg; Chun-Che Liao; Yen-Hui Chen; Jia-Tsrong Jan; Cheng-Pu Sun; Yin-Shiou Lin; Ping-Yi Wu; Yu-Chiuan Wang; Mi-Hua Tao; Yi-Ling Lin

    doi:10.1101/2021.01.07.425716 Date: 2021-01-07 Source: bioRxiv

    The pathogenesis of COVID-19 MESHD emerges as complex, with multiple factors leading to injury of different organs. Several studies on underlying cellular processes have produced contradictory claims, e.g. on SARS-CoV-2 cell entry or innate immune responses. However, clarity in these matters is imperative for therapy development. We therefore performed a meta-study with a diverse set of transcriptomes under infections with SARS-CoV-2, SARS-CoV MESHD and MERS-CoV, including data from different cells and COVID-19 MESHD patients. Using these data, we investigated viral entry routes and innate immune responses. First, our analyses support the existence of cell entry mechanisms for SARS and SARS-CoV-2 other than the ACE2 HGNC route with evidence of inefficient infection of cells without expression of ACE2 HGNC; expression of TMPRSS2 HGNC/TPMRSS4 is unnecessary for efficient SARS-CoV-2 infection MESHD with evidence of efficient infection of A549 cells transduced with a vector expressing human ACE2 HGNC. Second, we find that innate immune responses in terms of interferons and interferon simulated genes are strong in relevant cells, for example Calu3 cells, but vary markedly with cell type, virus dose, and virus type.

    TMPRSS2 structure-phylogeny repositions Avoralstat for SARS-CoV-2 prophylaxis in mice

    Authors: Young Joo Sun; Gabriel Velez; Dylan Parsons; Kun Li; Miguel Ortiz; Shaunik Sharma; Paul B McCray; Alexander G Bassuk; Vinit B Mahajan; Fionn Ma; Eric HY Lau; Samuel MS Cheng; Leo LM Poon; Malik JS Peiris; Sophie A Valkenburg; Niloufar Kavian; Mikaela Olausson; My Hedhammar; Hanna Tegel; Sara Mangsbo; Mia Phillipson; Anna Manberg; Sophia Hober; Peter Nilsson; Charlotte Thalin; Samuel Bates; Chevaun Morrison-Smith; Benjamin Nicholson; Edmond Wong; Leena El-Mufti; Michael Kann; Anna Bolling; Brooke Fortin; Hayden Ventresca; Wen Zhou; Santiago Pardo; Megan Kwock; Aditi Hazra; Leo Cheng; Rushdy Ahmad; James A. Toombs; Rebecca Larson; Haley Pleskow; Nell Meosky Luo; Christina Samaha; Unnati M. Pandya; Pushpamali De Silva; Sally Zhou; Zakary Ganhadeiro; Sara Yohannes; Rakiesha Gay; Jacqueline Slavik; Shibani S. Mukerji; Petr Jarolim; David R. Walt; Becky C. Carlyle; Lauren L. Ritterhouse; Sara Suliman

    doi:10.1101/2021.01.04.425289 Date: 2021-01-04 Source: bioRxiv

    Drugs targeting host proteins can act prophylactically to reduce viral burden early in disease and limit morbidity, even with antivirals and vaccination. Transmembrane serine protease 2 ( TMPRSS2 HGNC) is a human protease required for SARS-CoV-2 viral entry and may represent such a target.1-3 We hypothesized drugs selected from proteins related by their tertiary structure, rather than their primary structure, were likely to interact with TMPRSS2 HGNC. We created a structure-based phylogenetic computational tool 3DPhyloFold to systematically identify structurally similar serine proteases with known therapeutic inhibitors and demonstrated effective inhibition of SARS-CoV-2 infection MESHD in vitro and in vivo.4,5 Several candidate compounds, Avoralstat, PCI-27483, Antipain, and Soybean-Trypsin-Inhibitor, inhibited TMPRSS2 HGNC in biochemical and cell infection assays. Avoralstat, a clinically tested Kallikrein-related B1 inhibitor,6 inhibited SARS-CoV-2 entry MESHD and replication in human airway epithelial cells. In an in vivo proof of principle,5 Avoralstat significantly reduced lung tissue titers and mitigated weight-loss MESHD when administered prophylactically to SARS-CoV-2 susceptible mice indicating its potential to be repositioned for COVID-19 MESHD prophylaxis in humans.

