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1.
Proc Biol Sci ; 289(1979): 20220193, 2022 07 27.
Article in English | MEDLINE | ID: covidwho-1961305

ABSTRACT

Pandemics originating from non-human animals highlight the need to understand how natural hosts have evolved in response to emerging human pathogens and which groups may be susceptible to infection and/or potential reservoirs to mitigate public health and conservation concerns. Multiple zoonotic coronaviruses, such as severe acute respiratory syndrome-associated coronavirus (SARS-CoV), SARS-CoV-2 and Middle Eastern respiratory syndrome-associated coronavirus (MERS-CoV), are hypothesized to have evolved in bats. We investigate angiotensin-converting enzyme 2 (ACE2), the host protein bound by SARS-CoV and SARS-CoV-2, and dipeptidyl-peptidase 4 (DPP4 or CD26), the host protein bound by MERS-CoV, in the largest bat datasets to date. Both the ACE2 and DPP4 genes are under strong selection pressure in bats, more so than in other mammals, and in residues that contact viruses. Additionally, mammalian groups vary in their similarity to humans in residues that contact SARS-CoV, SARS-CoV-2 and MERS-CoV, and increased similarity to humans in binding residues is broadly predictive of susceptibility to SARS-CoV-2. This work augments our understanding of the relationship between coronaviruses and mammals, particularly bats, provides taxonomically diverse data for studies of how host proteins are bound by coronaviruses and can inform surveillance, conservation and public health efforts.


Subject(s)
Chiroptera , Middle East Respiratory Syndrome Coronavirus , Receptors, Coronavirus , SARS Virus , SARS-CoV-2 , Angiotensin-Converting Enzyme 2 , Animals , COVID-19 , Chiroptera/genetics , Dipeptidyl Peptidase 4/genetics , Dipeptidyl Peptidase 4/metabolism , Humans , Middle East Respiratory Syndrome Coronavirus/metabolism , SARS Virus/metabolism , SARS-CoV-2/metabolism
2.
J Virol ; 96(15): e0095822, 2022 08 10.
Article in English | MEDLINE | ID: covidwho-1949998

ABSTRACT

The spike protein on sarbecovirus virions contains two external, protruding domains: an N-terminal domain (NTD) with unclear function and a C-terminal domain (CTD) that binds the host receptor, allowing for viral entry and infection. While the CTD is well studied for therapeutic interventions, the role of the NTD is far less well understood for many coronaviruses. Here, we demonstrate that the spike NTD from SARS-CoV-2 and other sarbecoviruses binds to unidentified glycans in vitro similarly to other members of the Coronaviridae family. We also show that these spike NTD (S-NTD) proteins adhere to Calu3 cells, a human lung cell line, although the biological relevance of this is unclear. In contrast to what has been shown for Middle East respiratory syndrome coronavirus (MERS-CoV), which attaches sialic acids during cell entry, sialic acids present on Calu3 cells inhibited sarbecovirus infection. Therefore, while sarbecoviruses can interact with cell surface glycans similarly to other coronaviruses, their reliance on glycans for entry is different from that of other respiratory coronaviruses, suggesting sarbecoviruses and MERS-CoV have adapted to different cell types, tissues, or hosts during their divergent evolution. Our findings provide important clues for further exploring the biological functions of sarbecovirus glycan binding and adds to our growing understanding of the complex forces that shape coronavirus spike evolution. IMPORTANCE Spike N-terminal domains (S-NTD) of sarbecoviruses are highly diverse; however, their function remains largely understudied compared with the receptor-binding domains (RBD). Here, we show that sarbecovirus S-NTD can be phylogenetically clustered into five clades and exhibit various levels of glycan binding in vitro. We also show that, unlike some coronaviruses, including MERS-CoV, sialic acids present on the surface of Calu3, a human lung cell culture, inhibit SARS-CoV-2 and other sarbecoviruses. These results suggest that while glycan binding might be an ancestral trait conserved across different coronavirus families, the functional outcome during infection can vary, reflecting divergent viral evolution. Our results expand our knowledge on the biological functions of the S-NTD across diverse sarbecoviruses and provide insight on the evolutionary history of coronavirus spike.


Subject(s)
COVID-19 , Middle East Respiratory Syndrome Coronavirus , Humans , Middle East Respiratory Syndrome Coronavirus/metabolism , Polysaccharides , Receptors, Virus/metabolism , SARS-CoV-2 , Sialic Acids/metabolism , Spike Glycoprotein, Coronavirus/metabolism
3.
J Virol ; 96(13): e0068122, 2022 07 13.
Article in English | MEDLINE | ID: covidwho-1901926

