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1.
J Biol Chem ; 297(6): 101399, 2021 12.
Article in English | MEDLINE | ID: covidwho-1509947

ABSTRACT

The nonstructural protein 1 (nsp1) of severe acute respiratory syndrome coronavirus and severe acute respiratory syndrome coronavirus 2 is a critical viral protein that suppresses host gene expression by blocking the assembly of the ribosome on host mRNAs. To understand the mechanism of inhibition of host gene expression, we sought to identify cellular proteins that interact with nsp1. Using proximity-dependent biotinylation followed by proteomic analyses of biotinylated proteins, here we captured multiple dynamic interactions of nsp1 with host cell proteins. In addition to ribosomal proteins, we identified several pre-mRNA processing proteins that interact with nsp1, including splicing factors and transcription termination proteins, as well as exosome, and stress granule (SG)-associated proteins. We found that the interactions with transcription termination factors are primarily governed by the C-terminal region of nsp1 and are disrupted by the mutation of amino acids K164 and H165 that are essential for its host shutoff function. We further show that nsp1 interacts with Ras GTPase-activating protein SH3 domain-binding protein 1 (G3BP1) and colocalizes with G3BP1 in SGs under sodium arsenite-induced stress. Finally, we observe that the presence of nsp1 disrupts the maturation of SGs over a long period. Isolation of SG core at different times shows a gradual loss of G3BP1 in the presence of nsp1.


Subject(s)
COVID-19/metabolism , RNA-Dependent RNA Polymerase/metabolism , SARS Virus/metabolism , SARS-CoV-2/metabolism , Severe Acute Respiratory Syndrome/metabolism , Viral Nonstructural Proteins/metabolism , Biotinylation , COVID-19/virology , HEK293 Cells , Host-Pathogen Interactions , Humans , Proteomics , Ribosomal Proteins/metabolism , SARS Virus/physiology , SARS-CoV-2/physiology , Severe Acute Respiratory Syndrome/virology , /metabolism
2.
Pharmacol Res Perspect ; 9(1): e00691, 2021 02.
Article in English | MEDLINE | ID: covidwho-1384293

ABSTRACT

Coronaviruses represent global health threat. In this century, they have already caused two epidemics and one serious pandemic. Although, at present, there are no approved drugs and therapies for the treatment and prevention of human coronaviruses, several agents, FDA-approved, and preclinical, have shown in vitro and/or in vivo antiviral activity. An in-depth analysis of the current situation leads to the identification of several potential drugs that could have an impact on the fight against coronaviruses infections. In this review, we discuss the virology of human coronaviruses highlighting the main biological targets and summarize the current state-of-the-art of possible therapeutic options to inhibit coronaviruses infections. We mostly focus on FDA-approved and preclinical drugs targeting viral conserved elements.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , COVID-19/metabolism , Coronavirus Infections/metabolism , Coronavirus/metabolism , Dipeptidyl Peptidase 4/metabolism , Severe Acute Respiratory Syndrome/metabolism , Angiotensin-Converting Enzyme 2/antagonists & inhibitors , Angiotensin-Converting Enzyme Inhibitors/administration & dosage , Angiotensin-Converting Enzyme Inhibitors/metabolism , Animals , Anti-Inflammatory Agents, Non-Steroidal/administration & dosage , Anti-Inflammatory Agents, Non-Steroidal/metabolism , Antiviral Agents/administration & dosage , Antiviral Agents/metabolism , Azoles/administration & dosage , Azoles/metabolism , COVID-19/drug therapy , Coronavirus/drug effects , Coronavirus Infections/drug therapy , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/metabolism , Humans , Isoindoles , Naphthoquinones/administration & dosage , Naphthoquinones/metabolism , Organoselenium Compounds/administration & dosage , Organoselenium Compounds/metabolism , Severe Acute Respiratory Syndrome/drug therapy
3.
Sci Rep ; 11(1): 12948, 2021 06 21.
Article in English | MEDLINE | ID: covidwho-1279894

ABSTRACT

COVID 19 disease has become a global catastrophe over the past year that has claimed the lives of over two million people around the world. Despite the introduction of vaccines against the disease, there is still a long way to completely eradicate it. There are concerns about the complications following infection with SARS-CoV-2. This research aimed to evaluate the possible correlation between infection with SARS-CoV viruses and cancer in an in-silico study model. To do this, the relevent dataset was selected from GEO database. Identification of differentially expressed genes among defined groups including SARS-CoV, SARS-dORF6, SARS-BatSRBD, and H1N1 were screened where the |Log FC| ≥ 1and p < 0.05 were considered statistically significant. Later, the pathway enrichment analysis and gene ontology (GO) were used by Enrichr and Shiny GO databases. Evaluation with STRING online was applied to predict the functional interactions of proteins, followed by Cytoscape analysis to identify the master genes. Finally, analysis with GEPIA2 server was carried out to reveal the possible correlation between candidate genes and cancer development. The results showed that the main molecular function of up- and down-regulated genes was "double-stranded RNA binding" and actin-binding, respectively. STRING and Cytoscape analysis presented four genes, PTEN, CREB1, CASP3, and SMAD3 as the key genes involved in cancer development. According to TCGA database results, these four genes were up-regulated notably in pancreatic adenocarcinoma. Our findings suggest that pancreatic adenocarcinoma is the most probably malignancy happening after infection with SARS-CoV family.


