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1.
J Phys Chem B ; 124(34): 7336-7347, 2020 08 27.
Article in English | MEDLINE | ID: covidwho-752578

ABSTRACT

The 2019 novel coronavirus (SARS-CoV-2) epidemic, which was first reported in December 2019 in Wuhan, China, was declared a pandemic by the World Health Organization in March 2020. Genetically, SARS-CoV-2 is closely related to SARS-CoV, which caused a global epidemic with 8096 confirmed cases in more than 25 countries from 2002 to 2003. Given the significant morbidity and mortality rate, the current pandemic poses a danger to all of humanity, prompting us to understand the activity of SARS-CoV-2 at the atomic level. Experimental studies have revealed that spike proteins of both SARS-CoV-2 and SARS-CoV bind to angiotensin-converting enzyme 2 (ACE2) before entering the cell for replication. However, the binding affinities reported by different groups seem to contradict each other. Wrapp et al. (Science 2020, 367, 1260-1263) showed that the spike protein of SARS-CoV-2 binds to the ACE2 peptidase domain (ACE2-PD) more strongly than does SARS-CoV, and this fact may be associated with a greater severity of the new virus. However, Walls et al. (Cell 2020, 181, 281-292) reported that SARS-CoV-2 exhibits a higher binding affinity, but the difference between the two variants is relatively small. To understand the binding mechnism and experimental results, we investigated how the receptor binding domain (RBD) of SARS-CoV (SARS-CoV-RBD) and SARS-CoV-2 (SARS-CoV-2-RBD) interacts with a human ACE2-PD using molecular modeling. We applied a coarse-grained model to calculate the dissociation constant and found that SARS-CoV-2 displays a 2-fold higher binding affinity. Using steered all-atom molecular dynamics simulations, we demonstrate that, like a coarse-grained simulation, SARS-CoV-2-RBD was associated with ACE2-PD more strongly than was SARS-CoV-RBD, as evidenced by a higher rupture force and larger pulling work. We show that the binding affinity of both viruses to ACE2 is driven by electrostatic interactions.


Subject(s)
Betacoronavirus/chemistry , Peptidyl-Dipeptidase A/metabolism , Receptors, Virus/metabolism , SARS Virus/chemistry , Spike Glycoprotein, Coronavirus/metabolism , Humans , Molecular Dynamics Simulation , Mutation , Protein Binding , Spike Glycoprotein, Coronavirus/genetics , Static Electricity
2.
Cell Physiol Biochem ; 54(4): 767-790, 2020 Aug 25.
Article in English | MEDLINE | ID: covidwho-729851

ABSTRACT

The pandemic of the severe acute respiratory syndrome coronavirus (SARS-CoV)-2 at the end of 2019 marked the third outbreak of a highly pathogenic coronavirus affecting the human population in the past twenty years. Cross-species zoonotic transmission of SARS-CoV-2 has caused severe pathogenicity and led to more than 655,000 fatalities worldwide until July 28, 2020. Outbursts of this virus underlined the importance of controlling infectious pathogens across international frontiers. Unfortunately, there is currently no clinically approved antiviral drug or vaccine against SARS-CoV-2, although several broad-spectrum antiviral drugs targeting multiple RNA viruses have shown a positive response and improved recovery in patients. In this review, we compile our current knowledge of the emergence, transmission, and pathogenesis of SARS-CoV-2 and explore several features of SARS-CoV-2. We emphasize the current therapeutic approaches used to treat infected patients. We also highlight the results of in vitro and in vivo data from several studies, which have broadened our knowledge of potential drug candidates for the successful treatment of patients infected with and discuss possible virus and host-based treatment options against SARS-CoV-2.


Subject(s)
Betacoronavirus , Coronavirus Infections , Pandemics , Pneumonia, Viral , Animals , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Betacoronavirus/drug effects , Betacoronavirus/genetics , Betacoronavirus/physiology , Coronaviridae/pathogenicity , Coronaviridae Infections/epidemiology , Coronaviridae Infections/virology , Coronavirus Infections/drug therapy , Coronavirus Infections/epidemiology , Coronavirus Infections/prevention & control , Coronavirus Infections/therapy , Coronavirus Infections/transmission , Cytokine Release Syndrome/etiology , Cytokine Release Syndrome/prevention & control , Cytokines/antagonists & inhibitors , Drug Delivery Systems , Endocytosis/drug effects , Forecasting , Genome, Viral , Global Health , Humans , Immunity, Herd , Immunization, Passive , Pandemics/prevention & control , Peptide Hydrolases/pharmacology , Peptide Hydrolases/therapeutic use , Pneumonia, Viral/drug therapy , Pneumonia, Viral/epidemiology , Pneumonia, Viral/prevention & control , Pneumonia, Viral/transmission , RNA, Viral/genetics , Receptors, Virus/antagonists & inhibitors , Receptors, Virus/metabolism , Spike Glycoprotein, Coronavirus/antagonists & inhibitors , Spike Glycoprotein, Coronavirus/metabolism , Viral Vaccines , Virus Internalization/drug effects , Virus Replication/drug effects , Zoonoses
3.
Molecules ; 25(17)2020 Aug 22.
Article in English | MEDLINE | ID: covidwho-727433