    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.

    Enzalutamide, a prostate cancer MESHD therapeutic, downregulates TMPRSS2 HGNC in lung and reduces cellular entry of SARS-CoV-2

    Authors: D. A. Leach; A. Mohr; E. S. Giotis; A. M. Isac; L. L. Yates; W. S. Barclay; R. M. Zwacka; C. L. Bevan; G. N. Brooke

    doi:10.21203/rs.3.rs-137931/v1 Date: 2020-12-29 Source: ResearchSquare

    The COVID-19 pandemic MESHD, caused by the novel human coronavirus SARS-CoV-2 coronavirus MESHD, attacks various organs but most destructively the lung. It has been shown that SARS-CoV-2 entry into lung cells requires two host cell surface proteins: ACE2 HGNC and TMPRSS2 HGNC. Downregulation of one or both of these is thus a potential therapeutic approach for COVID-19 MESHD TMPRSS2 HGNC is a known target of the androgen receptor HGNC, a ligand-activated transcription factor; activation of the androgen receptor HGNC increases TMPRSS2 HGNC levels in various tissues, most notably the prostate. We show here that treatment with the antiandrogen enzalutamide – a well-tolerated drug widely used in advanced prostate cancer MESHD – reduces TMPRSS2 HGNC levels in human lung cells. Further, enzalutamide treatment of mice dramatically decreased Tmprss2 levels in the lung. To determine therapeutic potential, we assessed uptake of SARS-CoV-2 Spike MESHD SARS-CoV-2 Spike PROTEIN protein pseudotyped lentivirus and live SARS-CoV-2 into human lung cells and saw a significant reduction in viral entry and infection upon treatment with the antiandrogens enzalutamide and bicalutamide. In support of this new experimental data, analysis of existing datasets shows striking co-expression of AR and TMPRSS2 HGNC, including in specific lung cell types that are targeted by SARS-CoV-2. Together, the data presented provides strong evidence to support clinical trials to assess the efficacy of antiandrogens as a treatment option for COVID-19 MESHD.

    Non-covalent TMPRSS2 HGNC inhibitors identified from virtual screening

    Authors: Xin Hu; Jonathan H Shrimp; Hui Guo; Alexey V. Zakharov; Sankalp Jain; Paul Shinn; Anton Simeonov; Matthew Hall; Min Shen; Munif Haddad; Giordano Pula; Reiner Mailer; Hartmut Schlueter; Florian Langer; Klaus Pueschel; Kosta Panousis; Evi Stavrou; Coen Maas; Thomas Renne; Sachin B Surade; Omodele Ashiru; Lucia Crippa; Richard Cowan; Matthew W Bowler; Jamie I Campbell; Wing-Yiu Jason Lee; Mark D Carr; David Matthews; Paul Pfeffer; Simon E Hufton; Kovilen Sawmynaden; Jane Osbourn; John McCafferty; Aneesh Karatt-Vellatt

    doi:10.1101/2020.12.28.424413 Date: 2020-12-29 Source: bioRxiv

    The SARS-CoV-2 pandemic has prompted researchers to pivot their efforts to finding anti-viral compounds and vaccines. In this study, we focused on the human host cell transmembrane protease serine 2 HGNC ( TMPRSS2 HGNC), which plays an important role in the viral life cycle by cleaving the spike protein PROTEIN to initiate membrane fusion. TMPRSS2 HGNC is an attractive target and has received significant attention for the development of drugs against SARS and MERS. Starting with comparative structural modeling and binding model analysis, we developed an efficient pharmacophore-based approach and applied in a large-scale in silico database screening for small molecule inhibitors against TMPRSS2 HGNC. A number of novel inhibitors were identified, providing starting points for further development of drug candidates for the treatment of COVID-19 MESHD.

