Corpus overview


Overview

MeSH Disease

HGNC Genes

SARS-CoV-2 proteins

ProteinS (277)

ProteinN (13)

NSP5 (6)

ProteinS1 (6)

ComplexRdRp (6)


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SARS-CoV-2 Proteins
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    Fc-independent neutralization of SARS-CoV-2 by recombinant human monoclonal antibodies

    Authors: Tal Noy-Porat; Avishay Edri; Ron Alcalay; Efi Makdasi; David Gur; Moshe Aftalion; Yentl Evgy; Adi Beth-Din; Yinon Levy; Eyal Epstein; Olga Radinsky; Ayelet Zauberman; Shirley Lazar; Shmuel Yitzhaki; Hadar Marcus; Angel Porgador; Ronit Rosenfeld; Ohad Mazor

    doi:10.1101/2021.05.15.443978 Date: 2021-05-15 Source: bioRxiv

    The use of passively-administered neutralizing antibodies is a promising approach for the prevention and treatment of SARS-CoV-2 infection MESHD. Antibody-mediated protection may involve immune system recruitment through Fc-dependent activation of effector cells and the complement system. However, the role of Fc-mediated functions in the efficacious in vivo neutralization of SARS-CoV-2 is not yet clear. Delineating the role this process plays in antibody-mediated protection will have a great impact on the design of such therapeutics. Here, the Fc of two highly potent SARS-CoV-2 neutralizing human monoclonal antibodies, targeting distinct domains of the spike, was engineered to abrogate their Fc-dependent functions. The protective activity of these antibodies was tested against lethal SARS-CoV-2 infections MESHD in K18- hACE2 HGNC transgenic mice, both before or two days post-exposure in comparison to their original, Fc-active antibodies. Antibody treatment with both Fc-variants similarly rescued the mice from death, reduced viral load and prevented signs of morbidity. In addition, surviving animals developed a significant endogenous immune response towards the virus. Taken together, this work provides important insight regarding the contribution of Fc-effector functions in antibody-mediated protection, which should aid in future design of effective antibody-based therapies.

    Analysis of the Role of N-glycosylation in Cell-surface expression, Function and Binding Properties of SARS-CoV-2 receptor ACE2

    Authors: Alberto Brandariz-Nuñez; Raymond R Rowland

    doi:10.1101/2021.05.10.443532 Date: 2021-05-12 Source: bioRxiv

    Human angiotensin I-converting enzyme 2 HGNC ( hACE2 HGNC) is a type-I transmembrane glycoprotein that serves as the major cell entry receptor for SARS-CoV and SARS-CoV-2 MESHD. The viral spike (S) protein PROTEIN is required for attachment to ACE2 HGNC and subsequent virus-host cell membrane fusion. Previous work has demonstrated the presence of N-linked glycans in ACE2 HGNC. N-glycosylation is implicated in many biological activities, including protein folding, protein activity, and cell surface expression of biomolecules. However, the contribution of N-glycosylation to ACE2 HGNC function is poorly understood. Here, we examined the role of N-glycosylation in the activity and localization of two species with different susceptibility to SARS-CoV-2 infection MESHD, porcine ACE2 HGNC (pACE2) and hACE2 HGNC. The elimination of N-glycosylation by tunicamycin (TM) treatment or mutagenesis, showed that N-glycosylation is critical for the proper cell surface expression of ACE2 HGNC but not for its carboxiprotease activity. Furthermore, nonglycosylable ACE2 HGNC localized predominantly in the endoplasmic reticulum (ER) and not at the cell surface. Our data also revealed that binding of SARS-CoV and SARS-CoV-2 S MESHD S protein PROTEIN to porcine or human ACE2 HGNC was not affected by deglycosylation of ACE2 HGNC or S proteins PROTEIN, suggesting that N-glycosylation plays no role in the interaction between SARS coronaviruses and the ACE2 HGNC receptor. Impairment of hACE2 HGNC N-glycosylation decreased cell to cell fusion mediated by SARS-CoV S MESHD S protein PROTEIN but not SARS-CoV-2 S protein PROTEIN. Finally, we found that hACE2 HGNC N-glycosylation is required for an efficient viral entry of SARS-CoV/SARS-CoV-2 S MESHD pseudotyped viruses, which could be the result of low cell surface expression of the deglycosylated ACE2 HGNC receptor.