ABSTRACT

Presently, there are no approved drugs or vaccines to treat COVID-19, which has spread to over 200 countries and at the time of writing was responsible for over 650,000 deaths worldwide. Recent studies have shown that two human proteases, TMPRSS2 and cathepsin L, play a key role in host cell entry of SARS-CoV-2. Importantly, inhibitors of these proteases were shown to block SARS-CoV-2 infection. Here, we perform virtual screening of 14,011 phytochemicals produced by Indian medicinal plants to identify natural product inhibitors of TMPRSS2 and cathepsin L. AutoDock Vina was used to perform molecular docking of phytochemicals against TMPRSS2 and cathepsin L. Potential phytochemical inhibitors were filtered by comparing their docked binding energies with those of known inhibitors of TMPRSS2 and cathepsin L. Further, the ligand binding site residues and non-covalent interactions between protein and ligand were used as an additional filter to identify phytochemical inhibitors that either bind to or form interactions with residues important for the specificity of the target proteases. This led to the identification of 96 inhibitors of TMPRSS2 and 9 inhibitors of cathepsin L among phytochemicals of Indian medicinal plants. Further, we have performed molecular dynamics (MD) simulations to analyze the stability of the protein-ligand complexes for the three top inhibitors of TMPRSS2 namely, qingdainone, edgeworoside C and adlumidine, and of cathepsin L namely, ararobinol, (+)-oxoturkiyenine and 3α,17α-cinchophylline. Interestingly, several herbal sources of identified phytochemical inhibitors have antiviral or anti-inflammatory use in traditional medicine. Further in vitro and in vivo testing is needed before clinical trials of the promising phytochemical inhibitors identified here.


Subject(s)
Antiviral Agents/chemistry , Betacoronavirus/drug effects , Cathepsin L/chemistry , Phytochemicals/chemistry , Protease Inhibitors/chemistry , Receptors, Virus/chemistry , Serine Endopeptidases/chemistry , Amino Acid Sequence , Antiviral Agents/isolation & purification , Antiviral Agents/pharmacology , Betacoronavirus/pathogenicity , Binding Sites , Cathepsin L/antagonists & inhibitors , Cathepsin L/genetics , Cathepsin L/metabolism , Coronavirus Infections/drug therapy , Coronavirus Infections/enzymology , Coronavirus Infections/virology , Coumarins/chemistry , Coumarins/isolation & purification , Coumarins/pharmacology , Gene Expression , High-Throughput Screening Assays , Host-Pathogen Interactions/drug effects , Host-Pathogen Interactions/genetics , Humans , India , Molecular Docking Simulation , Molecular Dynamics Simulation , Monosaccharides/chemistry , Monosaccharides/isolation & purification , Monosaccharides/pharmacology , Pandemics , Phytochemicals/isolation & purification , Phytochemicals/pharmacology , Plants, Medicinal/chemistry , Pneumonia, Viral/drug therapy , Pneumonia, Viral/enzymology , Pneumonia, Viral/virology , Protease Inhibitors/isolation & purification , Protease Inhibitors/pharmacology , Protein Binding , Protein Conformation, alpha-Helical , Protein Conformation, beta-Strand , Protein Interaction Domains and Motifs , Quinazolines/chemistry , Quinazolines/isolation & purification , Quinazolines/pharmacology , Receptors, Virus/antagonists & inhibitors , Receptors, Virus/genetics , Receptors, Virus/metabolism , Serine Endopeptidases/genetics , Serine Endopeptidases/metabolism , Thermodynamics , Virus Internalization/drug effects
4.
PLoS Pathog ; 16(8): e1008762, 2020 08.
Article in English | MEDLINE | ID: covidwho-727333

ABSTRACT

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is a newly emerging, highly transmissible, and pathogenic coronavirus in humans that has caused global public health emergencies and economic crises. To date, millions of infections and thousands of deaths have been reported worldwide, and the numbers continue to rise. Currently, there is no specific drug or vaccine against this deadly virus; therefore, there is a pressing need to understand the mechanism(s) through which this virus enters the host cell. Viral entry into the host cell is a multistep process in which SARS-CoV-2 utilizes the receptor-binding domain (RBD) of the spike (S) glycoprotein to recognize angiotensin-converting enzyme 2 (ACE2) receptors on the human cells; this initiates host-cell entry by promoting viral-host cell membrane fusion through large-scale conformational changes in the S protein. Receptor recognition and fusion are critical and essential steps of viral infections and are key determinants of the viral host range and cross-species transmission. In this review, we summarize the current knowledge on the origin and evolution of SARS-CoV-2 and the roles of key viral factors. We discuss the structure of RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2 and its significance in drug discovery and explain the receptor recognition mechanisms of coronaviruses. Further, we provide a comparative analysis of the SARS-CoV and SARS-CoV-2 S proteins and their receptor-binding specificity and discuss the differences in their antigenicity based on biophysical and structural characteristics.