ABSTRACT

The ongoing pandemic of COVID-19, caused by SARS-CoV-2, has substantially increased the risk to global public health. Multiple vaccines and neutralizing antibodies (nAbs) have been authorized for preventing and treating SARS-CoV-2 infection. However, the emergence and spread of the viral variants may limit the effectiveness of these vaccines and antibodies. Fusion inhibitors targeting the HR1 domain of the viral S protein have been shown to broadly inhibit SARS-CoV-2 and its variants. In theory, peptide inhibitors targeting the HR2 domain of the S protein should also be able to inhibit viral infection. However, previously reported HR1-derived peptide inhibitors targeting the HR2 domain exhibit poor inhibitory activities. Here, we engineered a novel HR1 trimer (HR1MFd) by conjugating the trimerization motif foldon to the C terminus of the HR1-derived peptide. HR1MFd showed significantly improved inhibitory activity against SARS-CoV-2, SARS-CoV-2 variants of concern (VOCs), SARS-CoV, and MERS-CoV. Mechanistically, HR1MFd possesses markedly increased α-helicity, thermostability, higher HR2 domain binding affinity, and better inhibition of S protein-mediated cell-cell fusion compared to the HR1 peptide. Therefore, HR1MFd lays the foundation to develop HR1-based fusion inhibitors against SARS-CoV-2. IMPORTANCE Peptides derived from the SARS-CoV-2 HR1 region are generally poor inhibitors. Here, we constructed a trimeric peptide HR1MFd by fusing the trimerization motif foldon to the C terminus of the HR1 peptide. HR1MFd was highly effective in blocking transductions by SARS-CoV-2, SARS-CoV-2 variants, SARS-CoV, and MERS-CoV pseudoviruses. In comparison with HR1M, HR1MFd adopted a much higher helical conformation, better thermostability, increased affinity to the viral HR2 domain, and better inhibition of S protein-mediated cell-cell fusion. Overall, HR1MFd provides the information to develop effective HR1-derived peptides as fusion inhibitors against SARS-CoV-2 and its variants.


Subject(s)
COVID-19 , Middle East Respiratory Syndrome Coronavirus , Peptides , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Humans , Middle East Respiratory Syndrome Coronavirus/metabolism , Peptides/chemistry , Peptides/pharmacology , Protein Multimerization , SARS-CoV-2/drug effects , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/metabolism
4.
Metallomics ; 14(7)2022 07 20.
Article in English | MEDLINE | ID: covidwho-1901217

ABSTRACT

Severe acute respiratory syndrome (SARS) is a viral respiratory infection caused by human coronaviruses that include SARS-CoV-2, SARS-CoV, and Middle East respiratory syndrome coronavirus (MERS-CoV). Although their primary mode of transmission is through contaminated respiratory droplets from infected carriers, the deposition of expelled virus particles onto surfaces and fomites could contribute to viral transmission. Here, we use replication-deficient murine leukemia virus (MLV) pseudoviral particles expressing SARS-CoV-2, SARS-CoV, or MERS-CoV Spike (S) protein on their surface. These surrogates of native coronavirus counterparts serve as a model to analyze the S-mediated entry into target cells. Carboxymethyl cellulose (CMC) nanofibers that are combined with copper (Cu) exhibit strong antimicrobial properties. S-pseudovirions that are exposed to CMC-Cu nanoparticles (30 s) display a dramatic reduction in their ability to infect target Vero E6 cells, with ∼97% less infectivity as compared to untreated pseudovirions. In contrast, addition of the Cu chelator tetrathiomolybdate protects S-pseudovirions from CMC-Cu-mediated inactivation. When S-pseudovirions were treated with a hydrogen peroxide-based disinfectant (denoted SaberTM) used at 1:250 dilution, their infectivity was dramatically reduced by ∼98%. However, the combined use of SaberTM and CMC-Cu is the most effective approach to restrict infectivity of SARS-CoV-2-S, SARS-CoV-S, and MERS-CoV-S pseudovirions in Vero E6 cell assays. Together, these results show that cellulosic Cu nanoparticles enhance the effectiveness of diluted SaberTM sanitizer, setting up an improved strategy to lower the risk of surface- and fomite-mediated transmission of enveloped respiratory viruses.


Subject(s)
COVID-19 , Disinfectants , Middle East Respiratory Syndrome Coronavirus , Nanoparticles , Copper/pharmacology , Disinfectants/pharmacology , Humans , Hydrogen Peroxide/pharmacology , Mice , Middle East Respiratory Syndrome Coronavirus/metabolism , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/metabolism
5.
Viruses ; 14(4)2022 03 23.
Article in English | MEDLINE | ID: covidwho-1818212

