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1.
Mycopathologia ; 187(4): 355-362, 2022 Aug.
Article in English | MEDLINE | ID: covidwho-1899253

ABSTRACT

BACKGROUND: In experimental models, the expression of glucose-regulated protein 78 (GRP78) in endothelial cells played a role in the pathogenesis of mucormycosis. However, the role of GRP78 in COVID-19-associated mucormycosis (CAM) has not been studied. We hypothesized that serum GRP78 levels are elevated in subjects with CAM. OBJECTIVE: To compare the serum GRP78 levels in subjects with CAM and COVID-19 controls without mucormycosis. DESIGN AND SETTING: We performed a hospital-based, case-control study between 1 April 2021 and 31 May 2021. PARTICIPANTS: We enrolled 24 subjects each of CAM and COVID-19 subjects without mucormycosis. We also measured serum GRP78 levels in ten healthy controls. EXPOSURE: The primary exposure studied was serum GRP78 concentration, estimated using a commercially available ELISA kit in stored serum samples. RESULTS: We found the mean ± standard deviation (SD) serum GRP78 levels significantly higher (p = 0.0001) among the CAM (374.3 ± 127.3 pg/mL) than the COVID-19 (246.4 ± 67.0 pg/mL) controls. The proportion of subjects with an abnormal GRP78 level (> mean [184.8 pg/mL] plus two SD [23.2 pg/mL] of GRP78 from healthy participants) was 87.5% and 45.8% in the CAM group and COVID-19 controls, respectively. Serum GRP78 level was independently associated with CAM (odds ratio 1.011; 95% confidence interval [1.002-1.019]) after adjusting for diabetes mellitus and hypoxemia during acute COVID-19. CONCLUSION: Serum GRP78 levels were significantly higher in CAM than in COVID-19 controls. Further studies are required to the role of GRP78 in the pathogenesis of CAM.


Subject(s)
COVID-19 , Mucormycosis , Case-Control Studies , Endothelial Cells/metabolism , Endothelial Cells/pathology , Glucose/metabolism , Heat-Shock Proteins/metabolism , Humans , Mucormycosis/pathology
2.
Cell Rep ; 38(8): 110414, 2022 02 22.
Article in English | MEDLINE | ID: covidwho-1700507

ABSTRACT

Inflammasome activation exacerbates infectious disease caused by pathogens such as Listeria monocytogenes, Staphylococcus aureus, and severe acute respiratory syndrome coronavirus 2. Although these pathogens activate host inflammasomes to regulate pathogen expansion, the mechanisms by which pathogen toxins contribute to inflammasome activation remain poorly understood. Here we show that activation of inflammasomes by Listeria infection is promoted by amino acid residue T223 of listeriolysin O (LLO) independently of its pore-forming activity. LLO T223 is critical for phosphorylation of the inflammasome adaptor ASC at amino acid residue Y144 through Lyn-Syk signaling, which is essential for ASC oligomerization. Notably, a Listeria mutant expressing LLO T223A is impaired in inducing ASC phosphorylation and inflammasome activation. Furthermore, the virulence of LLO T223A mutant is markedly attenuated in vivo due to impaired ability to activate the inflammasome. Our results reveal a function of a pathogen toxin that exacerbates infection by promoting phosphorylation of ASC.


Subject(s)
Bacterial Proteins/metabolism , Bacterial Toxins/metabolism , CARD Signaling Adaptor Proteins/metabolism , Heat-Shock Proteins/metabolism , Hemolysin Proteins/metabolism , Inflammasomes/metabolism , Listeria monocytogenes/pathogenicity , Signal Transduction , Amino Acid Sequence , Animals , Bacterial Proteins/genetics , Bacterial Toxins/chemistry , Bacterial Toxins/genetics , CARD Signaling Adaptor Proteins/chemistry , CARD Signaling Adaptor Proteins/deficiency , CARD Signaling Adaptor Proteins/genetics , Gene Editing , Heat-Shock Proteins/chemistry , Heat-Shock Proteins/genetics , Hemolysin Proteins/chemistry , Hemolysin Proteins/genetics , Interleukin-18/metabolism , Listeria monocytogenes/metabolism , Macrophages, Peritoneal/cytology , Macrophages, Peritoneal/metabolism , Macrophages, Peritoneal/microbiology , Mice , Mice, Inbred C57BL , Mice, Knockout , Mutagenesis, Site-Directed , Phosphorylation , Syk Kinase/genetics , Syk Kinase/metabolism , Virulence , src-Family Kinases/genetics , src-Family Kinases/metabolism
3.
Cells ; 10(11)2021 11 12.
Article in English | MEDLINE | ID: covidwho-1512138

