scholarly journals A Multiscale and Comparative Model for Receptor Binding of 2019 Novel Coronavirus and the Implication of its Life Cycle in Host Cells

2020 ◽  
Author(s):  
Zhaoqian Su ◽  
Yinghao Wu
Keyword(s):  
Life Cycle ◽  
Severe Acute Respiratory Syndrome ◽  
Structural Model ◽  
Computational Study ◽  
Simulation Method ◽  
Multiscale Simulation ◽  
Host Cells ◽  
S Protein ◽  
New Type ◽  
Novel Coronavirus

ABSTRACTThe respiratory syndrome caused by a new type of coronavirus has been emerging from China and caused more than one million death globally since December 2019. This new virus, called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uses the same receptor called Angiotensin-converting enzyme 2 (ACE2) to attack humans as the coronavirus that caused the severe acute respiratory syndrome (SARS) seventeen years ago. Both viruses recognize ACE2 through the spike proteins (S-protein) on their surfaces. It was found that the S-protein from the SARS coronavirus (SARS-CoV) bind stronger to ACE2 than SARS-CoV-2. However, function of a bio-system is often under kinetic, rather than thermodynamic, control. To address this issue, we constructed a structural model for complex formed between ACE2 and the S-protein from SARS-CoV-2, so that the rate of their association can be estimated and compared with the binding of S-protein from SARS-CoV by a multiscale simulation method. Our simulation results suggest that the association of new virus to the receptor is slower than SARS, which is consistent with the experimental data obtained very recently. We further integrated this difference of association rate between virus and receptor into a mathematical model which describes the life cycle of virus in host cells and its interplay with the innate immune system. Interestingly, we found that the slower association between virus and receptor can result in longer incubation period, while still maintaining a relatively higher level of viral concentration in human body. Our computational study therefore provides, from the molecular level, one possible explanation that this new pandemic by far spread much faster than SARS.

scholarly journals Amino Acids 1055 to 1192 in the S2 Region of Severe Acute Respiratory Syndrome Coronavirus S Protein Induce Neutralizing Antibodies: Implications for the Development of Vaccines and Antiviral Agents

2005 ◽  
Vol 79 (6) ◽  
pp. 3289-3296 ◽  
Author(s):  
Choong-Tat Keng ◽  
Aihua Zhang ◽  
Shuo Shen ◽  
Kuo-Ming Lip ◽  
Burtram C. Fielding ◽  
...  
Keyword(s):  
Amino Acids ◽  
Severe Acute Respiratory Syndrome ◽  
Viral Entry ◽  
Neutralizing Antibodies ◽  
Antiviral Agents ◽  
Host Cells ◽  
Heptad Repeat ◽  
Antigenic Determinants ◽  
Amino Acid Residues ◽  
S Protein

ABSTRACT The spike (S) protein of the severe acute respiratory syndrome coronavirus (SARS-CoV) interacts with cellular receptors to mediate membrane fusion, allowing viral entry into host cells; hence it is recognized as the primary target of neutralizing antibodies, and therefore knowledge of antigenic determinants that can elicit neutralizing antibodies could be beneficial for the development of a protective vaccine. Here, we expressed five different fragments of S, covering the entire ectodomain (amino acids 48 to 1192), as glutathione S-transferase fusion proteins in Escherichia coli and used the purified proteins to raise antibodies in rabbits. By Western blot analysis and immunoprecipitation experiments, we showed that all the antibodies are specific and highly sensitive to both the native and denatured forms of the full-length S protein expressed in virus-infected cells and transfected cells, respectively. Indirect immunofluorescence performed on fixed but unpermeabilized cells showed that these antibodies can recognize the mature form of S on the cell surface. All the antibodies were also able to detect the maturation of the 200-kDa form of S to the 210-kDa form by pulse-chase experiments. When the antibodies were tested for their ability to inhibit SARS-CoV propagation in Vero E6 culture, it was found that the anti-SΔ10 antibody, which was targeted to amino acid residues 1029 to 1192 of S, which include heptad repeat 2, has strong neutralizing activities, suggesting that this region of S carries neutralizing epitopes and is very important for virus entry into cells.