Subject(s)
Betacoronavirus/pathogenicity , Coronavirus Infections/virology , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/virology , Spike Glycoprotein, Coronavirus/metabolism , Animals , Coronavirus Infections/metabolism , Humans , Pandemics , Pneumonia, Viral/metabolism , Receptors, Virus/immunology , Receptors, Virus/metabolism , Spike Glycoprotein, Coronavirus/immunology , Virus Internalization
5.
J Chem Phys ; 153(7): 075101, 2020 Aug 21.
Article in English | MEDLINE | ID: covidwho-726966

ABSTRACT

In 2020, the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected millions of people worldwide and caused the coronavirus disease 2019 (COVID-19). Spike (S) glycoproteins on the viral membrane bind to ACE2 receptors on the host cell membrane and initiate fusion, and S protein is currently among the primary drug target to inhibit viral entry. The S protein can be in a receptor inaccessible (closed) or accessible (open) state based on down and up positions of its receptor-binding domain (RBD), respectively. However, conformational dynamics and the transition pathway between closed to open states remain unexplored. Here, we performed all-atom molecular dynamics (MD) simulations starting from closed and open states of the S protein trimer in the presence of explicit water and ions. MD simulations showed that RBD forms a higher number of interdomain interactions and exhibits lower mobility in its down position than its up position. MD simulations starting from intermediate conformations between the open and closed states indicated that RBD switches to the up position through a semi-open intermediate that potentially reduces the free energy barrier between the closed and open states. Free energy landscapes were constructed, and a minimum energy pathway connecting the closed and open states was proposed. Because RBD-ACE2 binding is compatible with the semi-open state, but not with the closed state of the S protein, we propose that the formation of the intermediate state is a prerequisite for the host cell recognition.


Subject(s)
Betacoronavirus/chemistry , Spike Glycoprotein, Coronavirus/chemistry , Binding Sites , Hydrogen Bonding , Models, Chemical , Molecular Dynamics Simulation , Peptidyl-Dipeptidase A/chemistry , Peptidyl-Dipeptidase A/metabolism , Principal Component Analysis , Protein Binding , Protein Conformation , Protein Domains , Receptors, Virus/chemistry , Receptors, Virus/metabolism , Spike Glycoprotein, Coronavirus/metabolism , Thermodynamics
6.
Front Immunol ; 11: 1664, 2020.
Article in English | MEDLINE | ID: covidwho-724205

ABSTRACT

The rapidly spreading, highly contagious and pathogenic SARS-coronavirus 2 (SARS-CoV-2) associated Coronavirus Disease 2019 (COVID-19) has been declared as a pandemic by the World Health Organization (WHO). The novel 2019 SARS-CoV-2 enters the host cell by binding of the viral surface spike glycoprotein (S-protein) to cellular angiotensin converting enzyme 2 (ACE2) receptor. The virus specific molecular interaction with the host cell represents a promising therapeutic target for identifying SARS-CoV-2 antiviral drugs. The repurposing of drugs can provide a rapid and potential cure toward exponentially expanding COVID-19. Thereto, high throughput virtual screening approach was used to investigate FDA approved LOPAC library drugs against both the receptor binding domain of spike protein (S-RBD) and ACE2 host cell receptor. Primary screening identified a few promising molecules for both the targets, which were further analyzed in details by their binding energy, binding modes through molecular docking, dynamics and simulations. Evidently, GR 127935 hydrochloride hydrate, GNF-5, RS504393, TNP, and eptifibatide acetate were found binding to virus binding motifs of ACE2 receptor. Additionally, KT203, BMS195614, KT185, RS504393, and GSK1838705A were identified to bind at the receptor binding site on the viral S-protein. These identified molecules may effectively assist in controlling the rapid spread of SARS-CoV-2 by not only potentially inhibiting the virus at entry step but are also hypothesized to act as anti-inflammatory agents, which could impart relief in lung inflammation. Timely identification and determination of an effective drug to combat and tranquilize the COVID-19 global crisis is the utmost need of hour. Further, prompt in vivo testing to validate the anti-SARS-CoV-2 inhibition efficiency by these molecules could save lives is justified.


Subject(s)
Betacoronavirus/physiology , Computer Simulation , Coronavirus Infections/drug therapy , Drug Repositioning/methods , Pneumonia, Viral/drug therapy , User-Computer Interface , Virus Internalization/drug effects , Anti-Inflammatory Agents/therapeutic use , Binding Sites , Coronavirus Infections/virology , Genome, Viral/genetics , Humans , Models, Genetic , Molecular Docking Simulation , Molecular Dynamics Simulation , Pandemics , Peptidyl-Dipeptidase A/chemistry , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/virology , Protein Binding , Protein Domains , Receptors, Virus/metabolism , Spike Glycoprotein, Coronavirus/antagonists & inhibitors , Spike Glycoprotein, Coronavirus/chemistry , Virus Attachment
7.
Viruses ; 12(9)2020 08 19.
Article in English | MEDLINE | ID: covidwho-721525

ABSTRACT

COVID-19 novel coronavirus (CoV) disease caused by severe acquired respiratory syndrome (SARS)-CoV-2 manifests severe lethal respiratory illness in humans and has recently developed into a worldwide pandemic. The lack of effective treatment strategy and vaccines against the SARS-CoV-2 poses a threat to human health. An extremely high infection rate and multi-organ secondary infection within a short period of time makes this virus more deadly and challenging for therapeutic interventions. Despite high sequence similarity and utilization of common host-cell receptor, human angiotensin-converting enzyme-2 (ACE2) for virus entry, SARS-CoV-2 is much more infectious than SARS-CoV. Structure-based sequence comparison of the N-terminal domain (NTD) of the spike protein of Middle East respiratory syndrome (MERS)-CoV, SARS-CoV, and SARS-CoV-2 illustrate three divergent loop regions in SARS-CoV-2, which is reminiscent of MERS-CoV sialoside binding pockets. Comparative binding analysis with host sialosides revealed conformational flexibility of SARS-CoV-2 divergent loop regions to accommodate diverse glycan-rich sialosides. These key differences with SARS-CoV and similarity with MERS-CoV suggest an evolutionary adaptation of SARS-CoV-2 spike glycoprotein reciprocal interaction with host surface sialosides to infect host cells with wide tissue tropism.