ABSTRACT

Molecular chaperones, many of which are heat shock proteins, play a role in cell stress response and regulate the immune system in various ways, such as in inflammatory/autoimmune reactions. It would be interesting to study the involvement of these molecules in the damage done to COVID-19-infected lungs. In our study, we performed a histological analysis and an immunomorphological evaluation on lung samples from subjects who succumbed to COVID-19 and subjects who died from other causes. We also assessed Hsp60 and Hsp90 distribution in lung samples to determine their location and post-translational modifications. We found histological alterations that could be considered pathognomonic for COVID-19-related lung disease. Hsp60 and Hsp90 immunopositivity was significantly higher in the COVID-19 group compared to the controls, and immunolocalization was in the plasma membrane of the endothelial cells in COVID-19 subjects. The colocalization ratios for Hsp60/3-nitrotyrosine and Hsp60/acetylate-lisine were significantly increased in the COVID-19 group compared to the control group, similar to the colocalization ratio for Hsp90/acetylate-lisine. The histological and immunohistochemical findings led us to hypothesize that Hsp60 and Hsp90 might have a role in the onset of the thromboembolic phenomena that lead to death in a limited number of subjects affected by COVID-19. Further studies on a larger number of samples obtained from autopsies would allow to confirm these data as well as discover new biomarkers useful in the battle against this disease.


Subject(s)
COVID-19/pathology , Heat-Shock Proteins/metabolism , Lung/pathology , Adult , Aged , Autopsy , COVID-19/metabolism , Endothelial Cells/metabolism , Endothelial Cells/pathology , Female , Humans , Inflammation , Lung/metabolism , Male , Middle Aged , SARS-CoV-2
4.
Nat Commun ; 12(1): 5536, 2021 09 20.
Article in English | MEDLINE | ID: covidwho-1428813

ABSTRACT

Coronaviruses (CoVs) are important human pathogens for which no specific treatment is available. Here, we provide evidence that pharmacological reprogramming of ER stress pathways can be exploited to suppress CoV replication. The ER stress inducer thapsigargin efficiently inhibits coronavirus (HCoV-229E, MERS-CoV, SARS-CoV-2) replication in different cell types including primary differentiated human bronchial epithelial cells, (partially) reverses the virus-induced translational shut-down, improves viability of infected cells and counteracts the CoV-mediated downregulation of IRE1α and the ER chaperone BiP. Proteome-wide analyses revealed specific pathways, protein networks and components that likely mediate the thapsigargin-induced antiviral state, including essential (HERPUD1) or novel (UBA6 and ZNF622) factors of ER quality control, and ER-associated protein degradation complexes. Additionally, thapsigargin blocks the CoV-induced selective autophagic flux involving p62/SQSTM1. The data show that thapsigargin hits several central mechanisms required for CoV replication, suggesting that this compound (or derivatives thereof) may be developed into broad-spectrum anti-CoV drugs.


Subject(s)
Endoplasmic Reticulum Stress , SARS-CoV-2/physiology , Virus Replication/physiology , Animals , Autophagy/drug effects , Bronchi/pathology , COVID-19/pathology , COVID-19/virology , Cell Differentiation/drug effects , Cell Extracts , Cell Line , Cell Survival/drug effects , Chlorocebus aethiops , Coronavirus 229E, Human/physiology , Down-Regulation/drug effects , Endoplasmic Reticulum Stress/drug effects , Endoplasmic Reticulum Stress/genetics , Endoplasmic Reticulum-Associated Degradation/drug effects , Epithelial Cells/drug effects , Epithelial Cells/virology , Heat-Shock Proteins/metabolism , Humans , Macrolides/pharmacology , Middle East Respiratory Syndrome Coronavirus/drug effects , Middle East Respiratory Syndrome Coronavirus/physiology , Protein Biosynthesis/drug effects , Proteome/metabolism , RNA, Messenger/genetics , RNA, Messenger/metabolism , Reproducibility of Results , SARS-CoV-2/drug effects , Thapsigargin/pharmacology , Unfolded Protein Response/drug effects , Vero Cells , Virus Replication/drug effects
5.
Biochem Biophys Res Commun ; 562: 89-93, 2021 07 12.
Article in English | MEDLINE | ID: covidwho-1240200