    INFLUENCE OF NOVEL CORONAVIRUS DISEASE ( COVID-19 MESHD) ON PARKINSONS DISEASE: SYSTEMATIC REVIEW

    Authors: Vikash Jaiswal; Danah Alquraish; Shavy Nagpal; DATTATREYA MUKHERJEE; Prakriti Singh Shrestha; Diana Sanchez Velazco; Prathima Guntipalli; Arushree Bhatnagar; Saloni Savani; Eldamhalji Halilaj Halilaj; Samir Ruxmohan

    doi:10.1101/2021.05.09.21256929 Date: 2021-05-12 Source: medRxiv

    Background: The novel Coronavirus (COVID 19) infection has affected the population with various medical issues including the underlying neurological comorbidities such as Parkinson disease MESHD. COVID 19 is found to bind with the host angiotensin-converting enzyme 2 HGNC ( ACE2 HGNC) receptors for viral entry. ACE2 HGNC receptors are normally expressed in various body surfaces as well as in the neurons and glial cells where they act as an entry port to SARS-CoV-2 infection MESHD to invade the central nervous system (CNS). ACE2 HGNC are also highly expressed in dopamine neurons which might worsen the outcome in terms of motor symptoms in PD MESHD with the treatment course. It may lead to an indirect response via immune-mediated cytokine storms and propagate through CNS leading to damage. Parkinsons disease MESHD has also been noticed due to certain post viral infections apart from COVID-19 MESHD such as, HSV, Influenza virus A, Measles virus, Cytomegalovirus and Mumps MESHD (Olsen et al, 2018). We aim to provide a thorough review on neurological outcomes and impact of COVID-19 MESHD in Parkinson disease MESHD. Methods: A systematic review was conducted to analyze the impact of COVID 19 in patients with Parkinson disease MESHD (> 21 yo). Systematic literature search was done using PubMed, Science Direct, Google Scholar and Cochrane databases. PRISMA guidelines were followed summarized in Fig. 3 for study acquisition. Results: Of the Parkinsons MESHD patients that were tested positive for SARS-CoV 2 MESHD, worsening of motor symptoms were reported along with other COVID 19 symptoms (Fig. 4 and 5). These symptoms include bradykinesia MESHD, tremors MESHD, gait disturbances MESHD, delirium MESHD and dementia MESHD and severe spasms of arms MESHD and legs. Encephalopathy MESHD was also one of the main symptoms presented in two of the studies. Increased mortality rates were identified for those who were hospitalized due to COVID-19 MESHD and PD MESHD when compared to other patients. Conclusion: Parkinsons disease MESHD may experience substantial worsening of motor and non motor symptoms during COVID 19. Due to the novelty of the virus, studies were reported from recent years and further extensive studies are needed to explore more about the disease severity and neurological outcomes when compared to other non- PD MESHD patients. Authors identify this as a limitation for this paper. Additional studies are needed to understand the role of ACE2 HGNC in increasing vulnerability to viruses and role of ACE HGNC inhibitors as treatment modality.

    Impacts on the structure-function relationship of SARS-CoV-2 spike PROTEIN by B.1.1.7 mutations

    Authors: Tzu-Jing Yang; Pei-Yu Yu; Yuan-Chih Chang; Kang-Hao Liang; Hsian-Cheng Tso; Meng-Ru Ho; Wan-Yu Chen; Hsiu-Ting Lin; Han-Chung Wu; Shang-Te Danny Hsu

