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    Withaferin A: a potential therapeutic agent against COVID-19 MESHD infection

    Authors: Alex R. Straughn; Sham S. Kakar

    doi:10.21203/rs.3.rs-37637/v1 Date: 2020-06-23 Source: ResearchSquare

    The outbreak and continued spread of the novel coronavirus disease 2019 MESHD ( COVID-19 MESHD) is a preeminent global health threat that has resulted in the infection of over 6 million people worldwide. In addition, the pandemic has claimed the lives of over 350,000 people worldwide. Age and the presence of underlying comorbid conditions have been found to be key determinants of patient mortality. One such comorbidity is the presence of an oncological malignancy MESHD, with cancer MESHD patients exhibiting an approximate two-fold increase in mortality rate. Due to a lack of data, no consensus has been reached about the best practices for the diagnosis and treatment of cancer MESHD patients. Interestingly, two independent research groups have discovered that Withaferin A (WFA), a steroidal lactone with anti-inflammatory and anti-tumorigenic properties, may bind to the viral spike (S-) protein PROTEIN of SARS-CoV-2. Further, preliminary data from our research group has demonstrated that WFA does not alter expression of ACE2 in the lungs of tumor MESHD-bearing female mice. Downregulation of ACE2 has recently been demonstrated to increase the severity of COVID-19 MESHD. Therefore, WFA demonstrates real potential as a therapeutic agent to treat or prevent the spread of COVID-19 MESHD due to the reported interference in viral S-protein PROTEIN S-protein HGNC to host receptor binding and its lack of effect on ACE2 expression in the lungs.

    SARS-CoV-2 growth, furin-cleavage-site adaptation and neutralization using serum from acutely infected, hospitalized COVID-19 MESHD patients

    Authors: William B Klimstra; Natasha L Tilston-Lunel; Sham Nambulli; James Boslett; Cynthia M McMillen; Theron Gilliland; Matthew D Dunn; Chengun Sun; Sarah E Wheeler; Alan Wells; Amy L Hartman; Anita K McElroy; Douglas S Reed; Linda J Rennick; W. Paul Duprex

    doi:10.1101/2020.06.19.154930 Date: 2020-06-20 Source: bioRxiv

    SARS-CoV-2, the causative agent of COVID-19 MESHD, emerged at the end of 2019 and by mid-June 2020, the virus has spread to at least 215 countries, caused more than 8,000,000 confirmed infections and over 450,000 deaths, and overwhelmed healthcare systems worldwide. Like SARS-CoV MESHD, which emerged in 2002 and caused a similar disease, SARS-CoV-2 is a betacoronavirus. Both viruses use human angiotensin-converting enzyme 2 HGNC ( hACE2 HGNC) as a receptor to enter cells. However, the SARS-CoV-2 spike PROTEIN ( S) glycoprotein PROTEIN has a novel insertion that generates a putative furin HGNC cleavage signal and this has been postulated to expand the host range. Two low passage (P) strains of SARS-CoV-2 (Wash1: P4 and Munich: P1) were cultured twice in Vero-E6 cells and characterized virologically. Sanger and MinION sequencing demonstrated significant deletions in the furin cleavage signal of Wash1: P6 and minor variants in the Munich: P3 strain. Cleavage of the S glycoprotein PROTEIN in SARS-CoV-2-infected MESHD Vero-E6 cell lysates was inefficient even when an intact furin cleavage signal was present. Indirect immunofluorescence demonstrated the S glycoprotein PROTEIN reached the cell surface. Since the S protein HGNC S protein PROTEIN is a major antigenic target for the development of neutralizing antibodies we investigated the development of neutralizing antibody titers in serial serum samples obtained from COVID-19 MESHD human patients. These were comparable regardless of the presence of an intact or deleted furin HGNC cleavage signal. These studies illustrate the need to characterize virus stocks meticulously prior to performing either in vitro or in vivo pathogenesis studies.