Subject(s)
Adenocarcinoma/etiology , COVID-19/complications , Carcinogenesis/genetics , Influenza A Virus, H1N1 Subtype , Influenza, Human/complications , Pancreatic Neoplasms/etiology , SARS Virus , SARS-CoV-2 , Severe Acute Respiratory Syndrome/complications , COVID-19/genetics , COVID-19/metabolism , COVID-19/virology , Caspase 3/genetics , Cyclic AMP Response Element-Binding Protein/genetics , Gene Expression Regulation , Gene Ontology , Humans , Influenza, Human/genetics , Influenza, Human/metabolism , Influenza, Human/virology , PTEN Phosphohydrolase/genetics , Protein Interaction Maps , Risk , Severe Acute Respiratory Syndrome/genetics , Severe Acute Respiratory Syndrome/metabolism , Severe Acute Respiratory Syndrome/virology , Signal Transduction/genetics , Smad3 Protein/genetics , Up-Regulation/genetics
4.
Proc Natl Acad Sci U S A ; 118(23)2021 06 08.
Article in English | MEDLINE | ID: covidwho-1238061

ABSTRACT

The SARS-CoV-2 pandemic has caused a surge in research exploring all aspects of the virus and its effects on human health. The overwhelming publication rate means that researchers are unable to keep abreast of the literature. To ameliorate this, we present the CoronaCentral resource that uses machine learning to process the research literature on SARS-CoV-2 together with SARS-CoV and MERS-CoV. We categorize the literature into useful topics and article types and enable analysis of the contents, pace, and emphasis of research during the crisis with integration of Altmetric data. These topics include therapeutics, disease forecasting, as well as growing areas such as "long COVID" and studies of inequality. This resource, available at https://coronacentral.ai, is updated daily.


Subject(s)
COVID-19 , Machine Learning , Middle East Respiratory Syndrome Coronavirus/metabolism , Pandemics , SARS-CoV-2/metabolism , Severe Acute Respiratory Syndrome , Animals , COVID-19/epidemiology , COVID-19/metabolism , COVID-19/therapy , COVID-19/transmission , Humans , Middle East Respiratory Syndrome Coronavirus/pathogenicity , SARS-CoV-2/pathogenicity , Severe Acute Respiratory Syndrome/epidemiology , Severe Acute Respiratory Syndrome/metabolism , Severe Acute Respiratory Syndrome/therapy , Severe Acute Respiratory Syndrome/transmission
5.
Protein J ; 39(6): 644-656, 2020 12.
Article in English | MEDLINE | ID: covidwho-1196608

ABSTRACT

Novel coronavirus disease 2019 (COVID-19) has resulted in a global pandemic and is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Several studies have suggested that a precise disulfide-thiol balance is crucial for viral entry and fusion into the host cell and that oxidative stress generated from free radicals can affect this balance. Here, we reviewed the current knowledge about the role of oxidative stress on SARS-CoV and SARS-CoV-2 infections. We focused on the impact of antioxidants, like NADPH and glutathione, and redox proteins, such as thioredoxin and protein disulfide isomerase, that maintain the disulfide-thiol balance in the cell. The possible influence of these biomolecules on the binding of viral protein with the host cell angiotensin-converting enzyme II receptor protein as well as on the severity of COVID-19 infection was discussed.


Subject(s)
COVID-19/metabolism , Oxidative Stress , SARS Virus/physiology , SARS-CoV-2/physiology , Severe Acute Respiratory Syndrome/metabolism , Acetylcysteine/pharmacology , Angiotensin-Converting Enzyme 2/metabolism , Animals , Antiviral Agents/pharmacology , COVID-19/drug therapy , Drug Discovery , Humans , Models, Molecular , Oxidative Stress/drug effects , SARS-CoV-2/drug effects , Severe Acute Respiratory Syndrome/drug therapy , Spike Glycoprotein, Coronavirus/metabolism , Viral Envelope Proteins/metabolism
6.
Nature ; 594(7862): 246-252, 2021 06.
Article in English | MEDLINE | ID: covidwho-1180252

ABSTRACT

The emergence and global spread of SARS-CoV-2 has resulted in the urgent need for an in-depth understanding of molecular functions of viral proteins and their interactions with the host proteome. Several individual omics studies have extended our knowledge of COVID-19 pathophysiology1-10. Integration of such datasets to obtain a holistic view of virus-host interactions and to define the pathogenic properties of SARS-CoV-2 is limited by the heterogeneity of the experimental systems. Here we report a concurrent multi-omics study of SARS-CoV-2 and SARS-CoV. Using state-of-the-art proteomics, we profiled the interactomes of both viruses, as well as their influence on the transcriptome, proteome, ubiquitinome and phosphoproteome of a lung-derived human cell line. Projecting these data onto the global network of cellular interactions revealed crosstalk between the perturbations taking place upon infection with SARS-CoV-2 and SARS-CoV at different levels and enabled identification of distinct and common molecular mechanisms of these closely related coronaviruses. The TGF-ß pathway, known for its involvement in tissue fibrosis, was specifically dysregulated by SARS-CoV-2 ORF8 and autophagy was specifically dysregulated by SARS-CoV-2 ORF3. The extensive dataset (available at https://covinet.innatelab.org ) highlights many hotspots that could be targeted by existing drugs and may be used to guide rational design of virus- and host-directed therapies, which we exemplify by identifying inhibitors of kinases and matrix metalloproteases with potent antiviral effects against SARS-CoV-2.