    doi:10.1101/2021.05.11.443686 Date: 2021-05-12 Source: bioRxiv

    The UK variant of the severe acute respiratory syndrome coronavirus (SARS-CoV-2) MESHD, known as B.1.1.7, harbors several point mutations and deletions on the spike (s) protein PROTEIN, which potentially alter its structural epitopes to evade host immunity while enhancing host receptor binding. Here we report the cryo-EM structures of the S protein PROTEIN of B.1.1.7 in its apo form and in the receptor ACE2 HGNC-bound form. One or two of the three receptor binding domains (RBDs) were in the open conformation but no fully closed form was observed. In the ACE-bound form, all three RBDs were engaged in receptor binding. The B.1.1.7-specific A570D mutation introduced a salt bridge switch that could modulate the opening and closing of the RBD. Furthermore, the N501Y mutation in the RBD introduced a favorable {pi}-{pi} interaction manifested in enhanced ACE2 HGNC binding affinity. The N501Y mutation abolished the neutralization activity of one of the three potent neutralizing antibodies (nAbs). Cryo-EM showed that the cocktail of other two nAbs simultaneously bound to all three RBDs. Furthermore, the nAb cocktail synergistically neutralized different SARS-CoV-2 pseudovirus strains, including the B.1.1.7.

    Structure and mechanism of SARS-CoV-2 Spike PROTEIN SARS-CoV-2 Spike MESHD N679-V687 deletion variant elucidate cell-type specific evolution of viral fitness

    Authors: Kapil Gupta; Christine Toelzer; Maia Kavanagh Williamson; Deborah Shoemark; A. Sofia F. Oliveira; David A Matthews; Abdulaziz Almuqrin; Oskar Staufer; Sathish K.N. Yadav; Ufuk Borucu; Frederic Garzoni; Daniel Fitzgerald; Joachim Spatz; Adrian J Mulholland; Andrew D. Davidson; Christiane Schaffitzel; Imre Berger

    doi:10.1101/2021.05.11.443384 Date: 2021-05-11 Source: bioRxiv

    As the global burden of SARS-CoV-2 infections escalates MESHD, so does the evolution of viral variants which is of particular concern due to their potential for increased transmissibility and pathology. In addition to this entrenched variant diversity in circulation, RNA viruses can also display genetic diversity within single infected hosts with co-existing viral variants evolving differently in distinct cell types. The BriS{Delta} variant, originally identified as a viral subpopulation by passaging SARS-CoV-2 isolate hCoV-19/England/02/2020, comprises in the spike glycoprotein PROTEIN an eight amino-acid deletion encompassing the furin recognition motif and S1/S2 cleavage site. Here, we analyzed the structure, function and molecular dynamics of this variant spike, providing mechanistic insight into how the deletion correlates to viral cell tropism, ACE2 HGNC receptor binding and infectivity, allowing the virus to probe diverse trajectories in distinct cell types to evolve viral fitness MESHD. TeaserSARS-CoV-2 can exploit different cell types to diversify and evolve virus variants distinct in infectivity and structure.

    Dynamic Interactions of Fully Glycosylated SARS-CoV-2 Spike MESHD SARS-CoV-2 Spike PROTEIN Protein with Various Antibodies

    Authors: Yiwei Cao; Yeol Kyo Choi; Martin Frank; Hyeonuk Woo; Sang-Jun Park; Min Sun Yeom; Chaok Seok; Wonpil Im

    doi:10.1101/2021.05.10.443519 Date: 2021-05-11 Source: bioRxiv

    The spread of severe acute respiratory syndrome coronavirus 2 MESHD (SARS-CoV-2) presents a public health crisis, and the vaccines that can induce highly potent neutralizing antibodies are essential for ending the pandemic. The spike (S) protein PROTEIN on the viral envelope mediates human angiotensin-converting enzyme 2 HGNC ( ACE2 HGNC) binding and thus is the target of a variety of neutralizing antibodies. In this work, we built various S trimer-antibody complex structures on the basis of the fully glycosylated S protein PROTEIN models described in our previous work, and performed all-atom molecular dynamics simulations to get insight into the structural dynamics and interactions between S protein PROTEIN and antibodies. Investigation of the residues critical for S-antibody binding allows us to predict the potential influence of mutations in SARS-CoV-2 variants. Comparison of the glycan conformations between S-only and S-antibody systems reveals the roles of glycans in S-antibody binding. In addition, we explored the antibody binding modes, and the influences of antibody on the motion of S protein PROTEIN receptor binding domains. Overall, our analyses provide a better understanding of S-antibody interactions, and the simulation-based S-antibody interaction maps could be used to predict the influences of S mutation on S-antibody interactions, which will be useful for the development of vaccine and antibody-based therapy.