Subject(s)
Betacoronavirus/chemistry , Middle East Respiratory Syndrome Coronavirus/chemistry , Sialic Acids/metabolism , Spike Glycoprotein, Coronavirus/chemistry , Amino Sugars/metabolism , Betacoronavirus/physiology , Binding Sites , Models, Molecular , Molecular Docking Simulation , Molecular Dynamics Simulation , N-Acetylneuraminic Acid/metabolism , Protein Binding , Protein Domains , Receptors, Virus/chemistry , Receptors, Virus/metabolism , SARS Virus/chemistry , Sialyl Lewis X Antigen/metabolism , Spike Glycoprotein, Coronavirus/metabolism , Viral Tropism , Virus Internalization
8.
Emerg Microbes Infect ; 9(1): 1567-1579, 2020 Dec.
Article in English | MEDLINE | ID: covidwho-707709

ABSTRACT

Diverse SARS-like coronaviruses (SL-CoVs) have been identified from bats and other animal species. Like SARS-CoV, some bat SL-CoVs, such as WIV1, also use angiotensin converting enzyme 2 (ACE2) from human and bat as entry receptor. However, whether these viruses can also use the ACE2 of other animal species as their receptor remains to be determined. We report herein that WIV1 has a broader tropism to ACE2 orthologs than SARS-CoV isolate Tor2. Among the 9 ACE2 orthologs examined, human ACE2 exhibited the highest efficiency to mediate the infection of WIV1 pseudotyped virus. Our findings thus imply that WIV1 has the potential to infect a wide range of wild animals and may directly jump to humans. We also showed that cell entry of WIV1 could be restricted by interferon-induced transmembrane proteins (IFITMs). However, WIV1 could exploit the airway protease TMPRSS2 to partially evade the IFITM3 restriction. Interestingly, we also found that amphotericin B could enhance the infectious entry of SARS-CoVs and SL-CoVs by evading IFITM3-mediated restriction. Collectively, our findings further underscore the risk of exposure to animal SL-CoVs and highlight the vulnerability of patients who take amphotericin B to infection by SL-CoVs, including the most recently emerging (SARS-CoV-2).


Subject(s)
Betacoronavirus/physiology , Chiroptera/virology , Membrane Proteins/metabolism , Peptidyl-Dipeptidase A/metabolism , RNA-Binding Proteins/metabolism , Receptors, Virus/metabolism , Serine Endopeptidases/metabolism , Virus Internalization , Animals , Betacoronavirus/classification , HEK293 Cells , Humans , Rats , SARS Virus/physiology , Viverridae
9.
ACS Nano ; 14(8): 10616-10623, 2020 08 25.
Article in English | MEDLINE | ID: covidwho-696515

ABSTRACT

The receptor-binding domain (RBD) of the SARS-CoV-2 spike protein plays a crucial role in binding the human cell receptor ACE2 that is required for viral entry. Many studies have been conducted to target the structures of RBD-ACE2 binding and to design RBD-targeting vaccines and drugs. Nevertheless, mutations distal from the SARS-CoV-2 RBD also impact its transmissibility and antibody can target non-RBD regions, suggesting the incomplete role of the RBD region in the spike protein-ACE2 binding. Here, in order to elucidate distant binding mechanisms, we analyze complexes of ACE2 with the wild-type spike protein and with key mutants via large-scale all-atom explicit solvent molecular dynamics simulations. We find that though distributed approximately 10 nm away from the RBD, the SARS-CoV-2 polybasic cleavage sites enhance, via electrostatic interactions and hydration, the RBD-ACE2 binding affinity. A negatively charged tetrapeptide (GluGluLeuGlu) is then designed to neutralize the positively charged arginine on the polybasic cleavage sites. We find that the tetrapeptide GluGluLeuGlu binds to one of the three polybasic cleavage sites of the SARS-CoV-2 spike protein lessening by 34% the RBD-ACE2 binding strength. This significant binding energy reduction demonstrates the feasibility to neutralize RBD-ACE2 binding by targeting this specific polybasic cleavage site. Our work enhances understanding of the binding mechanism of SARS-CoV-2 to ACE2, which may aid the design of therapeutics for COVID-19 infection.


Subject(s)
Betacoronavirus/metabolism , Coronavirus Infections/virology , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/virology , Receptors, Virus/metabolism , Spike Glycoprotein, Coronavirus/metabolism , Amino Acid Substitution , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Betacoronavirus/chemistry , Betacoronavirus/genetics , Binding Sites/genetics , Drug Design , Host Microbial Interactions/drug effects , Humans , Molecular Dynamics Simulation , Mutation , Oligopeptides/chemistry , Oligopeptides/pharmacology , Pandemics , Peptidyl-Dipeptidase A/chemistry , Peptidyl-Dipeptidase A/genetics , Protein Binding/drug effects , Protein Binding/genetics , Protein Binding/physiology , Protein Domains , Receptors, Virus/chemistry , Receptors, Virus/genetics , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , Virus Internalization
10.
J Phys Chem B ; 124(34): 7336-7347, 2020 08 27.
Article in English | MEDLINE | ID: covidwho-696364