Subject(s)
COVID-19/metabolism , Host-Pathogen Interactions , Proteome/metabolism , Proteomics , SARS Virus/pathogenicity , SARS-CoV-2/pathogenicity , Severe Acute Respiratory Syndrome/metabolism , Animals , Antiviral Agents/pharmacology , Autophagy/drug effects , COVID-19/immunology , COVID-19/virology , Cell Line , Datasets as Topic , Drug Evaluation, Preclinical , Host-Pathogen Interactions/immunology , Humans , Matrix Metalloproteinase Inhibitors/pharmacology , Phosphorylation , Protein Interaction Maps , Protein Kinase Inhibitors/pharmacology , Protein Processing, Post-Translational , Proteome/chemistry , SARS Virus/immunology , SARS-CoV-2/immunology , Severe Acute Respiratory Syndrome/immunology , Severe Acute Respiratory Syndrome/virology , Transforming Growth Factor beta/metabolism , Ubiquitination , Viral Proteins/chemistry , Viral Proteins/metabolism , Viroporin Proteins/metabolism
7.
Biochem Biophys Res Commun ; 557: 273-279, 2021 06 11.
Article in English | MEDLINE | ID: covidwho-1174101

ABSTRACT

Recently, the novel coronavirus (SARS-CoV-2), which has spread from China to the world, was declared a global public health emergency, which causes lethal respiratory infections. Acetylation of several proteins plays essential roles in various biological processes, such as viral infections. We reported that the nucleoproteins of influenza virus and Zaire Ebolavirus were acetylated, suggesting that these modifications contributed to the molecular events involved in viral replication. Similar to influenza virus and Ebolavirus, the coronavirus also contains single-stranded RNA, as its viral genome interacts with the nucleocapsid (N) proteins. In this study, we report that SARS-CoV and SARS-CoV-2 N proteins are strongly acetylated by human histone acetyltransferases, P300/CBP-associated factor (PCAF), and general control nonderepressible 5 (GCN5), but not by CREB-binding protein (CBP) in vitro. Liquid chromatography-mass spectrometry analyses identified 2 and 12 acetyl-lysine residues from SARS-CoV and SARS-CoV-2 N proteins, respectively. Particularly in the SARS-CoV-2 N proteins, the acetyl-lysine residues were localized in or close to several functional sites, such as the RNA interaction domains and the M-protein interacting site. These results suggest that acetylation of SARS-CoV-2 N proteins plays crucial roles in their functions.


Subject(s)
COVID-19/metabolism , Coronavirus Nucleocapsid Proteins/metabolism , Histone Acetyltransferases/metabolism , SARS Virus/metabolism , SARS-CoV-2/metabolism , Severe Acute Respiratory Syndrome/metabolism , p300-CBP Transcription Factors/metabolism , Acetylation , CREB-Binding Protein/metabolism , Coronavirus Nucleocapsid Proteins/chemistry , Humans , Models, Molecular , Phosphoproteins/chemistry , Phosphoproteins/metabolism , SARS Virus/chemistry , SARS-CoV-2/chemistry
8.
FASEB J ; 35(4): e21360, 2021 04.
Article in English | MEDLINE | ID: covidwho-1145195

ABSTRACT

The novel coronavirus disease, COVID-19, has grown into a global pandemic and a major public health threat since its breakout in December 2019. To date, no specific therapeutic drug or vaccine for treating COVID-19 and SARS has been FDA approved. Previous studies suggest that berberine, an isoquinoline alkaloid, has shown various biological activities that may help against COVID-19 and SARS, including antiviral, anti-allergy and inflammation, hepatoprotection against drug- and infection-induced liver injury, as well as reducing oxidative stress. In particular, berberine has a wide range of antiviral activities such as anti-influenza, anti-hepatitis C, anti-cytomegalovirus, and anti-alphavirus. As an ingredient recommended in guidelines issued by the China National Health Commission for COVID-19 to be combined with other therapy, berberine is a promising orally administered therapeutic candidate against SARS-CoV and SARS-CoV-2. The current study comprehensively evaluates the potential therapeutic mechanisms of berberine in preventing and treating COVID-19 and SARS using computational modeling, including target mining, gene ontology enrichment, pathway analyses, protein-protein interaction analysis, and in silico molecular docking. An orally available immunotherapeutic-berberine nanomedicine, named NIT-X, has been developed by our group and has shown significantly increased oral bioavailability of berberine, increased IFN-γ production by CD8+ T cells, and inhibition of mast cell histamine release in vivo, suggesting a protective immune response. We further validated the inhibition of replication of SARS-CoV-2 in lung epithelial cells line in vitro (Calu3 cells) by berberine. Moreover, the expression of targets including ACE2, TMPRSS2, IL-1α, IL-8, IL-6, and CCL-2 in SARS-CoV-2 infected Calu3 cells were significantly suppressed by NIT-X. By supporting protective immunity while inhibiting pro-inflammatory cytokines; inhibiting viral infection and replication; inducing apoptosis; and protecting against tissue damage, berberine is a promising candidate in preventing and treating COVID-19 and SARS. Given the high oral bioavailability and safety of berberine nanomedicine, the current study may lead to the development of berberine as an orally, active therapeutic against COVID-19 and SARS.


