Corpus overview


MeSH Disease

HGNC Genes

SARS-CoV-2 proteins

ProteinS (42)

NSP5 (3)

ProteinS1 (1)

NSP3 (1)

ORF7a (1)


SARS-CoV-2 Proteins
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    Mechanism of inhibition of SARS-CoV-2 infection MESHD by the interaction of the spike glycoprotein PROTEIN with heparin

    Authors: Giulia Paiardi; Stefan Richter; Marco Rusnati; Rebecca C Wade

    id:2103.07722v1 Date: 2021-03-13 Source: arXiv

    Heparin is administered intravenously as an anticoagulant to COVID-19 MESHD patients and via aerosol to treat other lung diseases MESHD. It has recently been found to have antiviral activity against SARS-CoV-2 as it hinders attachment of the virus to the host cell by binding to the virus spike glycoprotein PROTEIN. Here, we describe molecular dynamics simulations to investigate how heparin binds to the spike and the mechanism by which it exerts its antiviral activity. The simulations show that heparin polyanionic chains can bind at long, mostly positively charged patches on the spike, preventing the binding of host cell heparan sulphate proteoglycans to the spike. Heparin can mask both the S1/S2 basic motif, thereby inhibiting furin HGNC cleavage and the formation of the prefusion conformation, and the basic residues of the receptor binding domain (RBD), thus acting on the hinge region responsible for the motion of the RBD between inactive closed and active open conformations of the spike. In simulations of the closed spike, heparin binds the RBD and the N-terminal domain of two adjacent spike subunits and hinders the opening. In simulations of the open spike, heparin binds similarly but induces stabilization of the hinge region and a change in RBD motion. Heparin is therefore able to inhibit host cell attachment directly and by two allosteric mechanisms. Furthermore, the simulations provide insights into how heparan sulphate proteoglycans on the host cell can facilitate viral infection MESHD. Our results will aid the rational optimization of heparin derivatives for SARS-CoV-2 antiviral therapy.

    An Innovative antibody-based Plug-and-Play strategy for SARS-CoV-2


    doi:10.1101/2021.03.11.434589 Date: 2021-03-12 Source: bioRxiv

    The novel and highly pathogenic coronavirus (SARS-CoV-2) remains a public health threat worldwide. SARS-CoV-2 enters human host lung cells via its spike protein PROTEIN binding to angiotensin-converting enzyme 2 HGNC ( ACE2 HGNC) in a process critical dependent on host protease-mediated fusion event. Thus, effective targeted therapies blocking the first step of viral fusion and cellular entry remains a critical unmet medical need to overcome disease pathology. Here we engineered and describe an antibody-based novel and targeted plug-and-play strategy, which directly competes with the proteolytic activation function of SAR-CoV-2 spike protein PROTEIN. The described strategy involves the engineering of furin HGNC substrate residues in IgG1 Fc-extended flexible region of spike targeting antibody. Our results with spike receptor-binding domain (RBD) targeting CR3022 antibody support blockade of the viral function using proof of concept ACE2 HGNC overexpressing cells. Our study reveals analytical, safe, and selective mechanistic insights for SARS-CoV-2 therapeutic design and is broadly applicable to the future coronaviridae family members (including newly identified mutant variants) exploiting the host protease system for their deadly pathology.

    Multiple Sites on SARS-CoV-2 Spike PROTEIN SARS-CoV-2 Spike MESHD Protein are Susceptible to Proteolysis by Cathepsins B, K, L, S, and V

    Authors: Keval Bollavaram; Tiffanie Leeman; Akhil Kulkarni; Sophia Upshaw; Maggie Lee; Jiabei Yang; Hannah Song; Manu O Platt

    doi:10.1101/2021.02.17.431617 Date: 2021-02-17 Source: bioRxiv

    SARS-CoV-2 is the coronavirus responsible for the COVID-19 pandemic MESHD. Proteases are central to the infection process of SARS-CoV-2 MESHD. Cleavage of the spike protein PROTEIN on the virus capsid causes the conformational change that leads to membrane fusion and viral entry into the target cell. Since inhibition of one protease, even the dominant protease like TMPRSS2 HGNC, may not be sufficient to block SARS-CoV-2 entry into cells, other proteases that may play an activating role and hydrolyze the spike protein PROTEIN must be identified. We identified amino acid sequences in all regions of spike protein PROTEIN, including the S1/S2 region critical for activation and viral entry, that are susceptible to cleavage by furin HGNC and cathepsins B, K, L, S, and V using PACMANS, a computational platform that identifies and ranks preferred sites of proteolytic cleavage on substrates, and verified with molecular docking analysis and immunoblotting to determine if binding of these proteases can occur on the spike protein PROTEIN that were identified as possible cleavage sites. Together, this study highlights cathepsins B, K, L, S, and V for consideration in SARS-CoV-2 infection MESHD and presents methodologies by which other proteases can be screened to determine a role in viral entry. This highlights additional proteases to be considered in COVID-19 MESHD studies, particularly regarding exacerbated damage in inflammatory preconditions where these proteases are generally upregulated.