ABSTRACT

The 2019 novel coronavirus (SARS-CoV-2) epidemic, which was first reported in December 2019 in Wuhan, China, was declared a pandemic by the World Health Organization in March 2020. Genetically, SARS-CoV-2 is closely related to SARS-CoV, which caused a global epidemic with 8096 confirmed cases in more than 25 countries from 2002 to 2003. Given the significant morbidity and mortality rate, the current pandemic poses a danger to all of humanity, prompting us to understand the activity of SARS-CoV-2 at the atomic level. Experimental studies have revealed that spike proteins of both SARS-CoV-2 and SARS-CoV bind to angiotensin-converting enzyme 2 (ACE2) before entering the cell for replication. However, the binding affinities reported by different groups seem to contradict each other. Wrapp et al. (Science 2020, 367, 1260-1263) showed that the spike protein of SARS-CoV-2 binds to the ACE2 peptidase domain (ACE2-PD) more strongly than does SARS-CoV, and this fact may be associated with a greater severity of the new virus. However, Walls et al. (Cell 2020, 181, 281-292) reported that SARS-CoV-2 exhibits a higher binding affinity, but the difference between the two variants is relatively small. To understand the binding mechnism and experimental results, we investigated how the receptor binding domain (RBD) of SARS-CoV (SARS-CoV-RBD) and SARS-CoV-2 (SARS-CoV-2-RBD) interacts with a human ACE2-PD using molecular modeling. We applied a coarse-grained model to calculate the dissociation constant and found that SARS-CoV-2 displays a 2-fold higher binding affinity. Using steered all-atom molecular dynamics simulations, we demonstrate that, like a coarse-grained simulation, SARS-CoV-2-RBD was associated with ACE2-PD more strongly than was SARS-CoV-RBD, as evidenced by a higher rupture force and larger pulling work. We show that the binding affinity of both viruses to ACE2 is driven by electrostatic interactions.


Subject(s)
Betacoronavirus/chemistry , Peptidyl-Dipeptidase A/metabolism , Receptors, Virus/metabolism , SARS Virus/chemistry , Spike Glycoprotein, Coronavirus/metabolism , Humans , Molecular Dynamics Simulation , Mutation , Protein Binding , Spike Glycoprotein, Coronavirus/genetics , Static Electricity
11.
Int J Environ Res Public Health ; 17(15)2020 08 02.
Article in English | MEDLINE | ID: covidwho-693532

ABSTRACT

The COVID-19/SARS-CoV-2 pandemic struck health, social and economic systems worldwide, and represents an open challenge for scientists -coping with the high inter-individual variability of COVID-19, and for policy makers -coping with the responsibility to understand environmental factors affecting its severity across different geographical areas. Air pollution has been warned of as a modifiable factor contributing to differential SARS-CoV-2 spread but the biological mechanisms underlying the phenomenon are still unknown. Air quality and COVID-19 epidemiological data from 110 Italian provinces were studied by correlation analysis, to evaluate the association between particulate matter (PM)2.5 concentrations and incidence, mortality rate and case fatality risk of COVID-19 in the period 20 February-31 March 2020. Bioinformatic analysis of the DNA sequence encoding the SARS-CoV-2 cell receptor angiotensin-converting enzyme 2 (ACE-2) was performed to identify consensus motifs for transcription factors mediating cellular response to pollutant insult. Positive correlations between PM2.5 levels and the incidence (r = 0.67, p < 0.0001), the mortality rate (r = 0.65, p < 0.0001) and the case fatality rate (r = 0.7, p < 0.0001) of COVID-19 were found. The bioinformatic analysis of the ACE-2 gene identified nine putative consensus motifs for the aryl hydrocarbon receptor (AHR). Our results confirm the supposed link between air pollution and the rate and outcome of SARS-CoV-2 infection and support the hypothesis that pollution-induced over-expression of ACE-2 on human airways may favor SARS-CoV-2 infectivity.


Subject(s)
Air Pollution/adverse effects , Coronavirus Infections/virology , Particulate Matter/adverse effects , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/virology , Receptors, Virus/metabolism , Base Sequence , Betacoronavirus , Coronavirus Infections/epidemiology , Humans , Italy/epidemiology , Pandemics , Peptidyl-Dipeptidase A/genetics , Pneumonia, Viral/epidemiology , Promoter Regions, Genetic , Receptors, Virus/genetics , Up-Regulation
13.
Elife ; 92020 07 30.
Article in English | MEDLINE | ID: covidwho-690669

ABSTRACT

The COVID-19 pandemic caused by the SARS-CoV-2 has recently emerged as a serious jolt to human life and economy. Initial knowledge established pulmonary complications as the chief symptom, however, the neurological aspect of the disease is also becoming increasingly evident. Emerging reports of encephalopathies and similar ailments with the detection of the virus in the CSF has elicited an urgent need for investigating the possibility of neuroinvasiveness of the virus, which cannot be ruled out given the expression of low levels of ACE2 receptors in the brain. Sensory impairments of the olfactory and gustatory systems have also been reported in a large proportion of the cases, indicating the involvement of the peripheral nervous system. Hence, the possibility of neurological damage caused by the virus demands immediate attention and investigation of the mechanisms involved, so as to customize the treatment of patients presenting with neurological complications.