ABSTRACT

Coronaviruses (CoVs) have caused several global outbreaks with relatively high mortality rates, including Middle East Respiratory Syndrome coronavirus (MERS)-CoV, which emerged in 2012, and Severe Acute Respiratory Syndrome (SARS)-CoV-1, which appeared in 2002. The recent emergence of SARS-CoV-2 highlights the need for immediate and greater understanding of the immune evasion mechanisms used by CoVs. Interferon (IFN)-α is the body's natural antiviral agent, but its Janus kinase/signal transducer and activators of transcription (JAK/STAT) signalling pathway is often antagonized by viruses, thereby preventing the upregulation of essential IFN stimulated genes (ISGs). Therapeutic IFN-α has disappointingly weak clinical responses in MERS-CoV and SARS-CoV-1 infected patients, indicating that these CoVs inhibit the IFN-α JAK/STAT pathway. Here we show that in lung alveolar A549 epithelial cells expression of MERS-CoV-nsp2 and SARS-CoV-1-nsp14, but not MERS-CoV-nsp5, increased basal levels of total and phosphorylated STAT1 & STAT2 protein, but reduced IFN-α-mediated phosphorylation of STAT1-3 and induction of MxA. While MERS-CoV-nsp2 and SARS-CoV-1-nsp14 similarly increased basal levels of STAT1 and STAT2 in bronchial BEAS-2B epithelial cells, unlike in A549 cells, they did not enhance basal pSTAT1 nor pSTAT2. However, both viral proteins reduced IFN-α-mediated induction of pSTAT1-3 and ISGs (MxA, ISG15 and PKR) in BEAS-2B cells. Furthermore, even though IFN-α-mediated induction of pSTAT1-3 was not affected by MERS-CoV-nsp5 expression in BEAS-2B cells, downstream ISG induction was reduced, revealing that MERS-CoV-nsp5 may use an alternative mechanism to reduce antiviral ISG induction in this cell line. Indeed, we subsequently discovered that all three viral proteins inhibited STAT1 nuclear translocation in BEAS-2B cells, unveiling another layer of inhibition by which these viral proteins suppress responses to Type 1 IFNs. While these observations highlight cell line-specific differences in the immune evasion effects of MERS-CoV and SARS-CoV-1 proteins, they also demonstrate the broad spectrum of immune evasion strategies these deadly coronaviruses use to stunt antiviral responses to Type IFN.


Subject(s)
Interferon-alpha , Janus Kinases , Middle East Respiratory Syndrome Coronavirus , SARS Virus , STAT Transcription Factors , Antiviral Agents/pharmacology , COVID-19 , Epithelial Cells/metabolism , Humans , Interferon-alpha/metabolism , Janus Kinases/metabolism , Middle East Respiratory Syndrome Coronavirus/metabolism , SARS Virus/metabolism , SARS-CoV-2 , STAT Transcription Factors/metabolism , Signal Transduction , Viral Proteins/metabolism
6.
J Virol ; 96(4): e0173921, 2022 02 23.
Article in English | MEDLINE | ID: covidwho-1703046

ABSTRACT

Two strains of Middle East respiratory syndrome coronavirus (MERS-CoV), England 1 and Erasmus Medical Centre/2012 (EMC/2012), were used to challenge common marmosets (Callithrix jacchus) by three routes of infection: aerosol, oral, and intranasal. Animals challenged by the intranasal and aerosol routes presented with mild, transient disease, while those challenged by the oral route presented with a subclinical immunological response. Animals challenged with MERS-CoV strain EMC/2012 by the aerosol route responded with primary and/or secondary pyrexia. Marmosets had minimal to mild multifocal interstitial pneumonia, with the greatest relative severity being observed in animals challenged by the aerosol route. Viable virus was isolated from the host in throat swabs and lung tissue. The transient disease described is consistent with a successful host response and was characterized by the upregulation of macrophage and neutrophil function observed in all animals at the time of euthanasia. IMPORTANCE Middle East respiratory syndrome is caused by a human coronavirus, MERS-CoV, similar to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Humans typically exhibit fever, cough, shortness of breath, gastrointestinal issues, and breathing difficulties, which can lead to pneumonia and/or renal complications. This emerging disease resulted in the first human lethal cases in 2012 and has a case fatality rate of approximately 36%. Consequently, there is a need for medical countermeasures and appropriate animal models for their assessment. This work has demonstrated the requirement for higher concentrations of virus to cause overt disease. Challenge by the aerosol, intranasal, and oral routes resulted in no or mild disease, but all animals had an immunological response. This shows that an appropriate early immunological response is able to control the disease.


Subject(s)
COVID-19/metabolism , Disease Models, Animal , Middle East Respiratory Syndrome Coronavirus/metabolism , SARS-CoV-2/metabolism , Animals , Callithrix , Humans
7.
J Biol Chem ; 298(2): 101584, 2022 02.
Article in English | MEDLINE | ID: covidwho-1699145