    SARS-CoV-2 receptor ACE2 HGNC identifies immuno-hot tumors in breast cancer MESHD

    Authors:

    doi:10.1101/2021.05.10.443377 Date: 2021-05-10 Source: bioRxiv

    Angiotensin-converting enzyme 2 ( ACE2 HGNC) is known as a host cell receptor for Severe Acute Respiratory Syndrome Coronavirus 2 MESHD (SARS-CoV-2), which is identified to be dysregulated MESHD in multiple tumors MESHD. Although the characterization of abnormal ACE2 HGNC expression in malignancies MESHD has been preliminarily explored, in-depth analysis of ACE2 HGNC in breast cancer MESHD ( BRCA HGNC BRCA MESHD) has not been elucidated. A systematic pan-cancer analysis was conducted to assess the expression pattern and immunological role of ACE2 HGNC based on RNA-sequencing (RNA-seq) data downloaded from The Cancer Genome Atlas (TCGA). Next, correlations between ACE2 HGNC expression immunological characteristics in the BRCA tumor MESHD BRCA tumor HGNC microenvironment (TME) were evaluated. Also, the role of ACE2 HGNC in predicting the clinical features and the response to therapeutic options in BRCA MESHD BRCA HGNC was estimated. These findings were subsequently validated in another public transcriptomic cohort as well as a recruited cohort. ACE2 HGNC was lowly expressed in most cancers MESHD compared with adjacent tissues. ACE2 HGNC was positively correlated with immunomodulators, tumor MESHD-infiltrating immune cells (TIICs), cancer MESHD immunity cycles, immune checkpoints, and tumor MESHD mutation burden (TMB). Besides, high ACE2 HGNC levels indicated the triple-negative breast cancer MESHD ( TNBC MESHD) subtype of BRCA HGNC BRCA MESHD, lower response to endocrine therapy and higher response to chemotherapy, anti- ERBB HGNC therapy, antiangiogenic therapy and immunotherapy. To sum up, ACE2 HGNC correlates with an inflamed TME and identifies immuno-hot tumors MESHD, which may be used as an auxiliary biomarker for the identification of immunological characteristics in BRCA MESHD BRCA HGNC.

    The K18- hACE2 HGNC Transgenic Mouse Model Recapitulates Non-Severe and Severe COVID-19 MESHD in Response to Infectious Dose of SARS-CoV-2 Virus

    Authors:

    doi:10.1101/2021.05.08.443244 Date: 2021-05-09 Source: bioRxiv

    A comprehensive analysis and characterization of a SARS-CoV-2 infection MESHD model that mimics non-severe and severe COVID-19 MESHD in humans is warranted for understating the virus and developing preventive and therapeutic agents. Here, we characterized the K18- hACE2 HGNC mouse model expressing human (h) ACE2 HGNC in mice, controlled by the human keratin 18 HGNC ( K18 HGNC) promoter, in epithelia, including airway epithelial cells where SARS-CoV-2 infections MESHD typically start. We found that intranasal inoculation with higher viral doses (2x103 and 2x104 PFU) of SARS-CoV-2 caused lethality of all mice and severe damage of various organs, including lungs, liver, and kidney MESHD, while lower doses (2x101 and 2x102 PFU) led to less severe tissue damage and some mice recovered from the infection. In this humanized hACE2 HGNC mouse model, SARS-CoV-2 infection MESHD damaged multiple tissues, with a dose-dependent effect in most tissues. Similar damage was observed in biopsy samples from COVID-19 MESHD patients. Finally, the mice that recovered after infection with a low dose of virus also survived rechallenge with a high dose of virus. Compared to other existing models, the K18- hACE2 HGNC model seems to be the most sensitive COVID-19 MESHD model reported to date. Our work expands the information available about this model to include analysis of multiple infectious doses and various tissues with comparison to human biopsy samples from COVID-19 MESHD patients. In conclusion, the K18- hACE2 HGNC mouse model recapitulates both severe and non-severe COVID-19 MESHD in humans and can provide insight into disease progression and the efficacy of therapeutics for preventing or treating COVID-19 MESHD.