    Kinetics of the humoral immune response to SARS-CoV-2: comparative analytical performance of seven commercial serology tests

    Authors: Pauline H. Herroelen; Geert Antoine Martens; Dieter De Smet; Koen Swaerts; An-Sofie Decavele

    doi:10.1101/2020.06.09.20124719 Date: 2020-06-12 Source: medRxiv

    Background SARS-CoV-2 serology tests are clinically useful to document a prior SARS-CoV-2 infection MESHD in patients with no or inconclusive PCR results and suspected COVID-19 MESHD disease or sequelae. Data are urgently needed to select the assays with optimal sensitivity at acceptable specificity. Methods A comparative analysis of analytical sensitivity was performed of seven commercial SARS-CoV-2 serology assays on 171 sera from 135 subjects with PCR-confirmed SARS-CoV-2 infection MESHD, composed of 71 patients hospitalized for COVID-19 MESHD pneumonia MESHD and 64 healthcare workers with paucisymptomatic infections. The kinetics of IgA/IgM/IgG seroconversion to viral N- and S-protein HGNC S-protein PROTEIN epitopes were studied from 0 to 54 days after symptom onset. Specificity was verified on 57 pre-pandemic samples. Results Wantai SARS-COV-2 Ab ELISA and Orient Gene COVID-19 MESHD IgG/IgM Rapid Test achieved a superior overall sensitivity. Elecsys Anti-SARS-CoV-2 assay and EUROIMMUN Anti-SARS-CoV-2 combined IgG/IgA also showed acceptable sensitivity (>95%) versus the consensus result of all assays from 10 days post symptom onset. Optimal specificity (>98%) was achieved only by Wantai SARS-COV-2 Ab ELISA, Elecsys Anti-SARS-CoV-2 assay and Innovita 2019-nCoV Ab rapid test. LIAISON SARS-CoV-2 S1/S2 IgG showed a significantly lower sensitivity as compared to all other assays. Lack of seroconversion by any test was seen in 1.4% of hospitalized and 4.7% of paucisymptomatic infections. Within 10 days from symptom onset, only the Wantai SARS-COV-2 Ab ELISA has acceptable sensitivity. Conclusions Wantai SARS-COV-2 Ab ELISA and Elecsys Anti-SARS-CoV-2 assays are suitable for sensitive and specific screening of a SARS-CoV-2 infection MESHD from 10 days after symptom onset.

    The utility of native MS for understanding the mechanism of action of repurposed therapeutics in COVID-19 MESHD: heparin as a disruptor of the SARS-CoV-2 interaction with its host cell receptor.

    Authors: Yang Yang; Yi Du; Igor A Kaltashov

    doi:10.1101/2020.06.09.142794 Date: 2020-06-10 Source: bioRxiv

    The emergence and rapid proliferation of the novel coronavirus (SARS-CoV-2) resulted in a global pandemic, with over six million cases and nearly four hundred thousand deaths reported world-wide by the end of May 2020. A rush to find the cures prompted re-evaluation of a range of existing therapeutics vis-a-vis their potential role in treating COVID-19 MESHD, placing a premium on analytical tools capable of supporting such efforts. Native mass spectrometry (MS) has long been a tool of choice in supporting the mechanistic studies of drug/therapeutic target interactions, but its applications remain limited in the cases that involve systems with a high level of structural heterogeneity. Both SARS-CoV-2 spike MESHD SARS-CoV-2 spike PROTEIN protein (S PROTEIN S-protein HGNC), a critical element of the viral entry to the host cell, and ACE2 HGNC, its docking site on the host cell surface, are extensively glycosylated, making them challenging targets for native MS. However, supplementing native MS with a gas-phase ion manipulation technique (limited charge reduction) allows meaningful information to be obtained on the non-covalent complexes formed by ACE2 HGNC and the receptor-binding domain (RBD) of the S-protein HGNC S-protein PROTEIN. Using this technique in combination with molecular modeling also allows the role of heparin in destabilizing the ACE2 HGNC/RBD association to be studied, providing critical information for understanding the molecular mechanism of its interference with the virus docking to the host cell receptor. Both short (pentasaccharide) and relatively long (eicosasaccharide) heparin oligomers form 1:1 complexes with RBD, indicating the presence of a single binding site. This association alters the protein conformation (to maximize the contiguous patch of the positive charge on the RBD surface), resulting in a notable decrease of its ability to associate with ACE2 HGNC. The destabilizing effect of heparin is more pronounced in the case of the longer chains due to the electrostatic repulsion between the low-pI ACE2 HGNC and the heparin segments not accommodated on the RBD surface. In addition to providing important mechanistic information on attenuation of the ACE2 HGNC/RBD association by heparin, the study demonstrates the yet untapped potential of native MS coupled to gas-phase ion chemistry as a means of facilitating rational repurposing of the existing medicines for treating COVID-19 MESHD. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=108 SRC="FIGDIR/small/142794v1_ufig1.gif" ALT="Figure 1"> View larger version (46K): org.highwire.dtl.DTLVardef@ce764corg.highwire.dtl.DTLVardef@b8909corg.highwire.dtl.DTLVardef@11e13fcorg.highwire.dtl.DTLVardef@1b2383a_HPS_FORMAT_FIGEXP M_FIG C_FIG

