SARS-CoV-2 proteins (version 2020.2) in the IUPHAR/BPS Guide to Pharmacology Database

CoronavirusesCoronaviruses are large, often spherical, enveloped, single-stranded positive-sense RNA viruses, ranging in size from 80-220 nm. Of the four structural proteins encoded in the viral genome, the RNA winds around the highly basic nucleocapsid (N) protein. The three other structural proteins, envelope (E), membrane (M) and spike (S), are transmembrane proteins. The E protein is a small (9-12 kDa) single transmembrane domain protein, which enables virus assembly with the M protein, a larger (23-35 kDa) 3TM protein. Coronaviruses are named for the crown-shaped appearance of the virus due to the large (120+ kDa) S spike 1TM glycoprotein, which forms extended homotrimers. The spike protein binds to the animal host cell by interacting with specific anchoring proteins, typically proteinases, such as angiotensin-converting enzyme 2 or aminopeptidase N. This binding facilitates viral entry into the cell and the release of the genome. Aside from the four structural proteins, the remainder of the genome encodes accessory or non-structural proteins and includes proteinases to cleave the two encoded polyproteins. The remainder of the genome encodes elements for viral replication, assembly and release, as well as proteins which manipulate the host's innate immune system.

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The SARS-CoV-2 Spike Glycoprotein as a Drug and Vaccine Target: Structural Insights into Its Complexes with ACE2 and Antibodies

Cells ◽

10.3390/cells9112343 ◽

2020 ◽

Vol 9 (11) ◽

pp. 2343

Author(s):

Anastassios C. Papageorgiou ◽

Imran Mohsin

Keyword(s):

Structural Biology ◽

Viral Entry ◽

Structural Information ◽

Current Knowledge ◽

Intervention Strategies ◽

Structural Proteins ◽

Envelope Membrane ◽

Spike Glycoprotein ◽

Angiotensin Converting Enzyme 2 ◽

Structural Insights

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the causative agent of the Coronavirus disease (COVID-19) pandemic, has so far resulted in more than 1.1 M deaths and 40 M cases worldwide with no confirmed remedy yet available. Since the first outbreak in Wuhan, China in December 2019, researchers across the globe have been in a race to develop therapies and vaccines against the disease. SARS-CoV-2, similar to other previously identified Coronaviridae family members, encodes several structural proteins, such as spike, envelope, membrane, and nucleocapsid, that are responsible for host penetration, binding, recycling, and pathogenesis. Structural biology has been a key player in understanding the viral infection mechanism and in developing intervention strategies against the new coronavirus. The spike glycoprotein has drawn considerable attention as a means to block viral entry owing to its interactions with the human angiotensin-converting enzyme 2 (ACE2), which acts as a receptor. Here, we review the current knowledge of SARS-CoV-2 and its interactions with ACE2 and antibodies. Structural information of SARS-CoV-2 spike glycoprotein and its complexes with ACE2 and antibodies can provide key input for the development of therapies and vaccines against the new coronavirus.

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Laboratory diagnosis of SARS-CoV-2: an Update for Clinicians

JMS SKIMS ◽

10.33883/jms.v23i2.766 ◽

2020 ◽

Vol 23 (2) ◽

Author(s):

Imtiyaz Ahmad Bhat ◽

Zafar Amin Shah ◽

Shariq R Masoodi

Keyword(s):