Subject(s)
Antiviral Agents/pharmacology , Berberine/pharmacology , COVID-19 , Gene Expression Regulation/drug effects , Models, Biological , SARS Virus/metabolism , SARS-CoV-2/metabolism , Severe Acute Respiratory Syndrome , Administration, Oral , COVID-19/drug therapy , COVID-19/metabolism , Cell Line , Computer Simulation , Humans , Pandemics , Severe Acute Respiratory Syndrome/drug therapy , Severe Acute Respiratory Syndrome/metabolism
9.
Cell Death Dis ; 12(3): 263, 2021 03 12.
Article in English | MEDLINE | ID: covidwho-1132058

ABSTRACT

The pathogenesis of SARS-CoV-2 remains to be completely understood, and detailed SARS-CoV-2 cellular cytopathic effects requires definition. We performed a comparative ultrastructural study of SARS-CoV-1 and SARS-CoV-2 infection in Vero E6 cells and in lungs from deceased COVID-19 patients. SARS-CoV-2 induces rapid death associated with profound ultrastructural changes in Vero cells. Type II pneumocytes in lung tissue showed prominent altered features with numerous vacuoles and swollen mitochondria with presence of abundant lipid droplets. The accumulation of lipids was the most striking finding we observed in SARS-CoV-2 infected cells, both in vitro and in the lungs of patients, suggesting that lipids can be involved in SARS-CoV-2 pathogenesis. Considering that in most cases, COVID-19 patients show alteration of blood cholesterol and lipoprotein homeostasis, our findings highlight a peculiar important topic that can suggest new approaches for pharmacological treatment to contrast the pathogenicity of SARS-CoV-2.


Subject(s)
COVID-19 , Lipid Droplets , Lipid Metabolism , Lung , SARS-CoV-2/metabolism , Animals , COVID-19/metabolism , COVID-19/pathology , Chlorocebus aethiops , Cytopathogenic Effect, Viral , Humans , Lipid Droplets/ultrastructure , Lipid Droplets/virology , Lung/metabolism , Lung/ultrastructure , Lung/virology , SARS Virus/metabolism , SARS Virus/ultrastructure , SARS-CoV-2/ultrastructure , Severe Acute Respiratory Syndrome/metabolism , Severe Acute Respiratory Syndrome/pathology , Vero Cells
10.
J Chem Inf Model ; 61(3): 1226-1243, 2021 03 22.
Article in English | MEDLINE | ID: covidwho-1096303

ABSTRACT

Angiotensin-converting enzyme 2 (ACE2) is the host cellular receptor that locks onto the surface spike protein of the 2002 SARS coronavirus (SARS-CoV-1) and of the novel, highly transmissible and deadly 2019 SARS-CoV-2, responsible for the COVID-19 pandemic. One strategy to avoid the virus infection is to design peptides by extracting the human ACE2 peptidase domain α1-helix, which would bind to the coronavirus surface protein, preventing the virus entry into the host cells. The natural α1-helix peptide has a stronger affinity to SARS-CoV-2 than to SARS-CoV-1. Another peptide was designed by joining α1 with the second portion of ACE2 that is far in the peptidase sequence yet grafted in the spike protein interface with ACE2. Previous studies have shown that, among several α1-based peptides, the hybrid peptidic scaffold is the one with the highest/strongest affinity for SARS-CoV-1, which is comparable to the full-length ACE2 affinity. In this work, binding and folding dynamics of the natural and designed ACE2-based peptides were simulated by the well-known coarse-grained structure-based model, with the computed thermodynamic quantities correlating with the experimental binding affinity data. Furthermore, theoretical kinetic analysis of native contact formation revealed the distinction between these processes in the presence of the different binding partners SARS-CoV-1 and SARS-CoV-2 spike domains. Additionally, our results indicate the existence of a two-state folding mechanism for the designed peptide en route to bind to the spike proteins, in contrast to a downhill mechanism for the natural α1-helix peptides. The presented low-cost simulation protocol demonstrated its efficiency in evaluating binding affinities and identifying the mechanisms involved in the neutralization of spike-ACE2 interaction by designed peptides. Finally, the protocol can be used as a computer-based screening of more potent designed peptides by experimentalists searching for new therapeutics against COVID-19.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , Antiviral Agents/pharmacology , COVID-19/drug therapy , Drug Design , Peptides/pharmacology , Spike Glycoprotein, Coronavirus/metabolism , Antiviral Agents/chemistry , COVID-19/metabolism , Humans , Models, Molecular , Peptides/chemistry , Protein Binding/drug effects , Protein Domains/drug effects , SARS Virus/drug effects , SARS Virus/metabolism , SARS-CoV-2/drug effects , SARS-CoV-2/metabolism , Severe Acute Respiratory Syndrome/drug therapy , Severe Acute Respiratory Syndrome/metabolism
11.
J Virol ; 95(9)2021 04 12.
Article in English | MEDLINE | ID: covidwho-1093846