    Mutations strengthened SARS-CoV-2 infectivity

    Authors: Jiahui Chen; Rui Wang; Menglun Wang; Guo-Wei Wei

    id:2005.14669v1 Date: 2020-05-27 Source: arXiv

    Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infectivity is a major concern in coronavirus disease 2019 MESHD ( COVID-19 MESHD) prevention and economic reopening. However, rigorous determination of SARS-COV-2 infectivity is essentially impossible owing to its continuous evolution with over 13752 single nucleotide polymorphisms (SNP) variants in six different subtypes. We develop an advanced machine learning algorithm based on the algebraic topology to quantitatively evaluate the binding affinity changes of SARS-CoV-2 spike PROTEIN glycoprotein (S PROTEIN S protein HGNC) and host angiotensin-converting enzyme 2 HGNC ( ACE2 HGNC) receptor following the mutations. Based on mutation-induced binding affinity changes, we reveal that five out of six SARS-CoV-2 subtypes have become either moderately or slightly more infectious, while one subtype has weakened its infectivity. We find that SARS-CoV-2 is slightly more infectious than SARS-CoV according to computed S protein PROTEIN S protein HGNC- ACE2 HGNC binding affinity changes. Based on a systematic evaluation of all possible 3686 future mutations on the S protein HGNC S protein PROTEIN receptor-binding domain (RBD), we show that most likely future mutations will make SARS-CoV-2 more infectious. Combining sequence alignment, probability analysis, and binding affinity calculation, we predict that a few residues on the receptor-binding motif (RBM), i.e., 452, 489, 500, 501, and 505, have very high chances to mutate into significantly more infectious COVID-19 MESHD strains.

    High Throughput Designing and Mutational Mapping of RBD- ACE2 HGNC Interface Guide Non-Conventional Therapeutic Strategies for COVID-19 MESHD

    Authors: Aditya K. Padhi; Parismita Kalita; Kam Y.J. Zhang; Timir Tripathi

    doi:10.1101/2020.05.19.104042 Date: 2020-05-19 Source: bioRxiv

    Considering the current status of the SARS-CoV-2 pandemic, sequence variations and possibly structural changes in the rapidly evolving SARS-CoV-2 is highly expected in the coming months. The SARS-CoV-2 spike PROTEIN ( S) protein PROTEIN is responsible for mediating viral attachment and fusion with cell membranes. Mutations in the receptor-binding domain (RBD) of the S-protein PROTEIN S-protein HGNC occur at the most variable part of the SARS-CoV-2 genome, and specific sites of S-protein HGNC S-protein PROTEIN have undergone positive selection impacting the viral pathogenicity. In the present work, we used high-throughput computation to design 100,000 mutants in RBD interfacial residues and identify novel affinity-enhancing and affinity-weakening mutations. Our data suggest that SARS-CoV-2 can establish a higher rate of infectivity and pathogenesis when it acquires combinatorial mutations at the interfacial residues in RBD. Mapping of the mutational landscape of the interaction site suggests that a few of these residues are the hot-spot residues with a very high tendency to undergo positive selection. Knowledge of the affinity-enhancing mutations may guide the identification of potential cold-spots for this mutation as targets for developing a possible therapeutic strategy instead of hot-spots, and vice versa. Understanding of the molecular interactions between the virus and host protein presents a detailed systems view of viral infection MESHD mechanisms. The applications of the present research can be explored in multiple antiviral strategies, including monoclonal antibody therapy, vaccine design, and importantly in understanding the clinical pathogenesis of the virus itself. Our work presents research directions for the exploitation of non-conventional solutions for COVID-19 MESHD.

    Controlling the SARS-CoV-2 Spike PROTEIN Glycoprotein Conformation

    Authors: Rory Henderson; Robert J Edwards; Katayoun Mansouri; Katarzyna Janowska; Victoria Stalls; Sophie Gobeil; Megan Kopp; Allen L Hsu; Mario J. Borgnia; Robert Parks; Barton F Haynes; Priyamvada Acharya