ABSTRACT

New SARS-CoV-2 variants emerged in the United Kingdom and South Africa in December 2020 in concomitant with the Brazillian variant in February 2021 (B.1.1.248 lineage) and currently sparking worldwide during the last few months. The new strain 501.V2 in South Africa bears three mutations in the spike receptor-binding domain (RBD); K417 N, E484K, and N501Y, while the Brazilian B.1.1.248 lineage has 12 mutations. In the current study, we simulate the complex ACE2-SARS-CoV-2 spike RBD system in which the RBD is in the wild-type and mutated isoforms. Additionally, the cell-surface Glucose Regulated Protein 78 (CS-GRP78) associated with the ACE2-SARS-CoV-2 spike RBD complex (ACE2-S RBD) is modeled at the presence of these mutant variants of the viral spike. The results showed that E484K and N501Y are critical in viral spike recognition through either ACE2 or CS-GRP78. The mutated variants (the UK, South African, and Brazilian) of the spike RBD tightly bind to GRP78 more than in the case of the wild-type RBD. These results point to the potent role of GRP78 with ACE2 in the attachment of the new variants, which could be a key for the design of inhibitors to block SARS-CoV-2 attachment and entry to the host cell.


Subject(s)
Computer Simulation , Heat-Shock Proteins/metabolism , SARS-CoV-2/metabolism , Angiotensin-Converting Enzyme 2/chemistry , Angiotensin-Converting Enzyme 2/metabolism , Brazil , Heat-Shock Proteins/chemistry , Humans , Molecular Docking Simulation , Molecular Dynamics Simulation , Mutation , Receptors, Virus/chemistry , Receptors, Virus/metabolism , SARS-CoV-2/chemistry , SARS-CoV-2/genetics , South Africa , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/metabolism , Substrate Specificity , United Kingdom , Virus Internalization
6.
J Biol Chem ; 296: 100759, 2021.
Article in English | MEDLINE | ID: covidwho-1219049

ABSTRACT

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of the COVID-19 global pandemic, utilizes the host receptor angiotensin-converting enzyme 2 (ACE2) for viral entry. However, other host factors might also play important roles in SARS-CoV-2 infection, providing new directions for antiviral treatments. GRP78 is a stress-inducible chaperone important for entry and infectivity for many viruses. Recent molecular docking analyses revealed putative interaction between GRP78 and the receptor-binding domain (RBD) of the SARS-CoV-2 Spike protein (SARS-2-S). Here we report that GRP78 can form a complex with SARS-2-S and ACE2 on the surface and at the perinuclear region typical of the endoplasmic reticulum in VeroE6-ACE2 cells and that the substrate-binding domain of GRP78 is critical for this interaction. In vitro binding studies further confirmed that GRP78 can directly bind to the RBD of SARS-2-S and ACE2. To investigate the role of GRP78 in this complex, we knocked down GRP78 in VeroE6-ACE2 cells. Loss of GRP78 markedly reduced cell surface ACE2 expression and led to activation of markers of the unfolded protein response. Treatment of lung epithelial cells with a humanized monoclonal antibody (hMAb159) selected for its safe clinical profile in preclinical models depleted cell surface GRP78 and reduced cell surface ACE2 expression, as well as SARS-2-S-driven viral entry and SARS-CoV-2 infection in vitro. Our data suggest that GRP78 is an important host auxiliary factor for SARS-CoV-2 entry and infection and a potential target to combat this novel pathogen and other viruses that utilize GRP78 in combination therapy.