Subject(s)
Betacoronavirus , Coronavirus Infections/complications , Nervous System Diseases/etiology , Pneumonia, Viral/complications , Ageusia/etiology , Betacoronavirus/pathogenicity , Betacoronavirus/physiology , Brain/metabolism , Brain/virology , Cerebrovascular Disorders/etiology , Coronavirus Infections/epidemiology , Coronavirus Infections/virology , Encephalitis, Viral/etiology , Host Microbial Interactions , Humans , Models, Neurological , Nervous System Diseases/physiopathology , Nervous System Diseases/virology , Olfaction Disorders/etiology , Pandemics , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/epidemiology , Pneumonia, Viral/virology , Receptors, Virus/metabolism
14.
Virol J ; 17(1): 117, 2020 07 29.
Article in English | MEDLINE | ID: covidwho-684739

ABSTRACT

Coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 infection has spread rapidly across the world and become an international public health emergency. Both SARS-CoV-2 and SARS-CoV belong to subfamily Coronavirinae in the family Coronaviridae of the order Nidovirales and they are classified as the SARS-like species while belong to different cluster. Besides, viral structure, epidemiology characteristics and pathological characteristics are also different. We present a comprehensive survey of the latest coronavirus-SARS-CoV-2-from investigating its origin and evolution alongside SARS-CoV. Meanwhile, pathogenesis, cardiovascular disease in COVID-19 patients, myocardial injury and venous thromboembolism induced by SARS-CoV-2 as well as the treatment methods are summarized in this review.


Subject(s)
Betacoronavirus , Coronavirus Infections , Pandemics , Pneumonia, Viral , Antiviral Agents/therapeutic use , Asymptomatic Infections , Betacoronavirus/chemistry , Betacoronavirus/classification , Betacoronavirus/pathogenicity , Betacoronavirus/physiology , Comorbidity , Coronavirus Infections/drug therapy , Coronavirus Infections/epidemiology , Coronavirus Infections/immunology , Coronavirus Infections/pathology , Coronavirus Infections/therapy , Disease Susceptibility , Evolution, Molecular , Genome, Viral , Humans , Immunization, Passive , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/epidemiology , Pneumonia, Viral/immunology , Pneumonia, Viral/pathology , Pneumonia, Viral/therapy , Receptors, Virus/metabolism , SARS Virus/chemistry , SARS Virus/classification , SARS Virus/pathogenicity , SARS Virus/physiology , Viral Proteins/chemistry
15.
J Gen Virol ; 101(6): 599-608, 2020 06.
Article in English | MEDLINE | ID: covidwho-662965

ABSTRACT

Infection of chicken coronavirus infectious bronchitis virus (IBV) is initiated by binding of the viral heavily N-glycosylated attachment protein spike to the alpha-2,3-linked sialic acid receptor Neu5Ac. Previously, we have shown that N-glycosylation of recombinantly expressed receptor binding domain (RBD) of the spike of IBV-M41 is of critical importance for binding to chicken trachea tissue. Here we investigated the role of N-glycosylation of the RBD on receptor specificity and virus replication in the context of the virus particle. Using our reverse genetics system we were able to generate recombinant IBVs for nine-out-of-ten individual N-glycosylation mutants. In vitro growth kinetics of these viruses were comparable to the virus containing the wild-type M41-S1. Furthermore, Neu5Ac binding by the recombinant viruses containing single N-glycosylation site knock-out mutations matched the Neu5Ac binding observed with the recombinant RBDs. Five N-glycosylation mutants lost the ability to bind Neu5Ac and gained binding to a different, yet unknown, sialylated glycan receptor on host cells. These results demonstrate that N-glycosylation of IBV is a determinant for receptor specificity.


Subject(s)
Coronavirus Infections/immunology , Host Specificity/immunology , Infectious bronchitis virus/chemistry , Protein Domains , Receptors, Virus/immunology , Spike Glycoprotein, Coronavirus/chemistry , Animals , Cell Line , Chick Embryo , Coronavirus Infections/virology , Glycosylation , Infectious bronchitis virus/immunology , Kidney/cytology , Kidney/embryology , Protein Binding , Receptors, Cell Surface/metabolism , Receptors, Virus/metabolism , Recombinant Proteins , Spike Glycoprotein, Coronavirus/metabolism , Viral Tropism/immunology , Virus Attachment , Virus Replication
16.
Infect Dis Poverty ; 9(1): 99, 2020 Jul 20.
Article in English | MEDLINE | ID: covidwho-655343

ABSTRACT

BACKGROUND: The outbreak of coronavirus disease 2019 (COVID-19) has caused a public catastrophe and global concern. The main symptoms of COVID-19 are fever, cough, myalgia, fatigue and lower respiratory tract infection signs. Almost all populations are susceptible to the virus, and the basic reproduction number (R0) is 2.8-3.9. The fight against COVID-19 should have two aspects: one is the treatment of infected patients, and the other is the mobilization of the society to avoid the spread of the virus. The treatment of patients includes supportive treatment, antiviral treatment, and oxygen therapy. For patients with severe acute respiratory distress syndrome (ARDS), extracorporeal membrane oxygenation (ECMO) and circulatory support are recommended. Plasma therapy and traditional Chinese medicine have also achieved good outcomes. This review is intended to summarize the research on this new coronavirus, to analyze the similarities and differences between COVID-19 and previous outbreaks of severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) and to provide guidance regarding new methods of prevention, diagnosis and clinical treatment based on autodock simulations. METHODS: This review compares the multifaceted characteristics of the three coronaviruses including COVID-19, SARS and MERS. Our researchers take the COVID-19, SARS, and MERS as key words and search literatures in the Pubmed database. We compare them horizontally and vertically which respectively means concluding the individual characteristics of each coronavirus and comparing the similarities and differences between the three coronaviruses. RESULTS: We searched for studies on each outbreak and their solutions and found that the main biological differences among SARS-CoV-2, SARS-CoV and MERS-CoV are in ORF1a and the sequence of gene spike coding protein-S. We also found that the types and severity of clinical symptoms vary, which means that the diagnosis and nursing measures also require differentiation. In addition to the common route of transmission including airborne transmission, these three viruses have their own unique routes of transmission such as fecal-oral route of transmission COVID-19. CONCLUSIONS: In evolutionary history, these three coronaviruses have some similar biological features as well as some different mutational characteristics. Their receptors and routes of transmission are not all the same, which makes them different in clinical features and treatments. We discovered through the autodock simulations that Met124 plays a key role in the efficiency of drugs targeting ACE2, such as remdesivir, chloroquine, ciclesonide and niclosamide, and may be a potential target in COVID-19.


