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1.
J Chin Med Assoc ; 83(8): 725-732, 2020 08.
Article in English | MEDLINE | ID: covidwho-709365

ABSTRACT

BACKGROUND: The outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused severe pneumonia at December 2019. Since then, it has been wildly spread from Wuhan, China, to Asia, European, and United States to become the pandemic worldwide. Now coronavirus disease 2019 were globally diagnosed over 3 084 740 cases with mortality of 212 561 toll. Current reports variants are found in SARS-CoV-2, majoring in functional ribonucleic acid (RNA) to transcribe into structural proteins as transmembrane spike (S) glycoprotein and the nucleocapsid (N) protein holds the virus RNA genome; the envelope (E) and membrane (M) alone with spike protein form viral envelope. The nonstructural RNA genome includes ORF1ab, ORF3, ORF6, 7a, 8, and ORF10 with highly conserved information for genome synthesis and replication in ORF1ab. METHODS: We apply genomic alignment analysis to observe SARS-CoV-2 sequences from GenBank (http://www.ncbi.nim.nih.gov/genebank/): MN 908947 (China, C1); MN985325 (United States: WA, UW); MN996527 (China, C2); MT007544 (Australia: Victoria, A1); MT027064 (United States: CA, UC); MT039890 (South Korea, K1); MT066175 (Taiwan, T1); MT066176 (Taiwan, T2); LC528232 (Japan, J1); and LC528233 (Japan, J2) and Global Initiative on Sharing All Influenza Data database (https://www.gisaid.org). We adopt Multiple Sequence Alignments web from Clustalw (https://www.genome.jp/tools-bin/clustalw) and Geneious web (https://www.geneious.com. RESULTS: We analyze database by genome alignment search for nonstructural ORFs and structural E, M, N, and S proteins. Mutations in ORF1ab, ORF3, and ORF6 are observed; specific variants in spike region are detected. CONCLUSION: We perform genomic analysis and comparative multiple sequence of SARS-CoV-2. Large scaling sequence alignments trace to localize and catch different mutant strains in United possibly to transmit severe deadly threat to humans. Studies about the biological symptom of SARS-CoV-2 in clinic animal and humans will be applied and manipulated to find mechanisms and shield the light for understanding the origin of pandemic crisis.


Subject(s)
Betacoronavirus/genetics , Genome, Viral , Open Reading Frames , Spike Glycoprotein, Coronavirus/physiology , Humans , Phylogeny , Point Mutation , Spike Glycoprotein, Coronavirus/genetics
2.
Med Sci (Paris) ; 36(8-9): 783-796, 2020.
Article in French | MEDLINE | ID: covidwho-706965

ABSTRACT

SARS-CoV-2 is a new human coronavirus (CoV), which emerged in People's Republic of China at the end of 2019 and is responsible for the global Covid-19 pandemic that caused more than 540 000 deaths in six months. Understanding the origin of this virus is an important issue and it is necessary to determine the mechanisms of its dissemination in order to be able to contain new epidemics. Based on phylogenetic inferences, sequence analysis and structure-function relationships of coronavirus proteins, informed by the knowledge currently available, we discuss the different scenarios evoked to account for the origin - natural or synthetic - of the virus. On the basis of currently available data, it is impossible to determine whether SARS-CoV-2 is the result of a natural zoonotic emergence or an accidental escape from experimental strains. Regardless of its origin, the study of the evolution of the molecular mechanisms involved in the emergence of this pandemic virus is essential to develop therapeutic and vaccine strategies.


Subject(s)
Betacoronavirus/genetics , Communicable Diseases, Emerging/virology , Coronavirus Infections/virology , Coronavirus/classification , Evolution, Molecular , Pandemics , Phylogeny , Pneumonia, Viral/virology , RNA, Viral/genetics , Amino Acid Sequence , Animals , Betacoronavirus/classification , Betacoronavirus/isolation & purification , Biohazard Release , China/epidemiology , Coronaviridae Infections/transmission , Coronaviridae Infections/veterinary , Coronaviridae Infections/virology , Coronavirus Infections/epidemiology , Coronavirus Infections/transmission , Disease Reservoirs , Gain of Function Mutation , Genome, Viral , HIV/genetics , Host Specificity , Humans , Mammals/virology , Pneumonia, Viral/epidemiology , Pneumonia, Viral/transmission , Reassortant Viruses/genetics , Sequence Alignment , Sequence Homology, Amino Acid , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/physiology , Zoonoses
3.
Acta Pharmacol Sin ; 41(9): 1141-1149, 2020 Sep.
Article in English | MEDLINE | ID: covidwho-694139

ABSTRACT

Coronavirus disease 2019 is a newly emerging infectious disease currently spreading across the world. It is caused by a novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The spike (S) protein of SARS-CoV-2, which plays a key role in the receptor recognition and cell membrane fusion process, is composed of two subunits, S1 and S2. The S1 subunit contains a receptor-binding domain that recognizes and binds to the host receptor angiotensin-converting enzyme 2, while the S2 subunit mediates viral cell membrane fusion by forming a six-helical bundle via the two-heptad repeat domain. In this review, we highlight recent research advance in the structure, function and development of antivirus drugs targeting the S protein.