ABSTRACT

With the outbreak of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), coronaviruses have begun to attract great attention across the world. Of the known human coronaviruses, however, Middle East respiratory syndrome coronavirus (MERS-CoV) is the most lethal. Coronavirus proteins can be divided into three groups: nonstructural proteins, structural proteins, and accessory proteins. While the number of each of these proteins varies greatly among different coronaviruses, accessory proteins are most closely related to the pathogenicity of the virus. We found for the first time that the ORF3 accessory protein of MERS-CoV, which closely resembles the ORF3a proteins of severe acute respiratory syndrome coronavirus and SARS-CoV-2, has the ability to induce apoptosis in cells in a dose-dependent manner. Through bioinformatics analysis and validation, we revealed that ORF3 is an unstable protein and has a shorter half-life in cells compared to that of severe acute respiratory syndrome coronavirus and SARS-CoV-2 ORF3a proteins. After screening, we identified a host E3 ligase, HUWE1, that specifically induces MERS-CoV ORF3 protein ubiquitination and degradation through the ubiquitin-proteasome system. This results in the diminished ability of ORF3 to induce apoptosis, which might partially explain the lower spread of MERS-CoV compared to other coronaviruses. In summary, this study reveals a pathological function of MERS-CoV ORF3 protein and identifies a potential host antiviral protein, HUWE1, with an ability to antagonize MERS-CoV pathogenesis by inducing ORF3 degradation, thus enriching our knowledge of the pathogenesis of MERS-CoV and suggesting new targets and strategies for clinical development of drugs for MERS-CoV treatment.


Subject(s)
Apoptosis , Coronavirus Infections/metabolism , Middle East Respiratory Syndrome Coronavirus/metabolism , Tumor Suppressor Proteins/metabolism , Ubiquitin-Protein Ligases/metabolism , Ubiquitination , Viral Nonstructural Proteins/metabolism , A549 Cells , Cell Line , Computational Biology , Coronavirus Infections/physiopathology , Coronavirus Infections/virology , Epithelial Cells/physiology , Epithelial Cells/virology , HEK293 Cells , Host-Pathogen Interactions , Humans
8.
Endocr Metab Immune Disord Drug Targets ; 21(7): 1242-1251, 2021.
Article in English | MEDLINE | ID: covidwho-1394672

ABSTRACT

Coronaviruses are a big family of viruses that can infect mammalians and birds. In humans they mainly cause respiratory tract infections, with a large spectrum of severity, from mild, self-limited infections to highly lethal forms as severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV) and Coronavirus Disease 2019 (COVID-19). Scanty data are reported for the involvement of endocrine glands in human coronaviruses, in particular SARS-CoV-2. In this review, we summarize endocrinological involvement in human coronaviruses, including data on animal coronaviruses. Avians, ferrets and bovine are affected by specific coronavirus syndromes, with variable involvement of endocrine glands. SARS-CoV and SARS-CoV-2 use angiotensin-converting enzyme 2 (ACE2) as a target receptor, so ACE2 plays a central role in viral transmission and initial organ involvement. Autoptic studies on SARS patients revealed that thyroid, parathyroid, pituitary gland, endocrine pancreas and especially adrenals and testis could be impaired by different mechanisms (direct damage by SARS-CoV, inflammation, vascular derangement and autoimmune reactions) and few clinical studies have evidenced functional endocrine impairment. Only few data are available for COVID-19 and gonads and endocrine pancreas seem to be involved. International endocrinological societies have brought some recommendations for the COVID-19 pandemic, but further studies need to be performed, especially to detect long-term hormonal sequelae.


Subject(s)
COVID-19/metabolism , Endocrine Glands/metabolism , Endocrine System Diseases/metabolism , Middle East Respiratory Syndrome Coronavirus/metabolism , SARS-CoV-2/metabolism , Angiotensin-Converting Enzyme 2/immunology , Angiotensin-Converting Enzyme 2/metabolism , Animals , COVID-19/epidemiology , COVID-19/immunology , Endocrine Glands/immunology , Endocrine System/immunology , Endocrine System/metabolism , Endocrine System Diseases/epidemiology , Endocrine System Diseases/immunology , Humans , Middle East Respiratory Syndrome Coronavirus/immunology , SARS-CoV-2/immunology
9.
Molecules ; 26(16)2021 Aug 17.
Article in English | MEDLINE | ID: covidwho-1359731

ABSTRACT

Middle East respiratory syndrome coronavirus (MERS-CoV) is a highly infectious zoonotic virus first reported into the human population in September 2012 on the Arabian Peninsula. The virus causes severe and often lethal respiratory illness in humans with an unusually high fatality rate. The N-terminal domain (NTD) of receptor-binding S1 subunit of coronavirus spike (S) proteins can recognize a variety of host protein and mediates entry into human host cells. Blocking the entry by targeting the S1-NTD of the virus can facilitate the development of effective antiviral drug candidates against the pathogen. Therefore, the study has been designed to identify effective antiviral drug candidates against the MERS-CoV by targeting S1-NTD. Initially, a structure-based pharmacophore model (SBPM) to the active site (AS) cavity of the S1-NTD has been generated, followed by pharmacophore-based virtual screening of 11,295 natural compounds. Hits generated through the pharmacophore-based virtual screening have re-ranked by molecular docking and further evaluated through the ADMET properties. The compounds with the best ADME and toxicity properties have been retrieved, and a quantum mechanical (QM) based density-functional theory (DFT) has been performed to optimize the geometry of the selected compounds. Three optimized natural compounds, namely Taiwanhomoflavone B (Amb23604132), 2,3-Dihydrohinokiflavone (Amb23604659), and Sophoricoside (Amb1153724), have exhibited substantial docking energy >-9.00 kcal/mol, where analysis of frontier molecular orbital (FMO) theory found the low chemical reactivity correspondence to the bioactivity of the compounds. Molecular dynamics (MD) simulation confirmed the stability of the selected natural compound to the binding site of the protein. Additionally, molecular mechanics generalized born surface area (MM/GBSA) predicted the good value of binding free energies (ΔG bind) of the compounds to the desired protein. Convincingly, all the results support the potentiality of the selected compounds as natural antiviral candidates against the MERS-CoV S1-NTD.