scholarly journals Cross-reactive neutralization of SARS-CoV-2 by serum antibodies from recovered SARS patients and immunized animals

2020 ◽  
Vol 6 (45) ◽  
pp. eabc9999 ◽  
Author(s):  
Yuanmei Zhu ◽  
Danwei Yu ◽  
Yang Han ◽  
Hongxia Yan ◽  
Huihui Chong ◽  
...  
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Receptor Binding ◽  
Binding Domain ◽  
Full Length ◽  
Receptor Binding Domain ◽  
Serum Antibodies ◽  
Serum Samples ◽  
S Protein ◽  
Novel Coronavirus

The current coronavirus disease 2019 (COVID-19) pandemic is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a novel coronavirus genetically close to SARS-CoV. To investigate the effects of previous SARS-CoV infection on the ability to recognize and neutralize SARS-CoV-2, we analyzed 20 convalescent serum samples collected from individuals infected with SARS-CoV during the 2003 SARS outbreak. All patient sera reacted strongly with the S1 subunit and receptor binding domain (RBD) of SARS-CoV; cross-reacted with the S ectodomain, S1, RBD, and S2 proteins of SARS-CoV-2; and neutralized both SARS-CoV and SARS-CoV-2 S protein–driven infections. Analysis of antisera from mice and rabbits immunized with a full-length S and RBD immunogens of SARS-CoV verified cross-reactive neutralization against SARS-CoV-2. A SARS-CoV–derived RBD from palm civets elicited more potent cross-neutralizing responses in immunized animals than the RBD from a human SARS-CoV strain, informing strategies for development of universal vaccines against emerging coronaviruses.

scholarly journals The SARS-CoV-2 spike protein disrupts the cooperative function of human cardiac pericytes - endothelial cells through CD147 receptor-mediated signalling: a potential non-infective mechanism of COVID-19 microvascular disease

2020 ◽  
Author(s):  
Elisa Avolio ◽  
Monica Gamez ◽  
Kapil Gupta ◽  
Rebecca Foster ◽  
Imre Berger ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Severe Acute Respiratory Syndrome ◽  
Network Formation ◽  
Cell Signalling ◽  
The Other ◽  
Host Cells ◽  
Added Value ◽  
Vascular Cell ◽  
S Protein ◽  
Cell Dysfunction

AbstractBackgroundSevere coronavirus disease 2019 (COVID-19) manifests as a life-threatening microvascular syndrome. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uses primarily the capsid spike (S) protein to engage with its receptors and infect host cells. To date, it is still not known if the S protein alone, without the other viral elements, is able to trigger vascular cell signalling and provoke cell dysfunction.MethodsWe investigated the effects of the recombinant, stabilised S protein on primary human cardiac pericytes (PCs) signalling and function. Endpoints included cell viability, proliferation, migration, cooperation with endothelial cells (ECs) in angiogenesis assays, and release of pro-inflammatory cytokines. Adopting a blocking strategy against the S protein receptors ACE2 and CD147, we explored which receptor mediates the S protein signalling in PCs.FindingsWe show, for the first time, that the recombinant S protein alone elicits functional alterations in cardiac PCs. This was documented as: (1) increased migration, (2) reduced ability to support EC network formation on Matrigel, (3) secretion of pro-inflammatory molecules typically involved in the cytokine storm, and (4) production of pro-apoptotic factors responsible for EC death. Furthermore, the S protein stimulates the phosphorylation/activation of the extracellular signal-regulated kinase 1/2 (ERK1/2) through the CD147 receptor, but not ACE2, in cardiac PCs. Accordingly, the neutralization of CD147, using a blocking antibody, prevented the activation of ERK1/2 and partially rescued the PC function in the presence of the S protein.InterpretationOur findings suggest the new, intriguing hypothesis that the S protein may elicit vascular cell dysfunction, potentially amplifying, or perpetuating, the damage caused by the whole coronavirus. This mechanism may have clinical and therapeutic implication.FundingElizabeth Blackwell Institute (EBI) Rapid Response COVID-19 award.Research in contextEvidence before this studyThe severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uses primarily the capsid spike (S) protein to engage with its receptors and infect host cells. Co-receptors and host cell proteases may also be involved. Angiotensin-converting enzyme 2 (ACE2) is the well-recognized entry receptor used by the virus in respiratory epithelial cells; it is also abundantly expressed in the human heart. Alongside ACE2, CD147 has recently emerged as a novel receptor for SARS-CoV-2. Yet, it is not clear if SARS-CoV-2 triggers adverse responses in cardiac vascular mural cells. Likewise, no investigation was devoted to verifying if the recombinant S protein alone can mimic the whole virus signalling.Added value of this studyThis study provides the first evidence that the recombinant S protein alone, without the other viral elements, is capable of eliciting cellular signalling in human cardiac pericytes, thereby inducing cell dysfunction. In addition, this study proposes CD147 as the leading receptor mediating S protein signalling in cardiac pericytes.Implications of all the available evidenceThese reports imply that fragments of the S protein might be able to elicit vascular cell dysfunction. Blocking the CD147 receptor may help protect the vasculature not only from infection, but also from the collateral damage caused by the S protein.