    SPINT2 HGNC controls SARS-CoV-2 viral infection and is associated to disease severity

    Authors: Carlos Ramirez; Ashwini Kumar Sharma; Carmon Kee; Leonie Thomas; Steeve Boulant; Carl Herrmann; Victoria A Avanzato; Jonathan E Schulz; Neeltje van Doremalen; Chad Clancy; Vincent Munster; Elisa Casa; Inesa Hyseni; Linda Benincasa; Emanuele Montomoli; Rommie E. Amaro; Jason S McLellan; Rino Rappuoli; Michael Diamond

    doi:10.1101/2020.12.28.424029 Date: 2020-12-28 Source: bioRxiv

    COVID-19 MESHD outbreak is the biggest threat to human health in recent history. Currently, there are over 1.5 million related deaths MESHD and 75 million people infected around the world (as of 22/12/2020). The identification of virulence factors which determine disease susceptibility and severity in different cell types remains an essential challenge. The serine protease TMPRSS2 HGNC has been shown to be important for S protein PROTEIN priming and viral entry, however, little is known about its regulation. SPINT2 HGNC is a member of the family of Kunitz type serine protease inhibitors and has been shown to inhibit TMPRSS2 HGNC. Here, we explored the existence of a co-regulation between SPINT2 HGNC/ TMPRSS2 HGNC and found a tightly regulated protease/inhibitor expression balance across tissues. We found that SPINT2 HGNC negatively correlates with SARS-CoV-2 expression in Calu-3 and Caco-2 cell lines and was down-regulated in secretory cells from COVID-19 MESHD patients. We validated our findings using Calu-3 cell lines and observed a strong increase in viral load after SPINT2 HGNC knockdown. Additionally, we evaluated the expression of SPINT2 HGNC in datasets from comorbid diseases using bulk and scRNA-seq data. We observed its down-regulation in colon, kidney and liver tumors MESHD as well as in alpha pancreatic islets cells from diabetes Type 2 MESHD patients, which could have implications for the observed comorbidities in COVID-19 MESHD patients suffering from chronic diseases MESHD.

    Dutasteride Reduces Viral Shedding, Inflammatory Responses and Time-to-Remission in COVID-19 MESHD: Biochemical Findings of a Randomized Double-Blind Placebo Controlled Interventional Trial (DUTA AndroCoV-Trial - Biochemical). 

    Authors: Flávio Adsuara Cadegiani; John McCoy; Carlos Gustavo Wambier; Andy Goren