Subject(s)
Antiviral Agents/pharmacology , Biological Products/pharmacology , Middle East Respiratory Syndrome Coronavirus/drug effects , Quantum Theory , Antiviral Agents/metabolism , Biological Products/metabolism , Catalytic Domain , Drug Evaluation, Preclinical , Middle East Respiratory Syndrome Coronavirus/metabolism , Molecular Docking Simulation , Molecular Dynamics Simulation , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/metabolism , User-Computer Interface
11.
Virology ; 562: 142-148, 2021 10.
Article in English | MEDLINE | ID: covidwho-1331288

ABSTRACT

SARS-CoV, MERS-CoV, and potentially SARS-CoV-2 emerged as novel human coronaviruses following cross-species transmission from animal hosts. Although the receptor binding characteristics of human coronaviruses are well documented, the role of carbohydrate binding in addition to recognition of proteinaceous receptors has not been fully explored. Using natural glycan microarray technology, we identified N-glycans in the human lung that are recognized by various human and animal coronaviruses. All viruses tested, including SARS-CoV-2, bound strongly to a range of phosphorylated, high mannose N-glycans and to a very specific set of sialylated structures. Examination of two linked strains, human CoV OC43 and bovine CoV Mebus, reveals shared binding to the sialic acid form Neu5Gc (not found in humans), supporting the evidence for cross-species transmission of the bovine strain. Our findings, revealing robust recognition of lung glycans, suggest that these receptors could play a role in the initial stages of coronavirus attachment and entry.


Subject(s)
COVID-19/virology , Host Microbial Interactions/physiology , Middle East Respiratory Syndrome Coronavirus/metabolism , Polysaccharides/metabolism , SARS-CoV-2/metabolism , Animals , Cattle , Humans , Lung/metabolism , Mannose/chemistry , Middle East Respiratory Syndrome Coronavirus/physiology , N-Acetylneuraminic Acid/chemistry , Phosphorylation , Protein Array Analysis , Protein Binding , SARS-CoV-2/physiology , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/physiology
12.
Methods Mol Biol ; 2099: 173-194, 2020.
Article in English | MEDLINE | ID: covidwho-1292552

ABSTRACT

Mass spectrometry (MS)-based, integrated proteomics, metabolomics, and lipidomics (collectively, multi-omics) studies provide a very detailed snapshot of virus-induced changes to the host following infection and can lead to the identification of novel prophylactic and therapeutic targets for preventing or lessening disease severity. Multi-omics studies with Middle East respiratory syndrome coronavirus (MERS-CoV) are challenging as the requirements of biosafety level 3 containment limit the numbers of samples that can be safely managed. To address these issues, the multi-omics sample preparation technique MPLEx (metabolite, protein, and lipid extraction) was developed to partition a single sample into three distinct parts (metabolites, proteins, and lipids) for multi-omics analysis, while simultaneously inactivating MERS-CoV by solubilizing and disrupting the viral envelope and denaturing viral proteins. Here we describe the MPLEx protocol, highlight the step of inactivation, and describe the details of downstream processing, instrumental analysis of the three separate analytes, and their subsequent informatics pipelines.


Subject(s)
Coronavirus Infections/virology , Host-Pathogen Interactions , Lipids/isolation & purification , Metabolomics , Middle East Respiratory Syndrome Coronavirus/metabolism , Proteomics , Humans , Mass Spectrometry , Virus Inactivation
13.
Methods Mol Biol ; 2099: 21-37, 2020.
Article in English | MEDLINE | ID: covidwho-1292545

ABSTRACT

The coronavirus spike envelope glycoprotein is an essential viral component that mediates virus entry events. Biochemical assessment of the spike protein is critical for understanding structure-function relationships and the roles of the protein in the viral life cycle. Coronavirus spike proteins are typically proteolytically processed and activated by host cell enzymes such as trypsin-like proteases, cathepsins, or proprotein-convertases. Analysis of coronavirus spike proteins by western blot allows the visualization and assessment of proteolytic processing by endogenous or exogenous proteases. Here, we present a method based on western blot analysis to investigate spike protein proteolytic cleavage by transient transfection of HEK-293 T cells allowing expression of the spike protein of the highly pathogenic Middle East respiratory syndrome coronavirus in the presence or absence of a cellular trypsin-like transmembrane serine protease, matriptase. Such analysis enables the characterization of cleavage patterns produced by a host protease on a coronavirus spike glycoprotein.