    doi:10.1101/2020.05.18.102087 Date: 2020-05-18 Source: bioRxiv

    The coronavirus (CoV) viral host cell fusion spike (S) protein PROTEIN is the primary immunogenic target for virus neutralization and the current focus of many vaccine design efforts. The highly flexible S-protein PROTEIN S-protein HGNC, with its mobile domains, presents a moving target to the immune system. Here, to better understand S-protein HGNC S-protein PROTEIN mobility, we implemented a structure-based vector analysis of available {beta}-CoV S-protein HGNC S-protein PROTEIN structures. We found that despite overall similarity in domain organization, different {beta}-CoV strains display distinct S-protein HGNC S-protein PROTEIN configurations. Based on this analysis, we developed two soluble ectodomain constructs in which the highly immunogenic and mobile receptor binding domain (RBD) is locked in either the all-RBDs down position or is induced to display a previously unobserved in SARS-CoV-2 2-RBDs up configuration. These results demonstrate that the conformation of the S-protein HGNC S-protein PROTEIN can be controlled via rational design and provide a framework for the development of engineered coronavirus spike proteins PROTEIN for vaccine applications.

    In silico Drug Repurposing for COVID-19 MESHD: Targeting SARS-CoV-2 Proteins through Docking and Quantum Mechanical Scoring

    Authors: Claudio Cavasotto; Juan Di Filippo

    doi:10.26434/chemrxiv.12110199.v2 Date: 2020-05-18 Source: ChemRxiv

    In December 2019, an infectious disease MESHD caused by the coronavirus SARS-CoV-2 appeared in Wuhan, China. This disease ( COVID-19 MESHD) spread rapidly worldwide, and on March 2020 was declared a pandemic by the World Health Organization (WHO). Today, more than 4.7 million people have been infected, with almost 320,000 casualties, while no vaccine nor antiviral drug is in sight. The development of a vaccine might take at least a year, and even longer for a novel drug; thus, finding a new use to an old drug (drug repurposing) could be the most effective strategy. We present a high-throughput docking approach using a novel quantum mechanical scoring for screening a chemical library of ~11,500 molecules built from FDA-approved drugs and compounds undergoing clinical trials, against three SARS-CoV-2 target proteins: the spike or S PROTEIN S-protein HGNC, and two proteases, the main PROTEIN protease and the papain-like PROTEIN protease. The S-protein PROTEIN S-protein HGNC binds directly to the Angiotensin Converting Enzyme 2 receptor of the human host cell surface, while the two proteases process viral polyproteins. Following the analysis of our structure-based virtual screening, we propose several structurally diverse compounds that could display antiviral activity against SARS-CoV-2. Clearly, these compounds should be further evaluated in experimental assays and clinical trials to confirm their actual activity against the disease. We hope that these findings may contribute to the rational drug design against COVID-19 MESHD.

    Missense variants in ACE2 HGNC are predicted to encourage and inhibit interaction with SARS-CoV-2 Spike PROTEIN and contribute to genetic risk in COVID-19 MESHD