Subject(s)
Angiotensin-Converting Enzyme 2/genetics , Heat-Shock Proteins/genetics , Host-Pathogen Interactions/genetics , SARS-CoV-2/drug effects , Spike Glycoprotein, Coronavirus/genetics , Virus Internalization/drug effects , Angiotensin-Converting Enzyme 2/metabolism , Animals , Antibodies, Monoclonal/pharmacology , Binding Sites , Chlorocebus aethiops , Endoplasmic Reticulum/drug effects , Endoplasmic Reticulum/metabolism , Endoplasmic Reticulum/virology , Gene Expression Regulation , Heat-Shock Proteins/antagonists & inhibitors , Heat-Shock Proteins/metabolism , Humans , Mutation , Protein Binding , Protein Domains , Protein Multimerization , RNA, Small Interfering/genetics , RNA, Small Interfering/metabolism , SARS-CoV-2/genetics , SARS-CoV-2/metabolism , Signal Transduction , Spike Glycoprotein, Coronavirus/metabolism , Unfolded Protein Response , Vero Cells
7.
Cell Stress Chaperones ; 26(2): 289-295, 2021 03.
Article in English | MEDLINE | ID: covidwho-1070950

ABSTRACT

Members of the Cell Stress Society International (CSSI), Patricija van Oosten-Hawle (University of Leeds, UK), Mehdi Mollapour (SUNY Upstate Medical University, USA), Andrew Truman (University of North Carolina at Charlotte, USA) organized a new virtual meeting format which took place on November 5-6, 2020. The goal of this congress was to provide an international platform for scientists to exchange data and ideas among the Cell Stress and Chaperones community during the Covid-19 pandemic. Here we will highlight the summary of the meeting and acknowledge those who were honored by the CSSI.


Subject(s)
Heat-Shock Proteins/metabolism , Molecular Chaperones/metabolism , HSP70 Heat-Shock Proteins/genetics , HSP70 Heat-Shock Proteins/metabolism , HSP90 Heat-Shock Proteins/genetics , HSP90 Heat-Shock Proteins/metabolism , Heat-Shock Proteins/genetics , Humans , Molecular Chaperones/genetics , Proteostasis/genetics , Proteostasis/physiology
8.
Int J Mol Sci ; 22(3)2021 Jan 20.
Article in English | MEDLINE | ID: covidwho-1067752

ABSTRACT

The occurrence of the novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), responsible for coronavirus disease 2019 (COVD-19), represents a catastrophic threat to global health. Protruding from the viral surface is a densely glycosylated spike (S) protein, which engages angiotensin-converting enzyme 2 (ACE2) to mediate host cell entry. However, studies have reported viral susceptibility in intra- and extrapulmonary immune and non-immune cells lacking ACE2, suggesting that the S protein may exploit additional receptors for infection. Studies have demonstrated interactions between S protein and innate immune system, including C-lectin type receptors (CLR), toll-like receptors (TLR) and neuropilin-1 (NRP1), and the non-immune receptor glucose regulated protein 78 (GRP78). Recognition of carbohydrate moieties clustered on the surface of the S protein may drive receptor-dependent internalization, accentuate severe immunopathological inflammation, and allow for systemic spread of infection, independent of ACE2. Furthermore, targeting TLRs, CLRs, and other receptors (Ezrin and dipeptidyl peptidase-4) that do not directly engage SARS-CoV-2 S protein, but may contribute to augmented anti-viral immunity and viral clearance, may represent therapeutic targets against COVID-19.