Subject(s)
Coronavirus Infections/virology , Middle East Respiratory Syndrome Coronavirus/metabolism , Spike Glycoprotein, Coronavirus/metabolism , Blotting, Western , Cell Line , Humans , Middle East Respiratory Syndrome Coronavirus/pathogenicity , Protein Processing, Post-Translational , Proteolysis , Serine Endopeptidases/metabolism , Virus Internalization
14.
IUBMB Life ; 73(8): 1005-1015, 2021 08.
Article in English | MEDLINE | ID: covidwho-1291220

ABSTRACT

The kidney is one of the main targets attacked by viruses in patients with a coronavirus infection. Until now, SARS-CoV-2 has been identified as the seventh member of the coronavirus family capable of infecting humans. In the past two decades, humankind has experienced outbreaks triggered by two other extremely infective members of the coronavirus family; the MERS-CoV and the SARS-CoV. According to several investigations, SARS-CoV causes proteinuria and renal impairment or failure. The SARS-CoV was identified in the distal convoluted tubules of the kidney of infected patients. Also, renal dysfunction was observed in numerous cases of MERS-CoV infection. And recently, during the 2019-nCoV pandemic, it was found that the novel coronavirus not only induces acute respiratory distress syndrome (ARDS) but also can induce damages in various organs including the liver, heart, and kidney. The kidney tissue and its cells are targeted massively by the coronaviruses due to the abundant presence of ACE2 and Dpp4 receptors on kidney cells. These receptors are characterized as the main route of coronavirus entry to the victim cells. Renal failure due to massive viral invasion can lead to undesirable complications and enhanced mortality rate, thus more attention should be paid to the pathology of coronaviruses in the kidney. Here, we have provided the most recent knowledge on the coronaviruses (SARS, MERS, and COVID19) pathology and the mechanisms of their impact on the kidney tissue and functions.


Subject(s)
COVID-19/mortality , Coronavirus Infections/mortality , Middle East Respiratory Syndrome Coronavirus/pathogenicity , SARS Virus/pathogenicity , SARS-CoV-2/pathogenicity , Severe Acute Respiratory Syndrome/mortality , Viral Tropism/genetics , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/genetics , COVID-19/pathology , COVID-19/virology , Coronavirus Infections/genetics , Coronavirus Infections/pathology , Coronavirus Infections/virology , Dipeptidyl Peptidase 4/genetics , Dipeptidyl Peptidase 4/metabolism , Gene Expression Regulation , Humans , Kidney/metabolism , Kidney/pathology , Kidney/virology , Middle East Respiratory Syndrome Coronavirus/genetics , Middle East Respiratory Syndrome Coronavirus/metabolism , Protein Binding , Receptors, Virus/genetics , Receptors, Virus/metabolism , SARS Virus/genetics , SARS Virus/metabolism , SARS-CoV-2/genetics , SARS-CoV-2/metabolism , Severe Acute Respiratory Syndrome/genetics , Severe Acute Respiratory Syndrome/pathology , Severe Acute Respiratory Syndrome/virology , Severity of Illness Index , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/metabolism , Survival Analysis
15.
Cells ; 10(7)2021 06 28.
Article in English | MEDLINE | ID: covidwho-1288809

ABSTRACT

Betacoronaviruses, responsible for the "Severe Acute Respiratory Syndrome" (SARS) and the "Middle East Respiratory Syndrome" (MERS), use the spikes protruding from the virion envelope to attach and subsequently infect the host cells. The coronavirus spike (S) proteins contain receptor binding domains (RBD), allowing the specific recognition of either the dipeptidyl peptidase CD23 (MERS-CoV) or the angiotensin-converting enzyme ACE2 (SARS-Cov, SARS-CoV-2) host cell receptors. The heavily glycosylated S protein includes both complex and high-mannose type N-glycans that are well exposed at the surface of the spikes. A detailed analysis of the carbohydrate-binding specificity of mannose-binding lectins from plants, algae, fungi, and bacteria, revealed that, depending on their origin, they preferentially recognize either complex type N-glycans, or high-mannose type N-glycans. Since both complex and high-mannose glycans substantially decorate the S proteins, mannose-specific lectins are potentially useful glycan probes for targeting the SARS-CoV, MERS-CoV, and SARS-CoV-2 virions. Mannose-binding legume lectins, like pea lectin, and monocot mannose-binding lectins, like snowdrop lectin or the algal lectin griffithsin, which specifically recognize complex N-glycans and high-mannose glycans, respectively, are particularly adapted for targeting coronaviruses. The biomedical prospects of targeting coronaviruses with mannose-specific lectins are wide-ranging including detection, immobilization, prevention, and control of coronavirus infection.