SARS-CoV-2 Entry inhibitors targeting virus-ACE2 or virus-TMPRSS2 interactions

2021 ◽  
Vol 28 ◽  
Author(s):  
Hao Lin ◽  
Srinivasulu Cherukupalli ◽  
Da Feng ◽  
Shenghua Gao ◽  
Dongwei Kang ◽  
...  
Keyword(s):  
Life Cycle ◽  
Host Cells ◽  
Cell Surface Receptor ◽  
Target Cells ◽  
S Protein ◽  
Angiotensin Converting Enzyme 2 ◽  
Entry Inhibitors ◽  
Concise Report ◽  
Surface Receptor ◽  
Transmembrane Serine Protease

: COVID-19 is an infectious disease caused by SARS-CoV-2. The life cycle of SARS-CoV-2 includes the entry into the target cells, replicase translation, replicating and transcribing genomes, translating structural proteins, assembling and releasing new virions. Entering host cells is a crucial stage in the early life cycle of the virus, and blocking this stage can effectively prevent virus infection. SARS enters the target cells mediated by the interaction between the viral S protein and the target cell surface receptor angiotensin-converting enzyme 2 (ACE2), as well as the cleavage effect of type-II transmembrane serine protease (TMPRSS2) on the S protein. Therefore, the ACE2 receptor and TMPRSS2 are important targets for SARS-CoV-2 entry inhibitors. Herein, we provide a concise report/information on drugs with potential therapeutic value targeting virus-ACE2 or virus-TMPRSS2 interactions, to provide a reference for the design and discovery of potential entry inhibitors against SARS-CoV-2.

scholarly journals A comparative study on virology, epidemiology, and clinical features of SARS and COVID-19

2021 ◽  
pp. 1-23
Author(s):  
Yanmei Zhao ◽  
Qianying Lu ◽  
Xiangyan Meng ◽  
Siyu Huang ◽  
Jianfeng Zhang ◽  
...  
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Comparative Study ◽  
Clinical Features ◽  
Human Coronavirus ◽  
Highly Pathogenic ◽  
New Type ◽  
Human Coronaviruses ◽  
Novel Coronavirus ◽  
And Control ◽  
Monitor And Control

Abstract In December 2019, an outbreak of an unknown cause of pneumonia [later named coronavirus disease 2019 (COVID-19)] occurred in Wuhan, China. This was found to be attributed to a novel coronavirus of zoonotic origin, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; previously named 2019 novel coronavirus or 2019-nCoV). The SARS-CoV-2, a new type of highly pathogenic human coronavirus related to severe acute respiratory syndrome coronavirus (SARS-CoV), spread rapidly worldwide and caused 53,164,803 confirmed infections, including 1,300,576 deaths, by November 13, 2020 (globally, 206,196,367 cases and 4,345,424 deaths as of August 13, 2021). SARS-CoV-2 and SARS-CoV vary in their specific characteristics, regarding epidemics and pathogenesis. This article focuses on the comparison of the virology, epidemiology, and clinical features of SARS-CoV and SARS-CoV-2 to reveal their common and distinct properties, to provide an up-to-date resource for the development of advanced systems and strategies to monitor and control future epidemics of highly pathogenic human coronaviruses.