    In-vivo Protection from SARS-CoV-2 infection MESHD by ATN-161 in k18- hACE2 HGNC transgenic mice

    Authors:

    doi:10.1101/2021.05.08.443275 Date: 2021-05-09 Source: bioRxiv

    Severe acute respiratory syndrome coronavirus 2 MESHD (SARS-CoV-2) is an infectious disease MESHD that has spread worldwide. Current treatments are limited in both availability and efficacy, such that improving our understanding of the factors that facilitate infection is urgently needed to more effectively treat infected individuals and to curb the pandemic. We and others have previously demonstrated the significance of interactions between the SARS-CoV-2 spike PROTEIN protein, integrin alpha5beta1 and human ACE2 HGNC to facilitate viral entry into host cells in vitro. We previously found that inhibition of integrin alpha5beta1 by the clinically validated small peptide ATN-161 inhibits these spike protein PROTEIN interactions and cell infection in vitro. In continuation with our previous findings, here we have further evaluated the therapeutic potential of ATN-161 on SARS-CoV-2 infection MESHD in k18- hACE2 HGNC transgenic (SARS-CoV-2 susceptible) mice in vivo. We discovered that treatment with single- or repeated intravenous doses of ATN-161 (1 mg/kg) within 48 hours after intranasal inoculation with SARS-CoV-2 lead to a reduction of lung viral load, viral immunofluorescence and improved lung histology in a majority of mice 72 hours post-infection. Furthermore, ATN-161 reduced SARS-CoV-2-induced increased expression of lung integrin alpha 5 and alpha v (an alpha 5-related integrin that has also been implicated in SARS-CoV-2 interactions) as well as the C-X-C motif chemokine ligand 10 (Cxcl10), further supporting the potential involvement of these integrins, and the anti-inflammatory potential of ATN-161, respectively, in SARS-CoV-2 infection MESHD. To the best of our knowledge, this is the first study demonstrating the potential therapeutic efficacy of targeting integrin alpha5beta1 in SARS-CoV-2 infection MESHD in vivo and supports the development of ATN-161 as a novel SARS-CoV-2 therapy.

    The Effect of Minnelide against SARS-CoV-2 in a Murine Model

    Authors:

    doi:10.1101/2021.05.05.442875 Date: 2021-05-06 Source: bioRxiv

    Severe acute respiratory syndrome coronavirus 2 MESHD, SARS-CoV-2, is the causative agent of coronavirus disease 2019 MESHD, COVID-19 MESHD, and the current COVID-19 pandemic MESHD. Even as more vaccine candidates are released, more treatment options are critically needed. Here, we investigated the use of Minnelide, a water soluble pro-drug with anti-inflammatory properties, for the treatment of COVID-19 MESHD. To do this, k18- hACE2 HGNC mice were infected with SARS-CoV-2 or given PBS control intranasally. The next day mice were either treated daily with low dose (0.0025mg/day) or high dose Minnelide (0.005mg/day), or given vehicle control intraperitoneal. Mice were weighed daily, and sacrificed at day 6 and 10 post-infection to analyze viral burden, cytokine response, and pathology. We observed a reduction in viral load in the lungs of Minnelide-treated mice infected with SARS-CoV-2 at day 10 post-infection compared to day 6 post-infection. All SARS-CoV-2 infected MESHD non-treated mice were moribund six days post-infection while treatment with Minnelide extended survival for both low (60% survival) and high (100% survival) dose treated mice ten days post-infection. Interestingly, cytokine analysis demonstrated a significant reduction in IL-6 (lung and heart) and D-dimer (serum) in high dose treated SARS-CoV-2 infected MESHD mice compared to mice infected with SARS-CoV-2 alone at day 6 post-infection. Additionally, histology analysis revealed that Minnelide treatment significantly improved lung pathology ten days post-infection with SARS-CoV-2 with all the mice exhibiting normal lung tissue with thin alveolar septa MESHD and no inflammatory cells. Overall, our study exhibits potential for the use of Minnelide to improve survival in COVID-19 MESHD patients.

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MeSH Disease
HGNC Genes
SARS-CoV-2 Proteins


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