Subject(s)
COVID-19/metabolism , COVID-19/pathology , SARS-CoV-2/physiology , Virus Internalization , Angiotensin-Converting Enzyme 2/immunology , Angiotensin-Converting Enzyme 2/metabolism , Animals , COVID-19/immunology , Disease Progression , Heat-Shock Proteins/immunology , Heat-Shock Proteins/metabolism , Host-Pathogen Interactions , Humans , Lectins, C-Type/immunology , Lectins, C-Type/metabolism , Neuropilin-1/immunology , Neuropilin-1/metabolism , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Spike Glycoprotein, Coronavirus/metabolism , Toll-Like Receptors/immunology , Toll-Like Receptors/metabolism
10.
Cell Stress Chaperones ; 25(6): 979-991, 2020 11.
Article in English | MEDLINE | ID: covidwho-679678

ABSTRACT

Heat shock proteins (HSPs) are ubiquitous polypeptides expressed in all living organisms that participate in several basic cellular processes, including protein folding, from which their denomination as molecular chaperones originated. There are several HSPs, including HSPA5, also known as 78-kDa glucose-regulated protein (GRP78) or binding immunoglobulin protein (BIP) that is an ER resident involved in the folding of polypeptides during their translocation into this compartment prior to the transition to the Golgi network. HSPA5 is detected on the surface of cells or secreted into the extracellular environment. Surface HSPA5 has been proposed to have various roles, such as receptor-mediated signal transduction, a co-receptor for soluble ligands, as well as a participant in tumor survival, proliferation, and resistance. Recently, surface HSPA5 has been reported to be a potential receptor of some viruses, including the novel SARS-CoV-2. In spite of these observations, the association of HSPA5 within the plasma membrane is still unclear. To gain information about this process, we studied the interaction of HSPA5 with liposomes made of different phospholipids. We found that HSPA5 has a high affinity for negatively charged phospholipids, such as palmitoyl-oleoyl phosphoserine (POPS) and cardiolipin (CL). The N-terminal and C-terminal domains of HSPA5 were independently capable of interacting with negatively charged phospholipids, but to a lesser extent than the full-length protein, suggesting that both domains are required for the maximum insertion into membranes. Interestingly, we found that the interaction of HSPA5 with negatively charged liposomes promotes an oligomerization process via intermolecular disulfide bonds in which the N-terminus end of the protein plays a critical role.


Subject(s)
Heat-Shock Proteins/metabolism , Liposomes/metabolism , Phospholipids/chemistry , Amino Acid Sequence , Betacoronavirus/isolation & purification , Betacoronavirus/metabolism , COVID-19 , Calorimetry , Cardiolipins/chemistry , Cardiolipins/metabolism , Coronavirus Infections/pathology , Coronavirus Infections/virology , Endoplasmic Reticulum/metabolism , HSP70 Heat-Shock Proteins/chemistry , HSP70 Heat-Shock Proteins/metabolism , Heat-Shock Proteins/chemistry , Heat-Shock Proteins/genetics , Humans , Liposomes/chemistry , Pandemics , Phosphatidylserines/chemistry , Phosphatidylserines/metabolism , Phospholipids/metabolism , Pneumonia, Viral/pathology , Pneumonia, Viral/virology , Protein Domains , Protein Multimerization , Recombinant Proteins/biosynthesis , Recombinant Proteins/chemistry , Recombinant Proteins/isolation & purification , SARS-CoV-2 , Sequence Alignment
11.
Signal Transduct Target Ther ; 5(1): 125, 2020 07 13.
Article in English | MEDLINE | ID: covidwho-654479

ABSTRACT

Stress proteins (SPs) including heat-shock proteins (HSPs), RNA chaperones, and ER associated stress proteins are molecular chaperones essential for cellular homeostasis. The major functions of HSPs include chaperoning misfolded or unfolded polypeptides, protecting cells from toxic stress, and presenting immune and inflammatory cytokines. Regarded as a double-edged sword, HSPs also cooperate with numerous viruses and cancer cells to promote their survival. RNA chaperones are a group of heterogeneous nuclear ribonucleoproteins (hnRNPs), which are essential factors for manipulating both the functions and metabolisms of pre-mRNAs/hnRNAs transcribed by RNA polymerase II. hnRNPs involve in a large number of cellular processes, including chromatin remodelling, transcription regulation, RNP assembly and stabilization, RNA export, virus replication, histone-like nucleoid structuring, and even intracellular immunity. Dysregulation of stress proteins is associated with many human diseases including human cancer, cardiovascular diseases, neurodegenerative diseases (e.g., Parkinson's diseases, Alzheimer disease), stroke and infectious diseases. In this review, we summarized the biologic function of stress proteins, and current progress on their mechanisms related to virus reproduction and diseases caused by virus infections. As SPs also attract a great interest as potential antiviral targets (e.g., COVID-19), we also discuss the present progress and challenges in this area of HSP-based drug development, as well as with compounds already under clinical evaluation.