Viral Genome ◽

Gc Content ◽

Laboratory Diagnosis ◽

Variable Number ◽

Structural Proteins ◽

Angiotensin Converting Enzyme 2 ◽

Distinctive Features ◽

N Protein ◽

Conserved Genes ◽

Spike Proteins

SARS-CoV-2 belongs to the genera Beta coronavirus with a spherical or pleomorphic virus enveloped particles. The SARS-CoV-2 has sequence homology with severe acute respiratory syndrome-related coronaviruses (SARSr-CoV) and acts on ACE2 (Angiotensin Converting Enzyme 2) receptor by using its spike proteins. The latter are primed by the enzyme, TMPRSS2 protease to complete this process for its entry into the cells [1-3]. The SARSr-CoV has a single-stranded positive-sense ribonucleic acid (RNA) as a genomic material associated with a nucleoprotein within a capsid comprised of matrix proteins. The envelope bears a club-shaped glycoprotein projection containing haemagglutinin-esterase proteins (HE) also. The size of Coronaviruses genome is around (26.4-31.7Kb), which is one of the largest genomes in RNA known viruses and bears the GC content of approximately 32 to 43%. The viral genome contains distinctive features including a unique N terminal fragment within the spike proteins. The genome contains a variable number of ORF (6–11) between the various conserved genes (ORF1ab, spike, envelope, membrane and nucleocapsid [4]. Two third of the SARS-CoV-2 viral RNA is located in the ORF (ORF1a/b) and synthesise polypeptides pp1a and pp1a, and 16 non-structural proteins (NSP) are encoded by these ORFs, and the remaining accessory proteins are translated by other ORFs. The genome that encodes essential structural proteins which are important in the pathogenicity of SARS-CoV-2 like spike (S) glycoprotein, small envelope (E) protein, matrix (M) protein, and nucleocapsid (N) protein are translated by the rest of the viral genome [5].

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Evolutionary Insights into the Envelope Protein of SARS-CoV-2

10.20944/preprints202008.0665.v1 ◽

2020 ◽

Author(s):

M. Shaminur Rahman ◽

M. Nazmul Hoque ◽

M. Rafiul Islam ◽

Israt Islam ◽

Israt Dilruba Mishu ◽

...

Keyword(s):

Continuous Monitoring ◽

Transmembrane Domain ◽

Virus Assembly ◽

Structural Proteins ◽

Structural Protein ◽

Cysteine Motif ◽

E Protein ◽

Key Factor ◽

And Control ◽

Major Impediment

The ongoing mutations in the structural proteins of SARS-CoV-2 is the major impediment for prevention and control of the COVID-19 disease. The envelope (E) protein of SARS-CoV-2 is a structural protein existing in both monomeric and homopentameric forms, associated with a multitude of functions including virus assembly, replication, dissemination, release of virions, infection, pathogenesis, and immune response stimulation. In the present study, 81,818 high quality E protein sequences retrieving from the GISAID were subjected to mutational analyses. Our analysis revealed that only 0.012 % (982/81818) stains possessed amino acid (aa) substitutions in 63 sites of the genome while 58.77% mutations in the primary structure of nucleotides in 134 sites. We found the V25A mutation in the transmembrane domain which is a key factor for the homopentameric conformation of E protein. We also observed a triple cysteine motif harboring mutations (L39M, A41S, A41V, C43F, C43R, C43S, C44Y, N45R) which may hinder the binding of E protein with spike glycoprotein. These results therefore suggest the continuous monitoring of each structural protein of SARS-CoV-2 since the number of genome sequences from across the world are continuously increasing.

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Structure and Function of Major SARS-CoV-2 and SARS-CoV Proteins

Bioinformatics and Biology Insights ◽

10.1177/11779322211025876 ◽

2021 ◽

Vol 15 ◽

pp. 117793222110258

Author(s):

Ritesh Gorkhali ◽

Prashanna Koirala ◽

Sadikshya Rijal ◽

Ashmita Mainali ◽

Adesh Baral ◽

...

Keyword(s):

Genomic Organization ◽

Membrane Vesicles ◽

Structural Proteins ◽

Host Immune System ◽

Accessory Proteins ◽

Nonstructural Proteins ◽

N Protein ◽

Small Proteins ◽

Methylation Mark ◽

And Function

SARS-CoV-2 virus, the causative agent of COVID-19 pandemic, has a genomic organization consisting of 16 nonstructural proteins (nsps), 4 structural proteins, and 9 accessory proteins. Relative of SARS-CoV-2, SARS-CoV, has genomic organization, which is very similar. In this article, the function and structure of the proteins of SARS-CoV-2 and SARS-CoV are described in great detail. The nsps are expressed as a single or two polyproteins, which are then cleaved into individual proteins using two proteases of the virus, a chymotrypsin-like protease and a papain-like protease. The released proteins serve as centers of virus replication and transcription. Some of these nsps modulate the host’s translation and immune systems, while others help the virus evade the host immune system. Some of the nsps help form replication-transcription complex at double-membrane vesicles. Others, including one RNA-dependent RNA polymerase and one exonuclease, help in the polymerization of newly synthesized RNA of the virus and help minimize the mutation rate by proofreading. After synthesis of the viral RNA, it gets capped. The capping consists of adding GMP and a methylation mark, called cap 0 and additionally adding a methyl group to the terminal ribose called cap1. Capping is accomplished with the help of a helicase, which also helps remove a phosphate, two methyltransferases, and a scaffolding factor. Among the structural proteins, S protein forms the receptor of the virus, which latches on the angiotensin-converting enzyme 2 receptor of the host and N protein binds and protects the genomic RNA of the virus. The accessory proteins found in these viruses are small proteins with immune modulatory roles. Besides functions of these proteins, solved X-ray and cryogenic electron microscopy structures related to the function of the proteins along with comparisons to other coronavirus homologs have been described in the article. Finally, the rate of mutation of SARS-CoV-2 residues of the proteome during the 2020 pandemic has been described. Some proteins are mutated more often than other proteins, but the significance of these mutation rates is not fully understood.