scholarly journals Distinct Structural Flexibility within SARS-CoV-2 Spike Protein Reveals Potential Therapeutic Targets

2020 ◽  
Author(s):  
Serena H. Chen ◽  
M. Todd Young ◽  
John Gounley ◽  
Christopher Stanley ◽  
Debsindhu Bhowmik
Keyword(s):  
Host Cells ◽  
Dynamics Simulation ◽  
Structural Flexibility ◽  
The Novel ◽  
Simulation Approach ◽  
S Protein ◽  
Therapeutic Development ◽  
Human Coronaviruses ◽  
Novel Coronavirus ◽  
S Proteins

AbstractThe emergence and rapid worldwide spread of the novel coronavirus disease, COVID-19, has prompted concerted efforts to find successful treatments. The causative virus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), uses its spike (S) protein to gain entry into host cells. Therefore, the S protein presents a viable target to develop a directed therapy. Here, we deployed an integrated artificial intelligence with molecular dynamics simulation approach to provide new details of the S protein structure. Based on a comprehensive structural analysis of S proteins from SARS-CoV-2 and previous human coronaviruses, we found that the protomer state of S proteins is structurally flexible. Without the presence of a stabilizing beta sheet from another protomer chain, two regions in the S2 domain and the hinge connecting the S1 and S2 subunits lose their secondary structures. Interestingly, the region in the S2 domain was previously identified as an immunodominant site in the SARS-CoV-1 S protein. We anticipate that the molecular details elucidated here will assist in effective therapeutic development for COVID-19.

An Updated Review on SARS-CoV-2 Main Proteinase (MPro): Protein Structure and Small-Molecule Inhibitors

2020 ◽  
Vol 20 ◽  
Author(s):  
Dima A. Sabbah ◽  
Rima Hajjo ◽  
Sanaa K. Bardaweel ◽  
Haizhen A. Zhong
Keyword(s):  
Viral Pathogenesis ◽  
Host Cells ◽  
The Novel ◽  
Medical Field ◽  
Disease Pathogenesis ◽  
S Protein ◽  
Host Tropism ◽  
Significant Interest ◽  
Novel Coronavirus ◽  
Corona Viruses

: Coronaviruses (CoVs) are enveloped positive-stranded RNA viruses with spike (S) protein projections that allow the virus to enter and infect host cells. The S protein is a key virulence factor determining viral pathogenesis, host tropism, and disease pathogenesis. There are currently diverse corona viruses that are known to cause disease in humans. The occurrence of Middle East respiratory syndrome coronavirus (MERS-CoV) and Severe Acute Respiratory Syndrome coronavirus (SARS-CoV), as fatal human CoV diseases, has induced significant interest in the medical field. The novel coronavirus disease (COVID-19) is an infectious disease caused by a novel strain of coronavirus (SAR-CoV-2). The SARSCoV2 outbreak has been evolved in Wuhan, China, in December 2019, and identified as a pandemic on March 2020 resulting in 53.24 M cases and 1.20M deaths worldwide. SARS-CoV-2 main proteinase (MPro), a key protease of CoV-2, mediates viral replication and transcription. SARS-CoV-2 MPro has been emerged as an attractive target for SARS-CoV-2 drug design and development. Diverse scaffolds have been released targeting SARS-CoV-2 MPro. In this review, we culminate the latest published information about SARS-CoV-2 main proteinase (MPro) and reported inhibitors.

scholarly journals Targeting Endolysosomal Two-Pore Channels to Treat Cardiovascular Disorders in the Novel COronaVIrus Disease 2019

2021 ◽  
Vol 12 ◽  
Author(s):  
Francesco Moccia ◽  
Sharon Negri ◽  
Pawan Faris ◽  
Angelica Perna ◽  
Antonio De Luca ◽  
...  
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Cardiovascular System ◽  
Ebola Virus ◽  
Cardiovascular Complications ◽  
Host Cells ◽  
Cardiovascular Disorders ◽  
The Novel ◽  
Life Threatening ◽  
Novel Coronavirus