Subject(s)
Antiviral Agents/pharmacology , Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Heat-Shock Proteins/genetics , Heterogeneous-Nuclear Ribonucleoproteins/genetics , Host-Pathogen Interactions/drug effects , Pneumonia, Viral/drug therapy , Antiviral Agents/chemical synthesis , Betacoronavirus/genetics , Betacoronavirus/pathogenicity , COVID-19 , Chromatin Assembly and Disassembly/drug effects , Coronavirus Infections/genetics , Coronavirus Infections/pathology , Coronavirus Infections/virology , Gene Expression Regulation , Heat-Shock Proteins/agonists , Heat-Shock Proteins/antagonists & inhibitors , Heat-Shock Proteins/metabolism , Heterogeneous-Nuclear Ribonucleoproteins/agonists , Heterogeneous-Nuclear Ribonucleoproteins/antagonists & inhibitors , Heterogeneous-Nuclear Ribonucleoproteins/metabolism , Host-Pathogen Interactions/genetics , Humans , Molecular Targeted Therapy/methods , Pandemics , Pneumonia, Viral/genetics , Pneumonia, Viral/pathology , Pneumonia, Viral/virology , RNA Polymerase II/genetics , RNA Polymerase II/metabolism , RNA Precursors/genetics , RNA Precursors/metabolism , SARS-CoV-2 , Severity of Illness Index , Signal Transduction , Transcription, Genetic/drug effects , Virus Replication/drug effects
12.
Virus Res ; 289: 198154, 2020 11.
Article in English | MEDLINE | ID: covidwho-752748

ABSTRACT

Recent reports have shown that small and big felines could be infected by SARS-CoV-2, while other animals, like swines and mice, are apparently not susceptible to this infection. These findings raise the question of the role of cell factors associated with early stages of the viral infection in host selectivity. The cellular receptor for SARS-CoV-2 is the Angiotensin Converting Enzyme (ACE2). Transmembrane protease serine 2 (TMPRSS2) has been shown to prime the viral spike for its interaction with its receptor. GRP78 has also been proposed as a possible co-receptor. In this study, we used several bioinformatics approaches to bring clues in the interaction of ACE2, TMPRSS2, and GRP78 with SARS-CoV-2. We selected several mammalian hosts that could play a key role in viral spread by acting as secondary hosts (cats, dogs, pigs, mice, and ferrets) and evaluated their predicted permissiveness by in silico analysis. Results showed that ionic pairs (salt bridges, N-O pair, and long-range interactions) produced between ACE2 and the viral spike has an essential function in the host interaction. On the other hand, TMPRSS2 and GRP78 are proteins with high homology in all the evaluated hosts. Thus, these proteins do not seem to play a role in host selectivity, suggesting that other factors may play a role in the non-permissivity in some of these hosts. These proteins represent however interesting cell targets that could be explored in order to control the virus replication in humans and in the intermediary hosts.


Subject(s)
Betacoronavirus/physiology , Coronavirus Infections/virology , Heat-Shock Proteins/chemistry , Mammals/metabolism , Peptidyl-Dipeptidase A/chemistry , Pneumonia, Viral/virology , Receptors, Virus/chemistry , Serine Endopeptidases/chemistry , Spike Glycoprotein, Coronavirus/metabolism , Viral Tropism , Amino Acid Sequence , Angiotensin-Converting Enzyme 2 , Animals , Antiviral Agents/pharmacology , Benzamidines , COVID-19 , Cats , Dogs , Ferrets , Guanidines/pharmacology , Heat-Shock Proteins/metabolism , Humans , Mice , Models, Molecular , Molecular Docking Simulation , Pandemics , Peptidyl-Dipeptidase A/metabolism , Protein Conformation , Receptors, Virus/metabolism , SARS-CoV-2 , Sequence Alignment , Sequence Homology, Amino Acid , Serine Endopeptidases/metabolism , Species Specificity , Swine , Virus Attachment , Virus Internalization
13.
Life Sci ; 260: 118317, 2020 Nov 01.
Article in English | MEDLINE | ID: covidwho-726683