    SARS-CoV-2 and the Secret of the Furin HGNC Site

    Authors: Antonio R. Romeu; Enric Ollé

    id:10.20944/preprints202102.0264.v1 Date: 2021-02-10 Source:

    The SARS-CoV-2 high infectivity is due to the functional polybasic furin HGNC cleavage site in the S protein PROTEIN. How it was acquired is unknown. There are two challenges to face: (i) an evolutionary model, to fit the origin of the coronavirus; and (ii) a molecular mechanism for the site acquisition. Here we show genomic fingerprints which are specific of Pangolin-CoVs, Bat-SARS-like (CoVZC45, CoVZXC21), bat RatG13 and human SARS-CoV-2 coronaviruses. This, along with phylogenetic analysis, we found that these species have the same evolutionary origin in the bat, including a genetic recombination of S gene between Pangolin-CoV (2017) and RatG13 ancestors. However, this does not explain why SARS-CoV-2 is the only of them with the furin HGNC site, which consists in four amino acid (PRRA) motif. The Arginine doublet is encoded by CGGCGG codons. Surprisingly, none of the Arginine doublet of other furin HGNC site of viral proteins from several type of viruses, are encoded by the CGGCGG codons. This makes it difficult to consider a virus recombination as mechanism for the PRRA acquisition. The origin of SARS-CoV-2, is the origin of the recognition cleavage site. The bat coronavirus RaTG13 appears to be the closest relative of the SARS-CoV-2, but was isolated in 2013. So, new RatG13 samples would provide insights into the acquisition of the polybasic motif.

    A novel antibody against the furin HGNC cleavage site of SARS-CoV-2 spike PROTEIN protein: effects on proteolytic cleavage and ACE2 HGNC binding

    Authors: Michael G Spelios; Jeanne M Capanelli; Adam W Li

    doi:10.1101/2021.02.09.430451 Date: 2021-02-09 Source: bioRxiv

    SARS-CoV-2 harbors a unique S1/S2 furin HGNC cleavage site within its spike protein PROTEIN, which can be cleaved by furin HGNC and other proprotein convertases. Proteolytic activation of SARS-CoV-2 spike PROTEIN protein at the S1 PROTEIN/S2 boundary facilitates interaction with host ACE2 HGNC receptor for cell entry. To address this, high titer antibody was generated against the SARS-CoV-2-specific furin HGNC motif. Using a series of innovative ELISA-based assays, this furin HGNC site blocking antibody displayed high sensitivity and specificity for the S1/S2 furin HGNC cleavage site, and demonstrated effective blockage of both enzyme-mediated cleavage and spike- ACE2 HGNC interaction. The results suggest that immunological blocking of the furin HGNC cleavage site may afford a suitable approach to stem proteolytic activation of SARS-CoV-2 spike PROTEIN protein and curtail viral infectivity.

    Furin HGNC cleavage of the SARS-CoV-2 spike PROTEIN is modulated by O-glycosylation

    Authors: Liping Zhang; Matthew Mann; Zulfeqhar Syed; Hayley M. Reynolds; E Tian; Nadine L. Samara; Darryl C. Zeldin; Lawrence A. Tabak; Kelly G. Ten Hagen

    doi:10.1101/2021.02.05.429982 Date: 2021-02-05 Source: bioRxiv

    The SARS-CoV-2 coronavirus responsible for the global pandemic contains a unique furin HGNC cleavage site in the spike protein (S PROTEIN) that increases viral infectivity and syncytia formation. Here, we show that O-glycosylation near the furin HGNC cleavage site is mediated by specific members of the GALNT enzyme family and is dependent on the novel proline at position 681 (P681). We further demonstrate that O-glycosylation of S decreases furin HGNC cleavage. Finally, we show that GALNT family members capable of glycosylating S are expressed in human respiratory cells that are targets for SARS-CoV-2 infection MESHD. Our results suggest that O-glycosylation may influence viral infectivity/tropism by modulating furin HGNC cleavage of S and provide mechanistic insight into the potential role of P681 mutations in the recently identified, highly transmissible B.1.1.7 variant.