Subject(s)
Antiviral Agents/chemistry , Coronavirus Infections , Pandemics , Peptidyl-Dipeptidase A/chemistry , Pneumonia, Viral , Receptors, Virus/chemistry , Severe Acute Respiratory Syndrome , Animals , Antiviral Agents/metabolism , Betacoronavirus/genetics , Betacoronavirus/physiology , Betacoronavirus/ultrastructure , Clinical Laboratory Techniques , Clinical Trials as Topic , Coronavirus Infections/diagnosis , Coronavirus Infections/drug therapy , Coronavirus Infections/epidemiology , Coronavirus Infections/therapy , Coronavirus Infections/transmission , Disease Reservoirs , Humans , Middle East Respiratory Syndrome Coronavirus/genetics , Middle East Respiratory Syndrome Coronavirus/physiology , Middle East Respiratory Syndrome Coronavirus/ultrastructure , Molecular Docking Simulation , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/diagnosis , Pneumonia, Viral/epidemiology , Pneumonia, Viral/therapy , Pneumonia, Viral/transmission , Receptors, Virus/metabolism , SARS Virus/genetics , SARS Virus/physiology , SARS Virus/ultrastructure , Severe Acute Respiratory Syndrome/diagnosis , Severe Acute Respiratory Syndrome/epidemiology , Severe Acute Respiratory Syndrome/transmission
17.
J Immunol ; 205(5): 1198-1206, 2020 09 01.
Article in English | MEDLINE | ID: covidwho-654195

ABSTRACT

Fever in infections correlates with inflammation, macrophage infiltration into the affected organ, macrophage activation, and release of cytokines involved in immune response, hematopoiesis, and homeostatic processes. Angiotensin-converting enzyme 2 (ACE2) is the canonical cell surface receptor for SARS-CoV-2. ACE2 together with angiotensin receptor types 1 and 2 and ACE2 are components of the renin-angiotensin system (RAS). Exacerbated production of cytokines, mainly IL-6, points to macrophages as key to understand differential COVID-19 severity. SARS-CoV-2 may modulate macrophage-mediated inflammation events by altering the balance between angiotensin II, which activates angiotensin receptor types 1 and 2, and angiotensin 1-7 and alamandine, which activate MAS proto-oncogene and MAS-related D receptors, respectively. In addition to macrophages, lung cells express RAS components; also, some lung cells are able to produce IL-6. Addressing how SARS-CoV-2 unbalances RAS functionality via ACE2 will help design therapies to attenuate a COVID-19-related cytokine storm.


Subject(s)
Betacoronavirus/metabolism , Coronavirus Infections/immunology , Interleukin-6/biosynthesis , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/immunology , Renin-Angiotensin System , Angiotensin I/metabolism , Animals , Betacoronavirus/immunology , Coronavirus Infections/virology , Humans , Inflammation/immunology , Macrophages/immunology , Pandemics , Peptide Fragments/metabolism , Pneumonia, Viral/virology , Proto-Oncogene Proteins/metabolism , Receptor, Angiotensin, Type 1/metabolism , Receptor, Angiotensin, Type 2/metabolism , Receptors, G-Protein-Coupled/metabolism , Receptors, Virus/metabolism
18.
J Virol ; 94(18)2020 08 31.
Article in English | MEDLINE | ID: covidwho-650660

ABSTRACT

The COVID-19 pandemic has caused an unprecedented global public health and economic crisis. The origin and emergence of its causal agent, SARS-CoV-2, in the human population remains mysterious, although bat and pangolin were proposed to be the natural reservoirs. Strikingly, unlike the SARS-CoV-2-like coronaviruses (CoVs) identified in bats and pangolins, SARS-CoV-2 harbors a polybasic furin cleavage site in its spike (S) glycoprotein. SARS-CoV-2 uses human angiotensin-converting enzyme 2 (ACE2) as its receptor to infect cells. Receptor recognition by the S protein is the major determinant of host range, tissue tropism, and pathogenesis of coronaviruses. In an effort to search for the potential intermediate or amplifying animal hosts of SARS-CoV-2, we examined receptor activity of ACE2 from 14 mammal species and found that ACE2s from multiple species can support the infectious entry of lentiviral particles pseudotyped with the wild-type or furin cleavage site-deficient S protein of SARS-CoV-2. ACE2 of human/rhesus monkey and rat/mouse exhibited the highest and lowest receptor activities, respectively. Among the remaining species, ACE2s from rabbit and pangolin strongly bound to the S1 subunit of SARS-CoV-2 S protein and efficiently supported the pseudotyped virus infection. These findings have important implications for understanding potential natural reservoirs, zoonotic transmission, human-to-animal transmission, and use of animal models.IMPORTANCE SARS-CoV-2 uses human ACE2 as a primary receptor for host cell entry. Viral entry mediated by the interaction of ACE2 with spike protein largely determines host range and is the major constraint to interspecies transmission. We examined the receptor activity of 14 ACE2 orthologs and found that wild-type and mutant SARS-CoV-2 lacking the furin cleavage site in S protein could utilize ACE2 from a broad range of animal species to enter host cells. These results have important implications in the natural hosts, interspecies transmission, animal models, and molecular basis of receptor binding for SARS-CoV-2.