Subject(s)
Antiviral Agents/pharmacology , Betacoronavirus , Coronavirus Infections , Pandemics , Pneumonia, Viral , Spike Glycoprotein, Coronavirus/physiology , Virus Internalization/drug effects , Betacoronavirus/drug effects , Betacoronavirus/physiology , Coronavirus Infections/drug therapy , Coronavirus Infections/virology , Drug Discovery/methods , Humans , Pneumonia, Viral/drug therapy , Pneumonia, Viral/virology
4.
Int J Mol Sci ; 21(12)2020 Jun 26.
Article in English | MEDLINE | ID: covidwho-627906

ABSTRACT

The recently emerged SARS-CoV-2 is the cause of the global health crisis of the coronavirus disease 2019 (COVID-19) pandemic. No evidence is yet available for CoV infection into hosts upon zoonotic disease outbreak, although the CoV epidemy resembles influenza viruses, which use sialic acid (SA). Currently, information on SARS-CoV-2 and its receptors is limited. O-acetylated SAs interact with the lectin-like spike glycoprotein of SARS CoV-2 for the initial attachment of viruses to enter into the host cells. SARS-CoV-2 hemagglutinin-esterase (HE) acts as the classical glycan-binding lectin and receptor-degrading enzyme. Most ß-CoVs recognize 9-O-acetyl-SAs but switched to recognizing the 4-O-acetyl-SA form during evolution of CoVs. Type I HE is specific for the 9-O-Ac-SAs and type II HE is specific for 4-O-Ac-SAs. The SA-binding shift proceeds through quasi-synchronous adaptations of the SA-recognition sites of the lectin and esterase domains. The molecular switching of HE acquisition of 4-O-acetyl binding from 9-O-acetyl SA binding is caused by protein-carbohydrate interaction (PCI) or lectin-carbohydrate interaction (LCI). The HE gene was transmitted to a ß-CoV lineage A progenitor by horizontal gene transfer from a 9-O-Ac-SA-specific HEF, as in influenza virus C/D. HE acquisition, and expansion takes place by cross-species transmission over HE evolution. This reflects viral evolutionary adaptation to host SA-containing glycans. Therefore, CoV HE receptor switching precedes virus evolution driven by the SA-glycan diversity of the hosts. The PCI or LCI stereochemistry potentiates the SA-ligand switch by a simple conformational shift of the lectin and esterase domains. Therefore, examination of new emerging viruses can lead to better understanding of virus evolution toward transitional host tropism. A clear example of HE gene transfer is found in the BCoV HE, which prefers 7,9-di-O-Ac-SAs, which is also known to be a target of the bovine torovirus HE. A more exciting case of such a switching event occurs in the murine CoVs, with the example of the ß-CoV lineage A type binding with two different subtypes of the typical 9-O-Ac-SA (type I) and the exclusive 4-O-Ac-SA (type II) attachment factors. The protein structure data for type II HE also imply the virus switching to binding 4-O acetyl SA from 9-O acetyl SA. Principles of the protein-glycan interaction and PCI stereochemistry potentiate the SA-ligand switch via simple conformational shifts of the lectin and esterase domains. Thus, our understanding of natural adaptation can be specified to how carbohydrate/glycan-recognizing proteins/molecules contribute to virus evolution toward host tropism. Under the current circumstances where reliable antiviral therapeutics or vaccination tools are lacking, several trials are underway to examine viral agents. As expected, structural and non-structural proteins of SARS-CoV-2 are currently being targeted for viral therapeutic designation and development. However, the modern global society needs SARS-CoV-2 preventive and therapeutic drugs for infected patients. In this review, the structure and sialobiology of SARS-CoV-2 are discussed in order to encourage and activate public research on glycan-specific interaction-based drug creation in the near future.