Subject(s)
Lectins/pharmacology , Middle East Respiratory Syndrome Coronavirus/metabolism , SARS Virus/metabolism , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/metabolism , COVID-19/drug therapy , COVID-19/virology , Cyanobacteria/chemistry , Drug Delivery Systems/methods , Fungi/chemistry , Humans , Lectins/isolation & purification , Lectins/therapeutic use , Middle East Respiratory Syndrome Coronavirus/physiology , Plants/chemistry , Protein Binding , SARS Virus/physiology , SARS-CoV-2/physiology , Species Specificity , Virus Internalization/drug effects
16.
Mol Cell Proteomics ; 20: 100120, 2021.
Article in English | MEDLINE | ID: covidwho-1284342

ABSTRACT

Human coronaviruses have become an increasing threat to global health; three highly pathogenic strains have emerged since the early 2000s, including most recently SARS-CoV-2, the cause of COVID-19. A better understanding of the molecular mechanisms of coronavirus pathogenesis is needed, including how these highly virulent strains differ from those that cause milder, common-cold-like disease. While significant progress has been made in understanding how SARS-CoV-2 proteins interact with the host cell, nonstructural protein 3 (nsp3) has largely been omitted from the analyses. Nsp3 is a viral protease with important roles in viral protein biogenesis, replication complex formation, and modulation of host ubiquitinylation and ISGylation. Herein, we use affinity purification-mass spectrometry to study the host-viral protein-protein interactome of nsp3 from five coronavirus strains: pathogenic strains SARS-CoV-2, SARS-CoV, and MERS-CoV; and endemic common-cold strains hCoV-229E and hCoV-OC43. We divide each nsp3 into three fragments and use tandem mass tag technology to directly compare the interactors across the five strains for each fragment. We find that few interactors are common across all variants for a particular fragment, but we identify shared patterns between select variants, such as ribosomal proteins enriched in the N-terminal fragment (nsp3.1) data set for SARS-CoV-2 and SARS-CoV. We also identify unique biological processes enriched for individual homologs, for instance, nuclear protein import for the middle fragment of hCoV-229E, as well as ribosome biogenesis of the MERS nsp3.2 homolog. Lastly, we further investigate the interaction of the SARS-CoV-2 nsp3 N-terminal fragment with ATF6, a regulator of the unfolded protein response. We show that SARS-CoV-2 nsp3.1 directly binds to ATF6 and can suppress the ATF6 stress response. Characterizing the host interactions of nsp3 widens our understanding of how coronaviruses co-opt cellular pathways and presents new avenues for host-targeted antiviral therapeutics.


Subject(s)
Activating Transcription Factor 6/metabolism , Coronavirus Papain-Like Proteases/metabolism , Host-Pathogen Interactions/physiology , SARS-CoV-2/pathogenicity , Coronavirus 229E, Human/metabolism , Coronavirus 229E, Human/pathogenicity , Coronavirus OC43, Human/metabolism , Coronavirus OC43, Human/pathogenicity , Coronavirus Papain-Like Proteases/genetics , Endoplasmic Reticulum-Associated Degradation , HEK293 Cells , Humans , Middle East Respiratory Syndrome Coronavirus/metabolism , Middle East Respiratory Syndrome Coronavirus/pathogenicity , Protein Interaction Maps , SARS-CoV-2/metabolism , Unfolded Protein Response , Viral Nonstructural Proteins/genetics , Viral Nonstructural Proteins/metabolism
17.
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
18.
Proteins ; 89(10): 1289-1299, 2021 10.
Article in English | MEDLINE | ID: covidwho-1233229

ABSTRACT

A novel virus, severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2), causing coronavirus disease 2019 (COVID-19) worldwide appeared in 2019. Detailed scientific knowledge of the members of the Coronaviridae family, including the Middle East Respiratory Syndrome Coronavirus (MERS-CoV) is currently lacking. Structural studies of the MERS-CoV proteins in the current literature are extremely limited. We present here detailed characterization of the structural properties of MERS-CoV macro domain in aqueous solution. Additionally, we studied the impacts of chosen force field parameters and parallel tempering simulation techniques on the predicted structural properties of MERS-CoV macro domain in aqueous solution. For this purpose, we conducted extensive Hamiltonian-replica exchange molecular dynamics simulations and Temperature-replica exchange molecular dynamics simulations using the CHARMM36m and AMBER99SB parameters for the macro domain. This study shows that the predicted secondary structure properties including their propensities depend on the chosen simulation technique and force field parameter. We perform structural clustering based on the radius of gyration and end-to-end distance of MERS-CoV macro domain in aqueous solution. We also report and analyze the residue-level intrinsic disorder features, flexibility and secondary structure. Furthermore, we study the propensities of this macro domain for protein-protein interactions and for the RNA and DNA binding. Overall, results are in agreement with available nuclear magnetic resonance spectroscopy findings and present more detailed insights into the structural properties of MERS CoV macro domain in aqueous solution. All in all, we present the structural properties of the aqueous MERS-CoV macro domain using different parallel tempering simulation techniques, force field parameters and bioinformatics tools.