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Human Immunodeficiency Viruses Pseudotyped with SARS-CoV-2 Spike Proteins Infect a Broad Spectrum of Human Cell Lines through Multiple Entry Mechanisms

Viruses ◽

10.3390/v13060953 ◽

2021 ◽

Vol 13 (6) ◽

pp. 953

Author(s):

Chuan Xu ◽

Annie Wang ◽

Ke Geng ◽

William Honnen ◽

Xuening Wang ◽

...

Keyword(s):

Cell Lines ◽

Viral Entry ◽

Broad Spectrum ◽

A549 Cells ◽

Cell Types ◽

Pseudotyped Virus ◽

Angiotensin Converting Enzyme 2 ◽

Human Immunodeficiency Viruses ◽

Tyrosine Protein Kinase ◽

Overexpressing Cell

Severe acute respiratory syndrome-related coronavirus (SARS-CoV-2), the causative agent of coronavirus disease 19 (COVID-19), enters cells through attachment to the human angiotensin converting enzyme 2 (hACE2) via the receptor-binding domain (RBD) in the surface/spike (S) protein. Several pseudotyped viruses expressing SARS-CoV-2 S proteins are available, but many of these can only infect hACE2-overexpressing cell lines. Here, we report the use of a simple, two-plasmid, pseudotyped virus system comprising a SARS-CoV-2 spike-expressing plasmid and an HIV vector with or without vpr to investigate the SARS-CoV-2 entry event in various cell lines. When an HIV vector without vpr was used, pseudotyped SARS-CoV-2 viruses produced in the presence of fetal bovine serum (FBS) were able to infect only engineered hACE2-overexpressing cell lines, whereas viruses produced under serum-free conditions were able to infect a broader range of cells, including cells without hACE2 overexpression. When an HIV vector containing vpr was used, pseudotyped viruses were able to infect a broad spectrum of cell types regardless of whether viruses were produced in the presence or absence of FBS. Infection sensitivities of various cell types did not correlate with mRNA abundance of hACE2, TMPRSS2, or TMPRSS4. Pseudotyped SARS-CoV-2 viruses and replication-competent SARS-CoV-2 virus were equally sensitive to neutralization by an anti-spike RBD antibody in cells with high abundance of hACE2. However, the anti-spike RBD antibody did not block pseudotyped viral entry into cell lines with low abundance of hACE2. We further found that CD147 was involved in viral entry in A549 cells with low abundance of hACE2. Thus, our assay is useful for drug and antibody screening as well as for investigating cellular receptors, including hACE2, CD147, and tyrosine-protein kinase receptor UFO (AXL), for the SARS-CoV-2 entry event in various cell lines.

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De-Coding the Contributions of the Viral RNAs to Alphaviral Pathogenesis

Pathogens ◽

10.3390/pathogens10060771 ◽

2021 ◽

Vol 10 (6) ◽

pp. 771

Author(s):

Autumn T. LaPointe ◽

Kevin J. Sokoloski

Keyword(s):

Host Response ◽

Severe Disease ◽

Review Article ◽

Structural Proteins ◽

Virulence Determinants ◽

Healthy Individuals ◽

Viral Rnas ◽

Positive Sense ◽

Identification And Characterization

Alphaviruses are positive-sense RNA arboviruses that are capable of causing severe disease in otherwise healthy individuals. There are many aspects of viral infection that determine pathogenesis and major efforts regarding the identification and characterization of virulence determinants have largely focused on the roles of the nonstructural and structural proteins. Nonetheless, the viral RNAs of the alphaviruses themselves play important roles in regard to virulence and pathogenesis. In particular, many sequences and secondary structures within the viral RNAs play an important part in the development of disease and may be considered important determinants of virulence. In this review article, we summarize the known RNA-based virulence traits and host:RNA interactions that influence alphaviral pathogenesis for each of the viral RNA species produced during infection. Overall, the viral RNAs produced during infection are important contributors to alphaviral pathogenesis and more research is needed to fully understand how each RNA species impacts the host response to infection as well as the development of disease.