Subject(s)
Animal Diseases/metabolism , Animal Diseases/virology , Betacoronavirus/physiology , Coronavirus Infections/veterinary , Pandemics/veterinary , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/veterinary , Receptors, Virus/metabolism , Amino Acid Sequence , Animals , Betacoronavirus/classification , Cell Line , Host Specificity , Humans , Models, Molecular , Mutation , Peptidyl-Dipeptidase A/chemistry , Phylogeny , Protein Binding , Protein Domains , Proteolysis , Receptors, Virus/chemistry , Spike Glycoprotein, Coronavirus/metabolism , Structure-Activity Relationship , Viral Tropism , Virus Internalization
19.
Euro Surveill ; 25(25)2020 06.
Article in English | MEDLINE | ID: covidwho-649992

ABSTRACT

The advent of COVID-19, has posed a risk that human respiratory samples containing human influenza viruses may also contain SARS-CoV-2. This potential risk may lead to SARS-CoV-2 contaminating conventional influenza vaccine production platforms as respiratory samples are used to directly inoculate embryonated hen's eggs and continuous cell lines that are used to isolate and produce influenza vaccines. We investigated the ability of these substrates to propagate SARS-CoV-2 and found that neither could support SARS-CoV-2 replication.


Subject(s)
Chickens/immunology , Coronavirus/physiology , Influenza Vaccines/immunology , Influenza, Human/prevention & control , Madin Darby Canine Kidney Cells , Receptors, Virus/metabolism , Virus Cultivation/methods , Virus Replication , Animals , Betacoronavirus , Cell Line , Chickens/virology , Coronavirus Infections/epidemiology , Coronavirus Infections/virology , Dogs , Eggs , Humans , Pandemics , Pneumonia, Viral , Severe Acute Respiratory Syndrome
20.
Respir Res ; 21(1): 182, 2020 Jul 14.
Article in English | MEDLINE | ID: covidwho-647112

ABSTRACT

BACKGROUND: Severe acute respiratory syndrome (SARS)-CoV-2-induced coronavirus disease-2019 (COVID-19) is a pandemic disease that affects > 2.8 million people worldwide, with numbers increasing dramatically daily. However, there is no specific treatment for COVID-19 and much remains unknown about this disease. Angiotensin-converting enzyme (ACE)2 is a cellular receptor of SARS-CoV-2. It is cleaved by type II transmembrane serine protease (TMPRSS)2 and disintegrin and metallopeptidase domain (ADAM)17 to assist viral entry into host cells. Clinically, SARS-CoV-2 infection may result in acute lung injury and lung fibrosis, but the underlying mechanisms of COVID-19 induced lung fibrosis are not fully understood. METHODS: The networks of ACE2 and its interacting molecules were identified using bioinformatic methods. Their gene and protein expressions were measured in human epithelial cells after 24 h SARS-CoV-2 infection, or in existing datasets of lung fibrosis patients. RESULTS: We confirmed the binding of SARS-CoV-2 and ACE2 by bioinformatic analysis. TMPRSS2, ADAM17, tissue inhibitor of metalloproteinase (TIMP)3, angiotensinogen (AGT), transformation growth factor beta (TGFB1), connective tissue growth factor (CTGF), vascular endothelial growth factor (VEGF) A and fibronectin (FN) were interacted with ACE2, and the mRNA and protein of these molecules were expressed in lung epithelial cells. SARS-CoV-2 infection increased ACE2, TGFB1, CTGF and FN1 mRNA that were drivers of lung fibrosis. These changes were also found in lung tissues from lung fibrosis patients. CONCLUSIONS: Therefore, SARS-CoV-2 binds with ACE2 and activates fibrosis-related genes and processes to induce lung fibrosis.


Subject(s)
Coronavirus Infections/genetics , Gene Expression Regulation , Peptidyl-Dipeptidase A/genetics , Pneumonia, Viral/genetics , Pulmonary Fibrosis/genetics , Respiratory Distress Syndrome, Adult/genetics , SARS Virus/genetics , China , Coronavirus Infections/epidemiology , Coronavirus Infections/physiopathology , Disease Progression , Epithelial Cells/cytology , Epithelial Cells/metabolism , Female , Humans , Male , Pandemics/statistics & numerical data , Pneumonia, Viral/epidemiology , Pneumonia, Viral/physiopathology , Prevalence , Pulmonary Fibrosis/epidemiology , Pulmonary Fibrosis/etiology , Receptors, Virus/metabolism , Respiratory Distress Syndrome, Adult/diagnosis , Respiratory Distress Syndrome, Adult/epidemiology , Risk Assessment , Survival Analysis , Transcription, Genetic , Transcriptional Activation/genetics
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