ABSTRACT

BACKGROUND: Glucose regulating protein 78 (GRP78) is one member of the Heat Shock Protein family of chaperone proteins (HSPA5) found in eukaryotes. It acts as the master of the Unfolded Protein Response (UPR) process in the lumen of the Endoplasmic Reticulum (ER). SCOPE: Under the stress of unfolded proteins, GRP78 binds to the unfolded proteins to prevent misfolding, while under the load of the unfolded protein, it drives the cell to autophagy or apoptosis. Several attempts reported the overexpression of GRP78 on the cell membrane of cancer cells and cells infected with viruses or fungi. MAJOR CONCLUSIONS: Cell-surface GRP78 is used as a cancer cell target in previous studies. Additionally, GRP78 is used as a drug target to stop the progression of cancer cells by different compounds, including peptides, antibodies, and some natural compounds. Additionally, it can be used as a protein target to reduce the infectivity of different viruses, including the pandemic SARS-CoV-2. Besides, GRP78 targeting is used in diagnosis and imaging modalities using radionuclides. GENERAL SIGNIFICANCE: This review summarizes the various attempts that used GRP78 both in therapy (fighting cancer, viral and fungal infections) and diagnosis (imaging).


Subject(s)
Antineoplastic Agents/therapeutic use , Betacoronavirus/drug effects , Biological Products/therapeutic use , Coronavirus Infections/drug therapy , Heat-Shock Proteins/antagonists & inhibitors , Molecular Targeted Therapy , Neoplasms/drug therapy , Pneumonia, Viral/drug therapy , Betacoronavirus/isolation & purification , COVID-19 , Coronavirus Infections/complications , Coronavirus Infections/metabolism , Coronavirus Infections/virology , Heat-Shock Proteins/metabolism , Humans , Neoplasms/complications , Neoplasms/metabolism , Neoplasms/virology , Pandemics , Pneumonia, Viral/complications , Pneumonia, Viral/metabolism , Pneumonia, Viral/virology , SARS-CoV-2
16.
J Infect ; 80(5): 554-562, 2020 05.
Article in English | MEDLINE | ID: covidwho-6255

ABSTRACT

OBJECTIVES: Understanding the novel coronavirus (COVID-19) mode of host cell recognition may help to fight the disease and save lives. The spike protein of coronaviruses is the main driving force for host cell recognition. METHODS: In this study, the COVID-19 spike binding site to the cell-surface receptor (Glucose Regulated Protein 78 (GRP78)) is predicted using combined molecular modeling docking and structural bioinformatics. The COVID-19 spike protein is modeled using its counterpart, the SARS spike. RESULTS: Sequence and structural alignments show that four regions, in addition to its cyclic nature have sequence and physicochemical similarities to the cyclic Pep42. Protein-protein docking was performed to test the four regions of the spike that fit tightly in the GRP78 Substrate Binding Domain ß (SBDß). The docking pose revealed the involvement of the SBDß of GRP78 and the receptor-binding domain of the coronavirus spike protein in recognition of the host cell receptor. CONCLUSIONS: We reveal that the binding is more favorable between regions III (C391-C525) and IV (C480-C488) of the spike protein model and GRP78. Region IV is the main driving force for GRP78 binding with the predicted binding affinity of -9.8 kcal/mol. These nine residues can be used to develop therapeutics specific against COVID-19.


Subject(s)
Betacoronavirus/chemistry , Coronavirus Infections/virology , Heat-Shock Proteins/chemistry , Models, Molecular , Pneumonia, Viral/virology , Spike Glycoprotein, Coronavirus/chemistry , Betacoronavirus/metabolism , Binding Sites , COVID-19 , Coronavirus Infections/metabolism , Heat-Shock Proteins/metabolism , Humans , Molecular Docking Simulation , Pandemics , Pneumonia, Viral/metabolism , Protein Domains , Protein Structure, Tertiary , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/metabolism
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