ABSTRACT

Severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) infects cells through interaction of its spike protein (SARS2-S) with angiotensin-converting enzyme 2 (ACE2) and activation by proteases, in particular transmembrane protease serine 2 (TMPRSS2). Viruses can also spread through fusion of infected with uninfected cells. We compared the requirements of ACE2 expression, proteolytic activation, and sensitivity to inhibitors for SARS2-S-mediated and SARS-CoV-S (SARS1-S)-mediated cell-cell fusion. SARS2-S-driven fusion was moderately increased by TMPRSS2 and strongly by ACE2, while SARS1-S-driven fusion was strongly increased by TMPRSS2 and less so by ACE2 expression. In contrast to that of SARS1-S, SARS2-S-mediated cell-cell fusion was efficiently activated by batimastat-sensitive metalloproteases. Mutation of the S1/S2 proteolytic cleavage site reduced effector cell-target cell fusion when ACE2 or TMPRSS2 was limiting and rendered SARS2-S-driven cell-cell fusion more dependent on TMPRSS2. When both ACE2 and TMPRSS2 were abundant, initial target cell-effector cell fusion was unaltered compared to that of wild-type (wt) SARS2-S, but syncytia remained smaller. Mutation of the S2 cleavage (S2') site specifically abrogated activation by TMPRSS2 for both cell-cell fusion and SARS2-S-driven pseudoparticle entry but still allowed for activation by metalloproteases for cell-cell fusion and by cathepsins for particle entry. Finally, we found that the TMPRSS2 inhibitor bromhexine, unlike the inhibitor camostat, was unable to reduce TMPRSS2-activated cell-cell fusion by SARS1-S and SARS2-S. Paradoxically, bromhexine enhanced cell-cell fusion in the presence of TMPRSS2, while its metabolite ambroxol exhibited inhibitory activity under some conditions. On Calu-3 lung cells, ambroxol weakly inhibited SARS2-S-driven lentiviral pseudoparticle entry, and both substances exhibited a dose-dependent trend toward weak inhibition of authentic SARS-CoV-2.IMPORTANCE Cell-cell fusion allows viruses to infect neighboring cells without the need to produce free virus and contributes to tissue damage by creating virus-infected syncytia. Our results demonstrate that the S2' cleavage site is essential for activation by TMPRSS2 and unravel important differences between SARS-CoV and SARS-CoV-2, among those, greater dependence of SARS-CoV-2 on ACE2 expression and activation by metalloproteases for cell-cell fusion. Bromhexine, reportedly an inhibitor of TMPRSS2, is currently being tested in clinical trials against coronavirus disease 2019. Our results indicate that bromhexine enhances fusion under some conditions. We therefore caution against the use of bromhexine in high dosages until its effects on SARS-CoV-2 spike activation are better understood. The related compound ambroxol, which similarly to bromhexine is clinically used as an expectorant, did not exhibit activating effects on cell-cell fusion. Both compounds exhibited weak inhibitory activity against SARS-CoV-2 infection at high concentrations, which might be clinically attainable for ambroxol.


Subject(s)
COVID-19/metabolism , SARS Virus/metabolism , SARS-CoV-2/metabolism , Severe Acute Respiratory Syndrome/metabolism , Spike Glycoprotein, Coronavirus/metabolism , Virus Internalization , Ambroxol/pharmacology , Amino Acid Substitution , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/metabolism , Bromhexine/pharmacology , COVID-19/genetics , Cell Line , Humans , Mutation, Missense , Proteolysis/drug effects , SARS Virus/genetics , SARS-CoV-2/genetics , Serine Endopeptidases/genetics , Serine Endopeptidases/metabolism , Severe Acute Respiratory Syndrome/genetics , Spike Glycoprotein, Coronavirus/genetics
12.
Molecules ; 26(4)2021 Feb 13.
Article in English | MEDLINE | ID: covidwho-1085052

ABSTRACT

Coronaviruses (CoVs) are positive-sense RNA enveloped viruses, members of the family Coronaviridae, that cause infections in a broad range of mammals including humans. Several CoV species lead to mild upper respiratory infections typically associated with common colds. However, three human CoV (HCoV) species: Severe Acute Respiratory Syndrome (SARS)-CoV-1, Middle East Respiratory Syndrome (MERS)-CoV, and SARS-CoV-2, are responsible for severe respiratory diseases at the origin of two recent epidemics (SARS and MERS), and of the current COronaVIrus Disease 19 (COVID-19), respectively. The easily transmissible SARS-CoV-2, emerging at the end of 2019 in China, spread rapidly worldwide, leading the World Health Organization (WHO) to declare COVID-19 a pandemic. While the world waits for mass vaccination, there is an urgent need for effective drugs as short-term weapons to combat the SARS-CoV-2 infection. In this context, the drug repurposing approach is a strategy able to guarantee positive results rapidly. In this regard, it is well known that several nucleoside-mimicking analogs and nucleoside precursors may inhibit the growth of viruses providing effective therapies for several viral diseases, including HCoV infections. Therefore, this review will focus on synthetic nucleosides and nucleoside precursors active against different HCoV species, paying great attention to SARS-CoV-2. This work covers progress made in anti-CoV therapy with nucleoside derivatives and provides insight into their main mechanisms of action.


Subject(s)
Antiviral Agents , COVID-19/drug therapy , Drug Repositioning , Nucleosides , SARS Virus/metabolism , SARS-CoV-2/metabolism , Severe Acute Respiratory Syndrome/drug therapy , Animals , Antiviral Agents/chemistry , Antiviral Agents/therapeutic use , COVID-19/epidemiology , COVID-19/metabolism , Humans , Nucleosides/chemistry , Nucleosides/therapeutic use , Severe Acute Respiratory Syndrome/epidemiology , Severe Acute Respiratory Syndrome/metabolism
13.
BMC Bioinformatics ; 22(1): 18, 2021 Jan 07.
Article in English | MEDLINE | ID: covidwho-1059737