    D614G Substitution of SARS-CoV-2 Spike MESHD SARS-CoV-2 Spike PROTEIN Protein Increases Syncytium Formation and Viral Transmission via Enhanced Furin HGNC-mediated Spike Cleavage

    Authors: Ya-Wen Cheng; Tai-Ling Chao; Chiao-Ling Li; Sheng-Han Wang; Han-Chieh Kao; Ya-Min Tsai; Hurng-Yi Wang; Chi-Ling Hsieh; Pei-Jer Chen; Sui-Yuan Chang; Shiou-Hwei Yeh

    doi:10.1101/2021.01.27.428541 Date: 2021-01-28 Source: bioRxiv

    Since the D614G substitution in the spike (S) of SARS-CoV-2 emerged, the variant strain underwent rapid expansion to become the most abundant strain worldwide. Therefore, this substitution may provide an advantage of viral spreading. To explore the mechanism, we analyzed 18 viral isolates containing S proteins PROTEIN with either G614 or D614. Both the virus titer and syncytial phenotype were significantly increased in S-G614 than in S-D614 isolates. We further showed increased cleavage of S at the furin HGNC substrate site, a key event that promotes syncytium, in S-G614 isolates. These functions of the D614G substitution were validated in cells expressing S protein PROTEIN. The effect on syncytium was abolished by furin HGNC inhibitor treatment and mutation of the furin HGNC-cleavage site, suggesting its dependence on cleavage by furin HGNC. Our study provides a mechanistic explanation for the increased transmissibility of S-G614 containing SARS-CoV-2 through enhanced furin HGNC-mediated S cleavage, which increases membrane fusion and virus infectivity.

    Unravelling Vitamins as Wonder Molecules for Covid-19 MESHD Management via Structure-based Virtual Screening

    Authors: Medha Pandya; Sejal Shah; Dhanalakshmi Menamadathil; Ayushman Gadnayak; Tanzil Juneja; Amisha Patel; Kajari Das; Jayashankar Das

    doi:10.21203/ Date: 2021-01-09 Source: ResearchSquare

    The emergence situation of coronavirus disease 2019 MESHD ( COVID-19 MESHD) pandemic has realised the global scientific communities to develop strategies for immediate priorities and long-term approaches for utilization of existing knowledge and resources which can be diverted to pandemic preparedness planning. Lack of proper vaccine candidate and therapeutic management has accelerated the researchers to repurpose the existing drugs with known preclinical and toxicity MESHD profiles, which can easily enter Phase 3 or 4 or can be used directly in clinical settings. We focused to justify even exploration of supplements, nutrients and vitamins to dampen the disease burden of the current pandemic may play a crucial role for its management. We have explored structure based virtual screening of 15 vitamins against non-structural ( NSP3 HGNC NSP3 PROTEIN, NSP5 PROTEIN NSP5 HGNC, ORF7a PROTEIN, NSP12 PROTEIN, ORF3a PROTEIN), structural (Spike & Hemagglutinin esterase) and host protein furin HGNC. The in silico analysis exhibited that vitamin B12, Vitamin B9, Vitamin D3 determined suitable binding while vitamin B15 manifested remarkable H-bond interactions with all targets. Vitamin B12 bestowed the lowest energies with human furin HGNC and SARS-COV-2 RNA dependent RNA polymerase PROTEIN. Furin HGNC mediated cleavage of the viral spike glycoprotein PROTEIN is directly related to enhanced virulence of SARS-CoV-2. In contrast to these, vitamin B12 showed zero affinity with SARS-CoV-2 spike PROTEIN protein. These upshots intimate that Vitamin B12 could be the wonder molecule to shrink the virulence by hindering the furin HGNC mediated entry of spike to host cell. These identified molecules may effectively assist in SARS-CoV-2 therapeutic management to boost the immunity by inhibiting the virus imparting relief in lung inflammation MESHD.

    Fibrinolysis influences SARS-CoV-2 infection MESHD in ciliated cells

    Authors: Myoung Ryoul Park; Chunmei Cai; Min-Jung Seo; Hong-Tae Yun; Soo-Kwon Park; Man-Soo Choi; Chang-Hwan Park; Jung Kyung Moon