Subject(s)
Middle East Respiratory Syndrome Coronavirus/chemistry , Middle East Respiratory Syndrome Coronavirus/metabolism , Molecular Dynamics Simulation , Water/chemistry , Water/metabolism , Humans , Protein Domains/physiology , Protein Structure, Secondary , Solutions
19.
PLoS One ; 16(5): e0251913, 2021.
Article in English | MEDLINE | ID: covidwho-1232467

ABSTRACT

Last decade has witnessed three major pandemics caused by SARS-CoV, SARS-CoV-2 and MERS-CoV that belong to Coronavirus family. Currently, there are no effective therapies available for corona virus infections. Since the three viruses belong to the same family and share many common features, we can theoretically design a drug that can be effective on all the three of them. In this study, using computational approach, we designed a peptide (Peptide 7) that can bind to the Receptor Binding Domain (RBD) of SARS-CoV, SARS-CoV-2 and MERS-CoV thereby preventing the entry of the viruses into the host cell. The peptide inhibitor was designed as a consensus peptide from three different peptides that might individually bind to the RBD of the three viruses. Docking studies and molecular dynamic simulations using Peptide 7 has shown that it binds with higher affinity than the native receptors of the RBD and forms a stable complex thereby preventing further viral-receptor interaction and inhibiting their cellular entry. This effective binding is observed for the three RBDs, despite the Peptide 7 interactions being slightly different. Hence; this peptide inhibitor can be used as a potential candidate for the development of peptide based anti-viral therapy against Corona viruses.


Subject(s)
Middle East Respiratory Syndrome Coronavirus/physiology , Peptides/pharmacology , SARS Virus/physiology , SARS-CoV-2/physiology , Virus Internalization/drug effects , Amino Acid Sequence , Binding Sites , Humans , Hydrogen Bonding , Middle East Respiratory Syndrome Coronavirus/metabolism , Molecular Docking Simulation , Molecular Dynamics Simulation , Peptides/chemistry , Peptides/metabolism , Protein Binding , Receptors, Virus/chemistry , Receptors, Virus/metabolism , SARS Virus/metabolism , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/metabolism
20.
Int J Mol Sci ; 22(9)2021 May 02.
Article in English | MEDLINE | ID: covidwho-1219848

ABSTRACT

Cancer and viruses have a long history that has evolved over many decades. Much information about the interplay between viruses and cell proliferation and metabolism has come from the history of clinical cases of patients infected with virus-induced cancer. In addition, information from viruses used to treat some types of cancer is valuable. Now, since the global coronavirus pandemic erupted almost a year ago, the scientific community has invested countless time and resources to slow down the infection rate and diminish the number of casualties produced by this highly infectious pathogen. A large percentage of cancer cases diagnosed are strongly related to dysregulations of the tyrosine kinase receptor (TKR) family and its downstream signaling pathways. As such, many therapeutic agents have been developed to strategically target these structures in order to hinder certain mechanisms pertaining to the phenotypic characteristics of cancer cells such as division, invasion or metastatic potential. Interestingly, several authors have pointed out that a correlation between coronaviruses such as the SARS-CoV-1 and -2 or MERS viruses and dysregulations of signaling pathways activated by TKRs can be established. This information may help to accelerate the repurposing of clinically developed anti-TKR cancer drugs in COVID-19 management. Because the need for treatment is critical, drug repurposing may be an advantageous choice in the search for new and efficient therapeutic compounds. This approach would be advantageous from a financial point of view as well, given that the resources used for research and development would no longer be required and can be potentially redirected towards other key projects. This review aims to provide an overview of how SARS-CoV-2 interacts with different TKRs and their respective downstream signaling pathway and how several therapeutic agents targeted against these receptors can interfere with the viral infection. Additionally, this review aims to identify if SARS-CoV-2 can be repurposed to be a potential viral vector against different cancer types.


Subject(s)
Antineoplastic Agents/pharmacology , Antiviral Agents/pharmacology , COVID-19/metabolism , Neoplasms/metabolism , Receptor Protein-Tyrosine Kinases/metabolism , SARS-CoV-2/metabolism , Signal Transduction/drug effects , Antineoplastic Agents/therapeutic use , Antiviral Agents/therapeutic use , COVID-19/complications , Drug Repositioning , ErbB Receptors/metabolism , Humans , Middle East Respiratory Syndrome Coronavirus/metabolism , Neoplasms/complications , Neoplasms/drug therapy , Neoplasms/virology , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors , Signal Transduction/genetics
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