ABSTRACT

BACKGROUND: The ongoing global COVID-19 pandemic is caused by SARS-CoV-2, a novel coronavirus first discovered at the end of 2019. It has led to more than 50 million confirmed cases and more than 1 million deaths across 219 countries as of 11 November 2020, according to WHO statistics. SARS-CoV-2, SARS-CoV, and MERS-CoV are similar. They are highly pathogenic and threaten public health, impair the economy, and inflict long-term impacts on society. No drug or vaccine has been approved as a treatment for these viruses. Efforts to develop antiviral measures have been hampered by the insufficient understanding of how the human body responds to viral infections at the cellular and molecular levels. RESULTS: In this study, journal articles and transcriptomic and proteomic data surveying coronavirus infections were collected. Response genes and proteins were then identified by differential analyses comparing gene/protein levels between infected and control samples. Finally, the H2V database was created to contain the human genes and proteins that respond to SARS-CoV-2, SARS-CoV, and MERS-CoV infection. CONCLUSIONS: H2V provides molecular information about the human response to infection. It can be a powerful tool to discover cellular pathways and processes relevant for viral pathogenesis to identify potential drug targets. It is expected to accelerate the process of antiviral agent development and to inform preparations for potential future coronavirus-related emergencies. The database is available at: http://www.zhounan.org/h2v .


Subject(s)
COVID-19/metabolism , Coronavirus Infections/metabolism , Databases, Genetic , Databases, Protein , Severe Acute Respiratory Syndrome/metabolism , User-Computer Interface , COVID-19/genetics , COVID-19/pathology , COVID-19/virology , Coronavirus Infections/genetics , Coronavirus Infections/pathology , Coronavirus Infections/virology , Humans , Middle East Respiratory Syndrome Coronavirus/physiology , Proteomics , SARS Virus/physiology , SARS-CoV-2/physiology , Severe Acute Respiratory Syndrome/genetics , Severe Acute Respiratory Syndrome/pathology , Severe Acute Respiratory Syndrome/virology
14.
FASEB J ; 35(2): e21245, 2021 02.
Article in English | MEDLINE | ID: covidwho-1048438

ABSTRACT

Lymphopenia is commonly observed in SARS and COVID-19 patients although the lymphocyte count is not always below 0.8 × 109 /L in all the patients. It is suggested that lymphopenia serves as a useful predictor for prognosis in the patients. It is also hypothesized that lymphopenia is related to glucocorticoids and apoptosis. However, the ordering between lymphopenia and apoptosis appears different between SARS and COVID-19 patients, ie, lymphopenia is prior to apoptosis in SARS patients whereas apoptosis is prior to lymphopenia in COVID-19 patients. This paper attempts to figure out this contradiction through three players, lymphopenia, glucocorticoids, and apoptosis. Although the literature does not provide a solid explanation, the level of glucocorticoids could determine the ordering between lymphopenia and apoptosis because the administration of high doses of glucocorticoids could lead to lymphopenia whereas low doses of glucocorticoids could benefit patients. In the meantime, this paper raises several questions, which need to be answered in order to better understand the whole course of COVID-19.


Subject(s)
COVID-19 , Glucocorticoids , Lymphopenia , SARS Virus/metabolism , SARS-CoV-2/metabolism , Severe Acute Respiratory Syndrome , Apoptosis/drug effects , COVID-19/complications , COVID-19/drug therapy , COVID-19/metabolism , Glucocorticoids/adverse effects , Glucocorticoids/therapeutic use , Humans , Lymphopenia/drug therapy , Lymphopenia/etiology , Lymphopenia/metabolism , Severe Acute Respiratory Syndrome/complications , Severe Acute Respiratory Syndrome/drug therapy , Severe Acute Respiratory Syndrome/metabolism
15.
BMC Bioinformatics ; 22(1): 18, 2021 Jan 07.
Article in English | MEDLINE | ID: covidwho-1015834

ABSTRACT

BACKGROUND: The ongoing global COVID-19 pandemic is caused by SARS-CoV-2, a novel coronavirus first discovered at the end of 2019. It has led to more than 50 million confirmed cases and more than 1 million deaths across 219 countries as of 11 November 2020, according to WHO statistics. SARS-CoV-2, SARS-CoV, and MERS-CoV are similar. They are highly pathogenic and threaten public health, impair the economy, and inflict long-term impacts on society. No drug or vaccine has been approved as a treatment for these viruses. Efforts to develop antiviral measures have been hampered by the insufficient understanding of how the human body responds to viral infections at the cellular and molecular levels. RESULTS: In this study, journal articles and transcriptomic and proteomic data surveying coronavirus infections were collected. Response genes and proteins were then identified by differential analyses comparing gene/protein levels between infected and control samples. Finally, the H2V database was created to contain the human genes and proteins that respond to SARS-CoV-2, SARS-CoV, and MERS-CoV infection. CONCLUSIONS: H2V provides molecular information about the human response to infection. It can be a powerful tool to discover cellular pathways and processes relevant for viral pathogenesis to identify potential drug targets. It is expected to accelerate the process of antiviral agent development and to inform preparations for potential future coronavirus-related emergencies. The database is available at: http://www.zhounan.org/h2v .