    Authors: Stuart A MacGowan; Geoffrey J Barton

    doi:10.1101/2020.05.03.074781 Date: 2020-05-04 Source: bioRxiv

    SARS-CoV-2 invades host cells via an endocytic pathway that begins with the interaction of the SARS-CoV-2 Spike MESHD SARS-CoV-2 Spike PROTEIN glycoprotein (S PROTEIN S-protein HGNC) and human Angiotensin-converting enzyme 2 HGNC ( ACE2 HGNC). Genetic variability in ACE2 HGNC may be one factor that mediates the broad-spectrum severity of SARS-CoV-2 infection MESHD and COVID-19 MESHD outcomes. We investigated the capacity of ACE2 HGNC variation to influence SARS-CoV-2 infection MESHD with a focus on predicting the effect of missense variants on the ACE2 HGNC SARS-CoV-2 S-protein PROTEIN S-protein HGNC interaction. We validated the mCSM-PPI2 variant effect prediction algorithm with 26 published ACE2 HGNC mutant SARS-CoV S-protein HGNC S-protein PROTEIN binding assays and found it performed well in this closely related system (True Positive Rate = 0.7, True Negative Rate = 1). Application of mCSM-PPI2 to ACE2 HGNC missense variants from the Genome Aggregation Consortium Database (gnomAD) identified three that are predicted to strongly inhibit or abolish the S-protein PROTEIN S-protein HGNC ACE2 HGNC interaction altogether (p.Glu37Lys, p.Gly352Val and p.Asp355Asn) and one that is predicted to promote the interaction (p.Gly326Glu). The S-protein HGNC S-protein PROTEIN ACE2 HGNC inhibitory variants are expected to confer a high degree of resistance to SARS-CoV-2 infection MESHD whilst the S-protein PROTEIN S-protein HGNC ACE2 HGNC affinity enhancing variant may lead to additional susceptibility and severity. We also performed in silico saturation mutagenesis of the S-protein PROTEIN S-protein HGNC ACE2 HGNC interface and identified a further 38 potential missense mutations that could strongly inhibit binding and one more that is likely to enhance binding (Thr27Arg). A conservative estimate places the prevalence of the strongly protective variants between 12-70 per 100,000 population but there is the possibility of higher prevalence in local populations or those underrepresented in gnomAD. The probable interplay between these ACE2 HGNC affinity variants and ACE2 HGNC expression polymorphisms is highlighted as well as gender differences in penetrance arising from ACE2 HGNCs situation on the X-chromosome. It is also described how our data can help power future genetic association studies of COVID-19 MESHD phenotypes and how the saturation mutant predictions can help design a mutant ACE2 HGNC with tailored S-protein PROTEIN S-protein HGNC affinity, which may be an improvement over a current recombinant ACE2 HGNC that is undergoing clinical trial. Key resultsO_LI1 ACE2 HGNC gnomAD missense variant (p.Gly326Glu) and one unobserved missense mutation (Thr27Arg) are predicted to enhance ACE2 HGNC binding with SARS-CoV-2 Spike PROTEIN protein, which could result in increased susceptibility and severity of COVID-19 MESHD C_LIO_LI3 ACE2 HGNC missense variants in gnomAD plus another 38 unobserved missense mutations are predicted to inhibit Spike binding, these are expected to confer a high degree of resistance to infection C_LIO_LIThe prevalence of the strongly protective variants is estimated between 12-70 per 100,000 population but higher prevalence may exist in local populations or those underrepresented in gnomAD C_LIO_LIA strategy to design a recombinant ACE2 HGNC with tailored affinity towards Spike and its potential therapeutic value is presented C_LIO_LIThe predictions were extensively validated against published ACE2 HGNC mutant binding assays for SARS-CoV Spike protein PROTEIN C_LI

    Structural and Functional Implications of Non-synonymous Mutations in the Spike protein PROTEIN of 2,954 SARS-CoV-2 Genomes

    Authors: Shijulal Nelson-Sathi; Perunthottathu K Umasankar; Sreekumar Easwaran; Radhakrishnan R Nair; Iype Joseph; Sai Ravi Chandra Nori; Jamiema Sara Philip; Roshny Prasad; Kolaparamba V Navyasree; Shikha Ramesh; Heera Pillai; Sanu Gosh; Santhosh Kumar TR; M Radhakrishna Pillai

    doi:10.1101/2020.05.02.071811 Date: 2020-05-02 Source: bioRxiv

    SARS-CoV-2, the causative agent of COVID-19 pandemic MESHD COVID-19 pandemic MESHD, is an RNA virus prone to mutations. Interaction of SARS-CoV-2 Spike PROTEIN SARS-CoV-2 Spike MESHD ( S) protein PROTEIN with the host cell receptor, Angiotensin-I Converting Enzyme 2 HGNC ( ACE2 HGNC) is pivotal for attachment and entry of the virus. Yet, natural mutations acquired on S protein PROTEIN during the pandemic and their impact on viral infectivity, transmission dynamics and disease pathogenesis remains poorly understood. Here, we analysed 2952 SARS-CoV-2 genomes across the globe, and identified a total of 1815 non-synonymous mutations in the S-protein HGNC S-protein PROTEIN that fall into 54 different types. We observed that six of these distinct mutations were located in the Receptor Binding Domain (RBD) region that directly engages host ACE2 HGNC. Molecular phylogenetic analysis revealed that these RBD mutations cluster into distinct phyletic clades among global subtypes of SARS-CoV-2 implying possible emergence of novel sublineages of the strain. Structure-guided homology modelling and docking analysis predicted key molecular rearrangements in the ACE2 HGNC binding interface of RBD mutants that could result in altered virus-host interactions. We propose that our findings could be significant in understanding disease dynamics and in developing vaccines, antibodies and therapeutics for COVID-19 MESHD. Importance COVID-19 pandemic MESHD shows considerable variations in disease transmission and pathogenesis globally, yet reasons remain unknown. Our study identifies key S-protein HGNC S-protein PROTEIN mutations prevailing in SARS-CoV-2 strain that could alter viral attachment and infectivity. We propose that the interplay of these mutations could be one of the factors driving global variations in COVID-19 MESHD spread. In addition, the mutations identified in this study could be an important indicator in predicting efficacies of vaccines, antibodies and therapeutics that target SARS-CoV-2 RBD- ACE2 HGNC interface.

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MeSH Disease
HGNC Genes
SARS-CoV-2 Proteins

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