Emerging evidence hints in favor of a life-threatening link between severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) and the cardiovascular system. SARS-CoV-2 may result in dramatic cardiovascular complications, whereas the severity of COronaVIrus Disease 2019 (COVID-19) and the incidence of fatalities tend to increase in patients with pre-existing cardiovascular complications. SARS-CoV-2 is internalized into the host cells by endocytosis and may then escape the endolysosomal system via endosomes. Two-pore channels drive endolysosomal trafficking through the release of endolysosomal Ca2+. Recent evidence suggested that the pharmacological inhibition of TPCs prevents Ebola virus and Middle East Respiratory Syndrome COronaVirus (MERS-CoV) entry into host cells. In this perspective, we briefly summarize the biophysical and pharmacological features of TPCs, illustrate their emerging role in the cardiovascular system, and finally present them as a reliable target to treat cardiovascular complications in COVID-19 patients.

scholarly journals The potential role of Bromhexine in the management of COVID-19: Decipher and a real game-changer

2021 ◽  
Vol 5 (01) ◽  
pp. 1-4
Author(s):  
Hayder M. Al-Kuraishy ◽  
Marwa S. Al-Niemi ◽  
Nawar R. Hussain ◽  
Ali I. Al-Gareeb ◽  
Claire Lugnier
Keyword(s):  
Potential Role ◽  
Host Cells ◽  
Bronchial Epithelial ◽  
S Protein ◽  
Angiotensin Converting Enzyme 2 ◽  
Novel Coronavirus ◽  
Transmembrane Serine Protease ◽  
Game Changer

Primary infection of SARS-CoV-2 (novel coronavirus or 2019-nCoV), which leads to Covid-19, targets specific cells, such as nasal, bronchial epithelial and pneumocytes, through the viral structural spike (S) protein that binds to the angiotensin-converting enzyme 2 (ACE2) receptor. Also, type 2 transmembrane serine protease (TMPRSS2) present in the host cell promotes viral uptake by cleaving ACE2 and triggering the SARS-CoV-2 S protein, which facilitates SARS-CoV-2 entry into host cells. One of the TMPRSS2 inhibitors with a greater distribution capacity into the lung tissue is bromhexine hydrochloride which attenuates the entry and proliferation of SARS-CoV-2. Bromhexine is an effective drug in the management and treatment of Covid-19 pneumonia via targeting ACE2/ TMPRSS2 pathway. However, prospective and controlled clinical trials are recommended to confirm this observation.

scholarly journals Comparative Genomics of Receptor Binding Domains of Spike Protein and Receptor Interaction in COVID-19 Patient

2020 ◽  
Author(s):  
Rimjhim Dasgupta
Keyword(s):  
Receptor Binding ◽  
Binding Domain ◽  
Host Cells ◽  
Receptor Interaction ◽  
Receptor Binding Domain ◽  
Furin Cleavage ◽  
S Protein ◽  
Human Coronaviruses ◽  
Novel Coronavirus ◽  
Bat Coronavirus

The current outbreak of viral pneumonia in the city of Wuhan, China, was caused by a novel coronavirus designated 2019-nCoV, as determined by sequencing the viral RNA genome. Among its genome, S protein is surface-exposed and mediates entry into host cells. Currently it is one of the main targets for designing antibodies (Abs), therapeutic and vaccine. Earlier studies stated that ACE2 (angiotensin converting enzyme 2) could facilitate S protein mediated entry for this newly emerged coronavirus. Here we have taken an attempt to compare the genetic structure of receptor binding domain within S protein of highly pathogenic human coronaviruses (special reference to 2019-nCoV) with Bat coronavirus RaTG13. We have compared 2019-nCov receptor binding domain (RBD) with other pathogenic human coronaviruses (MERS-CoV and SARS-CoV) and Bat coronavirus RaTG13. We found that it is closest to RaTG13 RBD than MERS-CoV and SARS-CoV. Our study shows that 2019-nCov RBD also has significant identity with pangolin S protein RBD. We have also predicted the amino acid residues within RDB those may play important role for ACE2 receptor interaction. We identified unique signature for furin cleavage in 2019-nCov S protein but not in of other pathogenic human coronaviruses (tested here), bat coronavirus RaTG13 or pangolin.

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