    doi:10.21203/rs.3.rs-135815/v1 Date: 2020-12-24 Source: ResearchSquare

    Importance: SARS-CoV-2 cell entry and infectivity is indirectly dependent on androgenic status and phenotype through the regulation of t ransmembrane protease serine 2 HGNC(T MPRSS2) HGNC, an androgen-mediated proteolytic enzyme that facilitates SARS-CoV-2 entry.  Males, particularly those affected by androgenetic alopecia (AGA) are overrepresented in severe COVID-19 MESHD, while the use of 5-alpha-reductase inhibitors (5ARis), an antiandrogenic drug class, may reduce COVID-19 MESHD severity. Objective: Our objective was to determine if dutasteride, a wide and potent 5ARi, would bring biochemical and virological benefits in early COVID-19 MESHD.Design, Setting, and Participants: A double-blinded, randomized, prospective, investigational study of dutasteride for the treatment of COVID-19 MESHD, as add-on therapy to the local standard of care, for mild or moderate, non-hospitalized subjects confirmed for S ARS-CoV-2 MESHD(The Duta AndroCoV Trial).Interventions:  Dutasteride 0.5mg/day or placebo for 30 days or until full COVID-19 MESHD remission. Nitazoxanide was given 500mg twice a day for six days and azithromycin was given 500mg/day for five days for all subjects.Main Outcome(s) and Measure(s): Remission times for fatigue, ageusia, anosmia, and overall disease, oxygen saturation (%), real-time polymerase chain reaction (rtPCR-SARS-CoV-2), ultrasensitive C -reactive protein HGNC(usCRP), D-dimer, lactate, dehydrogenase lactate (DHL), erythrocyte sedimentation rate (ESR), ultrasensitive troponin and ferritin.Results:  Compared to placebo group (n=44) with similar baseline characteristics, dutasteride (n=43) presented reduced fatigue, anosmia and overall disease duration (46.6%, 49.6% and 43.2% lower duration, respectively; p<.0001 for all), and in Day 7 presented higher rates of virologic cure (64.3% versus 11.8% cure; p=.0094), , increased recovery rate (84.7% versus 57.5%; p=.03), higher mean [SD] oxygen saturation (97.0% [1.4%] versus 95.7% [2.0%]; p=.02), lower median [IQR] usCRP (0.34mg/L [0.23mg/L -0.66mg/L] versus 1.47mg/L [0.70mg/L-3.37mg/L]; p<.0001),  lower median [IQR] lactate (2.01mmol/L [1.12mmol/L-2.43mmol/L] versus 2.66mmol/L [2.05mmol/L-3.55mmol/L]; p=.0049), lower median [IQR] ESR (5.0mm/1h [3.0mm/1h-11.0mm/1h] versus 14.0mm/1h [7.25mm/1h-18.5mm/1h]; p=.0007), lower median [IQR] LDH (165U/L [144U/L -198U/L] versus 210U/L [179U/L-249U/L]; p=.0013 and lower median [IQR] troponin levels (0.005ng/mL [0.003ng/mL-0.009ng/mL] versus 0.007ng/mL [0.006ng/mL-0.010ng/mL]; p=.048).Conclusions and Relevance: These findings suggest that dutasteride reduces clinical and virologic disease duration and inflammatory markers in males with mild-to-moderate, early-stage COVID-19 MESHD, and should be considered as a therapeutic option in the current context of the COVID-19 pandemic MESHD.Trial Registration: NCT04446429

    Platycodin D prevents both lysosome- and TMPRSS2 HGNC-driven SARS-CoV-2 infection MESHD in vitro by hindering membrane fusion

    Authors: Tai Young Kim; Sangeun Jeon; Youngho Jang; Lizaveta Gotina; Joungha Won; Yeon Ha Ju; Sunpil Kim; Minwoo Wendy Jang; Woojin Won; Mingu Gordon Park; Ae Nim Pae; Sunkyu Han; Seungtaek Kim; C. Justin Lee; Toby Passioura; Richard J Payne

    doi:10.1101/2020.12.22.423909 Date: 2020-12-23 Source: bioRxiv

    An ongoing pandemic of coronavirus disease 2019 MESHD ( COVID-19 MESHD) is now the greatest threat to the global public health. Herbal medicines and their derived natural products have drawn much attention to treat COVID-19 MESHD, but there has been no natural product showing inhibitory activity against SARS-CoV-2 infection MESHD with detailed mechanism. Here, we show that platycodin D (PD), a triterpenoid saponin abundant in Platycodon grandiflorum (PG), a dietary and medicinal herb commonly used in East Asia, effectively blocks the two main SARS-CoV-2 infection MESHD-routes via lysosome- and transmembrane protease, serine 2 ( TMPRSS2 HGNC)-driven entry. Mechanistically, PD prevents host-entry of SARS-CoV-2 by redistributing membrane cholesterol to prevent membrane fusion, which can be reinstated by treatment with a PD-encapsulating agent. Furthermore, the inhibitory effects of PD are recapitulated by a pharmacological inhibition or gene-silencing of NPC1 HGNC, which is mutated in Niemann-Pick type C ( NPC MESHD) patients displaying disrupted membrane cholesterol. Finally, readily available local foods or herbal medicines containing PG root show the similar inhibitory effects against SARS-CoV-2 infection MESHD. Our study proposes that PD is a potent natural product for preventing or treating COVID-19 MESHD and that a brief disruption of membrane cholesterol can be a novel therapeutic approach against SARS-CoV-2 infection MESHD.

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MeSH Disease
HGNC Genes
SARS-CoV-2 Proteins


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