Subject(s)
COVID-19/metabolism , Coronavirus Infections/metabolism , Databases, Genetic , Databases, Protein , Severe Acute Respiratory Syndrome/metabolism , User-Computer Interface , COVID-19/genetics , COVID-19/pathology , COVID-19/virology , Coronavirus Infections/genetics , Coronavirus Infections/pathology , Coronavirus Infections/virology , Humans , Middle East Respiratory Syndrome Coronavirus/physiology , Proteomics , SARS Virus/physiology , SARS-CoV-2/physiology , Severe Acute Respiratory Syndrome/genetics , Severe Acute Respiratory Syndrome/pathology , Severe Acute Respiratory Syndrome/virology
16.
Comput Biol Med ; 128: 104123, 2021 01.
Article in English | MEDLINE | ID: covidwho-967558

ABSTRACT

The ongoing COVID-19 pandemic caused by the coronavirus, SARS-CoV-2, has already caused in excess of 1.25 million deaths worldwide, and the number is increasing. Knowledge of the host transcriptional response against this virus and how the pathways are activated or suppressed compared to other human coronaviruses (SARS-CoV, MERS-CoV) that caused outbreaks previously can help in the identification of potential drugs for the treatment of COVID-19. Hence, we used time point meta-analysis to investigate available SARS-CoV and MERS-CoV in-vitro transcriptome datasets in order to identify the significant genes and pathways that are dysregulated at each time point. The subsequent over-representation analysis (ORA) revealed that several pathways are significantly dysregulated at each time point after both SARS-CoV and MERS-CoV infection. We also performed gene set enrichment analyses of SARS-CoV and MERS-CoV with that of SARS-CoV-2 at the same time point and cell line, the results of which revealed that common pathways are activated and suppressed in all three coronaviruses. Furthermore, an analysis of an in-vivo transcriptomic dataset of COVID-19 patients showed that similar pathways are enriched to those identified in the earlier analyses. Based on these findings, a drug repurposing analysis was performed to identify potential drug candidates for combating COVID-19.


Subject(s)
Antiviral Agents , COVID-19/metabolism , Databases, Nucleic Acid , Drug Repositioning , Middle East Respiratory Syndrome Coronavirus/metabolism , SARS Virus/metabolism , SARS-CoV-2/metabolism , Severe Acute Respiratory Syndrome/metabolism , Transcriptome , COVID-19/drug therapy , COVID-19/genetics , Humans , Middle East Respiratory Syndrome Coronavirus/genetics , SARS Virus/genetics , SARS-CoV-2/genetics , Severe Acute Respiratory Syndrome/drug therapy , Severe Acute Respiratory Syndrome/genetics
17.
ACS Infect Dis ; 6(12): 3174-3189, 2020 12 11.
Article in English | MEDLINE | ID: covidwho-954597

ABSTRACT

Human coronaviruses (hCoVs) have become a threat to global health and society, as evident from the SARS outbreak in 2002 caused by SARS-CoV-1 and the most recent COVID-19 pandemic caused by SARS-CoV-2. Despite a high sequence similarity between SARS-CoV-1 and -2, each strain has a distinctive virulence. A better understanding of the basic molecular mechanisms mediating changes in virulence is needed. Here, we profile the virus-host protein-protein interactions of two hCoV nonstructural proteins (nsps) that are critical for virus replication. We use tandem mass tag-multiplexed quantitative proteomics to sensitively compare and contrast the interactomes of nsp2 and nsp4 from three betacoronavirus strains: SARS-CoV-1, SARS-CoV-2, and hCoV-OC43-an endemic strain associated with the common cold. This approach enables the identification of both unique and shared host cell protein binding partners and the ability to further compare the enrichment of common interactions across homologues from related strains. We identify common nsp2 interactors involved in endoplasmic reticulum (ER) Ca2+ signaling and mitochondria biogenesis. We also identify nsp4 interactors unique to each strain, such as E3 ubiquitin ligase complexes for SARS-CoV-1 and ER homeostasis factors for SARS-CoV-2. Common nsp4 interactors include N-linked glycosylation machinery, unfolded protein response associated proteins, and antiviral innate immune signaling factors. Both nsp2 and nsp4 interactors are strongly enriched in proteins localized at mitochondria-associated ER membranes suggesting a new functional role for modulating host processes, such as calcium homeostasis, at these organelle contact sites. Our results shed light on the role these hCoV proteins play in the infection cycle, as well as host factors that may mediate the divergent pathogenesis of OC43 from SARS strains. Our mass spectrometry workflow enables rapid and robust comparisons of multiple bait proteins, which can be applied to additional viral proteins. Furthermore, the identified common interactions may present new targets for exploration by host-directed antiviral therapeutics.


Subject(s)
COVID-19/metabolism , Host-Pathogen Interactions/genetics , SARS-CoV-2/pathogenicity , Viral Nonstructural Proteins/metabolism , COVID-19/virology , Coronavirus OC43, Human/pathogenicity , Endoplasmic Reticulum/metabolism , HEK293 Cells , Humans , Membrane Proteins/metabolism , Mitochondria/metabolism , Protein Binding , Protein Interaction Maps/genetics , SARS Virus/pathogenicity , Severe Acute Respiratory Syndrome/metabolism , Severe Acute Respiratory Syndrome/virology , Transfection , Viral Nonstructural Proteins/genetics , Virulence/genetics , Virus Replication/genetics
18.
Viruses ; 12(10)2020 09 29.
Article in English | MEDLINE | ID: covidwho-904976

ABSTRACT

Severe acute respiratory syndrome virus 2 (SARS-CoV-2) is responsible for the current global coronavirus disease 2019 (COVID-19) pandemic, infecting millions of people and causing hundreds of thousands of deaths. The viral entry of SARS-CoV-2 depends on an interaction between the receptor-binding domain of its trimeric spike glycoprotein and the human angiotensin-converting enzyme 2 (ACE2) receptor. A better understanding of the spike/ACE2 interaction is still required to design anti-SARS-CoV-2 therapeutics. Here, we investigated the degree of cooperativity of ACE2 within both the SARS-CoV-2 and the closely related SARS-CoV-1 membrane-bound S glycoproteins. We show that there exist differential inter-protomer conformational transitions between both spike trimers. Interestingly, the SARS-CoV-2 spike exhibits a positive cooperativity for monomeric soluble ACE2 binding when compared to the SARS-CoV-1 spike, which might have more structural restraints. Our findings can be of importance in the development of therapeutics that block the spike/ACE2 interaction.