Subject(s)
Betacoronavirus/metabolism , Coronavirus Infections/virology , Evolution, Molecular , Host Microbial Interactions/physiology , Pneumonia, Viral/virology , Receptors, Virus/metabolism , Virus Internalization , Acetylesterase/metabolism , Animals , Betacoronavirus/genetics , Binding Sites , Cell Line , Coronavirus/genetics , Esterases , Gene Transfer, Horizontal , Glycosaminoglycans/metabolism , Hemagglutinins, Viral/genetics , Humans , Lectins/metabolism , Pandemics , Polysaccharides , Receptors, Virus/chemistry , Sialic Acids/chemistry , Sialic Acids/metabolism , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/physiology , Torovirus , Viral Fusion Proteins/genetics
5.
Aging (Albany NY) ; 12(12): 11263-11276, 2020 06 16.
Article in English | MEDLINE | ID: covidwho-601536

ABSTRACT

The outbreak of COVID-19 has now become a global pandemic that has severely impacted lives and economic stability. There is, however, no effective antiviral drug that can be used to treat COVID-19 to date. Built on the fact that SARS-CoV-2 initiates its entry into human cells by the receptor binding domain (RBD) of its spike protein binding to the angiotensin-converting enzyme 2 (hACE2), we extended a recently developed approach, EvoDesign, to design multiple peptide sequences that can competitively bind to the SARS-CoV-2 RBD to inhibit the virus from entering human cells. The protocol starts with the construction of a hybrid peptidic scaffold by linking two fragments grafted from the interface of the hACE2 protein (a.a. 22-44 and 351-357) with a linker glycine, which is followed by the redesign and refinement simulations of the peptide sequence to optimize its binding affinity to the interface of the SARS-CoV-2 RBD. The binding experiment analyses showed that the designed peptides exhibited a significantly stronger binding potency to hACE2 than the wild-type hACE2 receptor (with -53.35 vs. -46.46 EvoEF2 energy unit scores for the top designed and wild-type peptides, respectively). This study demonstrates a new avenue to utilize computationally designed peptide motifs to treat the COVID-19 disease by blocking the critical spike-RBD and hACE2 interactions.


Subject(s)
Coronavirus Infections/drug therapy , Peptides/chemical synthesis , Peptides/pharmacology , Peptidyl-Dipeptidase A/physiology , Pneumonia, Viral/drug therapy , Spike Glycoprotein, Coronavirus/physiology , Amino Acid Sequence , Antiviral Agents , Binding Sites , Drug Design , Evolution, Molecular , Humans , Models, Molecular , Pandemics , Protein Binding , Protein Conformation , Virus Internalization/drug effects
6.
Kaohsiung J Med Sci ; 36(6): 389-392, 2020 Jun.
Article in English | MEDLINE | ID: covidwho-505606

ABSTRACT

The spike glycoprotein on the virion surface docking onto the angiotensin-converting enzyme (ACE) 2 dimer is an essential step in the process of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in human cells-involves downregulation of ACE2 expression with systemic renin-angiotensin system (RAS) imbalance and promotion of multi-organ damage. In general, the RAS induces vasoconstriction, hypertension, inflammation, fibrosis, and proliferation via the ACE/Ang II/Ang II type 1 receptor (AT1R) axis and induces the opposite effects via the ACE2/Ang (1-7)/Mas axis. The RAS may be activated by chronic inflammation in hypertension, diabetes, obesity, and cancer. SARS-CoV-2 induces the ACE2 internalization and shedding, leading to the inactivation of the ACE2/Ang (1-7)/Mas axis. Therefore, we hypothesize that two hits to the RAS drives COVID-19 progression. In brief, the first hit originates from chronic inflammation activating the ACE/Ang II/AT1R axis, and the second originates from the COVID-19 infection inactivating the ACE2/Ang (1-7)/Mas axis. Moreover, the two hits to the RAS may be the primary reason for increased mortality in patients with COVID-19 who have comorbidities and may serve as a therapeutic target for COVID-19 treatment.


Subject(s)
Betacoronavirus , Coronavirus Infections/physiopathology , Pneumonia, Viral/physiopathology , Renin-Angiotensin System/physiology , Angiotensin II/physiology , Angiotensin Receptor Antagonists/therapeutic use , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Betacoronavirus/pathogenicity , Betacoronavirus/physiology , Comorbidity , Coronavirus Infections/drug therapy , Coronavirus Infections/epidemiology , Humans , Models, Biological , Pandemics , Peptidyl-Dipeptidase A/physiology , Pneumonia, Viral/drug therapy , Pneumonia, Viral/epidemiology , Receptor, Angiotensin, Type 1/physiology , Renin-Angiotensin System/drug effects , Spike Glycoprotein, Coronavirus/physiology
8.
J Clin Pathol ; 73(7): 366-369, 2020 Jul.
Article in English | MEDLINE | ID: covidwho-197863