    doi:10.1101/2021.01.07.425801 Date: 2021-01-08 Source: bioRxiv

    Rapid spread of COVID-19 MESHD has caused an unprecedented pandemic worldwide, and an inserted furin HGNC site in SARS-CoV-2 spike PROTEIN protein (S PROTEIN) may account for increased transmissibility. Plasmin HGNC, and other host proteases, may cleave the furin HGNC site of SARS-CoV-2 S protein PROTEIN and {gamma} subunits of epithelial sodium channels ({gamma} ENaC), resulting in an increment in virus infectivity and channel activity. As for the importance of ENaC in the regulation of airway surface and alveolar fluid homeostasis MESHD, whether SARS-CoV-2 will share and strengthen the cleavage network with ENaC proteins at the single-cell level is urgently worthy of consideration. To address this issue, we analyzed single-cell RNA sequence (scRNA-seq) datasets, and found the PLAU HGNC (encoding urokinase plasminogen activator), SCNN1G HGNC ({gamma}ENaC), and ACE2 HGNC (SARS-CoV-2 receptor) were co-expressed in alveolar epithelial MESHD, basal, club, and ciliated epithelial cells. The relative expression level of PLAU HGNC, TMPRSS2 HGNC, and ACE2 HGNC were significantly upregulated in severe COVID-19 MESHD patients and SARS-CoV-2 infected MESHD cell lines using Seurat and DESeq2 R packages. Moreover, the increments in PLAU HGNC, FURIN HGNC, TMPRSS2 HGNC, and ACE2 HGNC were predominately observed in different epithelial cells and leukocytes. Accordingly, SARS-CoV-2 may share and strengthen the ENaC fibrinolytic proteases network in ACE2 HGNC positive airway and alveolar MESHD epithelial cells, which may expedite virus infusion into the susceptible cells and bring about ENaC associated edematous respiratory condition MESHD.

    Furin HGNC cleaves SARS-CoV-2 spike PROTEIN-glycoprotein at S1/S2 and S2'for viral fusion/entry: indirect role for TMPRSS2

    Authors: Rachid Essalmani; Jaspreet Jain; Delia Susan-Resiga; Ursula Andreo; Alexandra Evagelidis; Rabeb Mouna Derbali; David Huynh; Frederic Dallaire; Melanie Laporte; Adrien Delpal; Priscila Sutto-Ortiz; Bruno Coutard; Claudine Mapa; Keith Wilcoxen; Etienne Decroly; Tram Pham; Eric A. Cohen; Nabil G. G Seidah; Massimo Zollo; Achille Iolascon; Mario Capasso; Nour Albes; Hani M. Al-Afghani; Bader Alghamdi; Mansour Almutair; Ebrahim Sabri Mahmoud; Leen Abu Safie; Hadeel El Bardisy; Fawz S. Al Harthi; Abdulraheem Alshareef; Bandar Ali Suliman; Saleh Alqahtani; Abdulaziz AlMalik; May M. Alrashed; Salam Massadeh; Vincent Mooser; Mark Lathrop; Yaseen Arabi; Hamdi Mbarek; Chadi Saad; Wadha Al-Muftah; Radja Badji; Asma Al Thani; Said I. Ismail; Ali G. Gharavi; Malak S. Abedalthagafi; J Brent Richards; David B. Goldstein; Krzysztof Kiryluk

    doi:10.1101/2020.12.18.423106 Date: 2020-12-20 Source: bioRxiv

    The Spike (S)-protein PROTEIN of SARS-CoV-2 binds host-cell receptor ACE2 HGNC and requires proteolytic 'priming' (S1/S2) and 'fusion-activation' (S2') for viral entry. The S-protein PROTEIN furin HGNC-like motifs PRRAR685{downarrow} and KPSKR815{downarrow} indicated that proprotein convertases promote virus entry. We demonstrate that furin HGNC and PC5A induce cleavage at both sites, ACE2 HGNC enhances S2' processing, and their pharmacological inhibition (BOS-inhibitors) block endogenous cleavages. S1/S2-mutations (S1/S2) limit S-protein PROTEIN-mediated cell-to-cell fusion, similarly to BOS-inhibitors. Unexpectedly, TMPRSS2 HGNC does not cleave at S1/S2 or S2', but it can: (i) cleave/inactivate S-protein PROTEIN into S2a/S2b; (ii) shed ACE2 HGNC; (iii) cleave S1-subunit into secreted S1', activities inhibited by Camostat. In lung-derived Calu-3 cells, BOS-inhibitors and S1/S2 severely curtail 'pH-independent' viral entry, and BOS-inhibitors alone/with Camostat potently reduce infectious viral titer and cytopathic effects. Overall, our results show that: furin HGNC plays a critical role in generating fusion-competent S-protein PROTEIN, and indirectly, TMPRSS2 HGNC promotes viral entry, supporting furin HGNC and TMPRSS2 HGNC inhibitors as potential antivirals against SARS-CoV-2

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MeSH Disease
HGNC Genes
SARS-CoV-2 Proteins

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