Subject(s)
Betacoronavirus/physiology , Coronavirus Infections/metabolism , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/metabolism , SARS Virus/physiology , Severe Acute Respiratory Syndrome/metabolism , Spike Glycoprotein, Coronavirus/metabolism , Angiotensin-Converting Enzyme 2 , Betacoronavirus/metabolism , COVID-19 , Carrier Proteins , Coronavirus Infections/virology , Cryoelectron Microscopy , HEK293 Cells , Humans , Pandemics , Pneumonia, Viral/virology , Protein Binding , Protein Interaction Domains and Motifs , SARS Virus/metabolism , SARS-CoV-2 , Severe Acute Respiratory Syndrome/virology , Virus Internalization
19.
Signal Transduct Target Ther ; 5(1): 240, 2020 10 15.
Article in English | MEDLINE | ID: covidwho-872677

ABSTRACT

The COVID-19 pandemic has emerged as a global health emergency due to its association with severe pneumonia and relative high mortality. However, the molecular characteristics and pathological features underlying COVID-19 pneumonia remain largely unknown. To characterize molecular mechanisms underlying COVID-19 pathogenesis in the lung tissue using a proteomic approach, fresh lung tissues were obtained from newly deceased patients with COVID-19 pneumonia. After virus inactivation, a quantitative proteomic approach combined with bioinformatics analysis was used to detect proteomic changes in the SARS-CoV-2-infected lung tissues. We identified significant differentially expressed proteins involved in a variety of fundamental biological processes including cellular metabolism, blood coagulation, immune response, angiogenesis, and cell microenvironment regulation. Several inflammatory factors were upregulated, which was possibly caused by the activation of NF-κB signaling. Extensive dysregulation of the lung proteome in response to SARS-CoV-2 infection was discovered. Our results systematically outlined the molecular pathological features in terms of the lung response to SARS-CoV-2 infection, and provided the scientific basis for the therapeutic target that is urgently needed to control the COVID-19 pandemic.


Subject(s)
Betacoronavirus/pathogenicity , Coronavirus Infections/genetics , Lung Injury/genetics , Pneumonia, Viral/genetics , Proteome/genetics , Proteomics/methods , Severe Acute Respiratory Syndrome/genetics , Aged , Autopsy , COVID-19 , Coronavirus Infections/metabolism , Coronavirus Infections/pathology , Coronavirus Infections/virology , Cytokines/genetics , Cytokines/metabolism , Female , Gene Expression Profiling , Gene Expression Regulation , Gene Ontology , Humans , Lung/metabolism , Lung/pathology , Lung/virology , Lung Injury/metabolism , Lung Injury/pathology , Lung Injury/virology , Male , Metabolic Networks and Pathways , Molecular Sequence Annotation , NF-kappa B/genetics , NF-kappa B/metabolism , Pandemics , Pneumonia, Viral/metabolism , Pneumonia, Viral/pathology , Pneumonia, Viral/virology , Proteome/metabolism , SARS-CoV-2 , Severe Acute Respiratory Syndrome/metabolism , Severe Acute Respiratory Syndrome/pathology , Severe Acute Respiratory Syndrome/virology , Severity of Illness Index , Signal Transduction
20.
Science ; 370(6521)2020 12 04.
Article in English | MEDLINE | ID: covidwho-873450

ABSTRACT

The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a grave threat to public health and the global economy. SARS-CoV-2 is closely related to the more lethal but less transmissible coronaviruses SARS-CoV-1 and Middle East respiratory syndrome coronavirus (MERS-CoV). Here, we have carried out comparative viral-human protein-protein interaction and viral protein localization analyses for all three viruses. Subsequent functional genetic screening identified host factors that functionally impinge on coronavirus proliferation, including Tom70, a mitochondrial chaperone protein that interacts with both SARS-CoV-1 and SARS-CoV-2 ORF9b, an interaction we structurally characterized using cryo-electron microscopy. Combining genetically validated host factors with both COVID-19 patient genetic data and medical billing records identified molecular mechanisms and potential drug treatments that merit further molecular and clinical study.


Subject(s)
COVID-19/metabolism , Coronavirus Nucleocapsid Proteins/metabolism , Host Microbial Interactions , Mitochondrial Membrane Transport Proteins/metabolism , Protein Interaction Maps , SARS Virus/metabolism , SARS-CoV-2/metabolism , Severe Acute Respiratory Syndrome/metabolism , Conserved Sequence , Coronavirus Nucleocapsid Proteins/genetics , Cryoelectron Microscopy , Humans , Mitochondrial Membrane Transport Proteins/genetics , Phosphoproteins/genetics , Phosphoproteins/metabolism , Protein Conformation
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