ABSTRACT

The year 2020 has seen a major and sustained outbreak of a novel betacoronavirus (severe acute respiratory syndrome (SARS)-coronavirus (CoV)-2) infection that causes fever, severe respiratory illness and pneumonia, a disease called COVID-19. At the time of writing, the death toll was greater than 120 000 worldwide with more than 2 million documented infections. The genome of the CoV encodes a number of structural proteins that facilitate cellular entry and assembly of virions, of which the spike protein S appears to be critical for cellular entry. The spike protein guides the virus to attach to the host cell. The spike protein contains a receptor-binding domain (RBD), a fusion domain and a transmembrane domain. The RBD of spike protein S binds to Angiotensin Converting Enzyme 2 (ACE2) to initiate cellular entry. The spike protein of SARS-CoV-2 shows more than 90% amino acid similarity to the pangolin and bat CoVs and these also use ACE2 as a receptor. Binding of the spike protein to ACE2 exposes the cleavage sites to cellular proteases. Cleavage of the spike protein by transmembrane protease serine 2 and other cellular proteases initiates fusion and endocytosis. The spike protein contains an addition furin cleavage site that may allow it to be 'preactivated' and highly infectious after replication. The fundamental role of the spike protein in infectivity suggests that it is an important target for vaccine development, blocking therapy with antibodies and diagnostic antigen-based tests. This review briefly outlines the structure and function of the 2019 novel CoV/SARS-CoV-2 spike protein S.


Subject(s)
Betacoronavirus/genetics , Betacoronavirus/pathogenicity , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/physiology
9.
Circulation ; 141(23): 1903-1914, 2020 06 09.
Article in English | MEDLINE | ID: covidwho-66430

ABSTRACT

Coronavirus disease 2019 (COVID-19) is a rapidly expanding global pandemic caused by severe acute respiratory syndrome coronavirus 2, resulting in significant morbidity and mortality. A substantial minority of patients hospitalized develop an acute COVID-19 cardiovascular syndrome, which can manifest with a variety of clinical presentations but often presents as an acute cardiac injury with cardiomyopathy, ventricular arrhythmias, and hemodynamic instability in the absence of obstructive coronary artery disease. The cause of this injury is uncertain but is suspected to be related to myocarditis, microvascular injury, systemic cytokine-mediated injury, or stress-related cardiomyopathy. Although histologically unproven, severe acute respiratory syndrome coronavirus 2 has the potential to directly replicate within cardiomyocytes and pericytes, leading to viral myocarditis. Systemically elevated cytokines are also known to be cardiotoxic and have the potential to result in profound myocardial injury. Prior experience with severe acute respiratory syndrome coronavirus 1 has helped expedite the evaluation of several promising therapies, including antiviral agents, interleukin-6 inhibitors, and convalescent serum. Management of acute COVID-19 cardiovascular syndrome should involve a multidisciplinary team including intensive care specialists, infectious disease specialists, and cardiologists. Priorities for managing acute COVID-19 cardiovascular syndrome include balancing the goals of minimizing healthcare staff exposure for testing that will not change clinical management with early recognition of the syndrome at a time point at which intervention may be most effective. This article aims to review the best available data on acute COVID-19 cardiovascular syndrome epidemiology, pathogenesis, diagnosis, and treatment. From these data, we propose a surveillance, diagnostic, and management strategy that balances potential patient risks and healthcare staff exposure with improvement in meaningful clinical outcomes.


Subject(s)
Cardiovascular Diseases/etiology , Coronavirus Infections/complications , Pneumonia, Viral/complications , Antiviral Agents/therapeutic use , Arrhythmias, Cardiac/etiology , Arrhythmias, Cardiac/physiopathology , Arrhythmias, Cardiac/therapy , Biomarkers , Cardiovascular Diseases/diagnosis , Cardiovascular Diseases/physiopathology , Cardiovascular Diseases/therapy , Coronavirus Infections/drug therapy , Coronavirus Infections/therapy , Cytokine Release Syndrome/etiology , Cytokine Release Syndrome/physiopathology , Cytokine Release Syndrome/therapy , Cytokines/metabolism , Disease Management , Hemodynamics , Humans , Immunization, Passive , Immunoglobulins, Intravenous/therapeutic use , Infectious Disease Transmission, Patient-to-Professional/prevention & control , Interleukin-6/antagonists & inhibitors , Molecular Targeted Therapy , Myocarditis/diagnosis , Myocarditis/etiology , Myocarditis/physiopathology , Myocarditis/therapy , Organ Specificity , Pandemics , Peptidyl-Dipeptidase A/physiology , Pneumonia, Viral/drug therapy , Receptors, Virus/physiology , Risk Factors , Serine Endopeptidases/physiology , Severe Acute Respiratory Syndrome/therapy , Spike Glycoprotein, Coronavirus/physiology , Viral Tropism
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