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Neurological and Neuropsychological Changes Associated with SARS-CoV-2 Infection: New Observations, New Mechanisms

The Neuroscientist ◽

10.1177/1073858420984106 ◽

2021 ◽

pp. 107385842098410

Author(s):

Muhammad Ali Haidar ◽

Hussam Jourdi ◽

Zeinab Haj Hassan ◽

Ohanes Ashekyan ◽

Manal Fardoun ◽

...

Keyword(s):

Viral Entry ◽

Health Workers ◽

The Elderly ◽

Circumventricular Organs ◽

Depression And Anxiety ◽

Virus Surface ◽

Angiotensin Converting Enzyme 2 ◽

Neuropsychological Changes ◽

High Risk Populations ◽

The Central Nervous System

SARS-CoV-2 infects cells through angiotensin-converting enzyme 2 (ACE2), a ubiquitous receptor that interacts with the virus’ surface S glycoprotein. Recent reports show that the virus affects the central nervous system (CNS) with symptoms and complications that include dizziness, altered consciousness, encephalitis, and even stroke. These can immerge as indirect immune effects due to increased cytokine production or via direct viral entry into brain tissue. The latter is possible through neuronal access via the olfactory bulb, hematogenous access through immune cells or directly across the blood-brain barrier (BBB), and through the brain’s circumventricular organs characterized by their extensive and highly permeable capillaries. Last, the COVID-19 pandemic increases stress, depression, and anxiety within infected individuals, those in isolation, and high-risk populations like children, the elderly, and health workers. This review surveys the recent updates of CNS manifestations post SARS-CoV-2 infection along with possible mechanisms that lead to them.

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Hepatitis C Virus Infection Is Inhibited by a Noncanonical Antiviral Signaling Pathway Targeted by NS3-NS4A

Journal of Virology ◽

10.1128/jvi.00725-19 ◽

2019 ◽

Vol 93 (23) ◽

Cited By ~ 9

Author(s):

Christine Vazquez ◽

Chin Yee Tan ◽

Stacy M. Horner

Keyword(s):

Hepatitis C ◽

Viral Replication ◽

Signaling Pathway ◽

Transmembrane Domain ◽

Innate Immune ◽

Hcv Infection ◽

Interferon Induction ◽

Innate Immune Signaling ◽

Huh7 Cells ◽

Irf3 Activation

ABSTRACT The hepatitis C virus (HCV) NS3-NS4A protease complex is required for viral replication and is the major viral innate immune evasion factor. NS3-NS4A evades antiviral innate immunity by inactivating several proteins, including MAVS, the signaling adaptor for RIG-I and MDA5, and Riplet, an E3 ubiquitin ligase that activates RIG-I. Here, we identified a Tyr-16-Phe (Y16F) change in the NS4A transmembrane domain that prevents NS3-NS4A targeting of Riplet but not MAVS. This Y16F substitution reduces HCV replication in Huh7 cells, but not in Huh-7.5 cells, known to lack RIG-I signaling. Surprisingly, deletion of RIG-I in Huh7 cells did not restore Y16F viral replication. Rather, we found that Huh-7.5 cells lack Riplet expression and that the addition of Riplet to these cells reduced HCV Y16F replication, whereas the addition of Riplet lacking the RING domain restored HCV Y16F replication. In addition, TBK1 inhibition or IRF3 deletion in Huh7 cells was sufficient to restore HCV Y16F replication, and the Y16F protease lacked the ability to prevent IRF3 activation or interferon induction. Taken together, these data reveal that the NS4A Y16 residue regulates a noncanonical Riplet-TBK1-IRF3-dependent, but RIG-I-MAVS-independent, signaling pathway that limits HCV infection. IMPORTANCE The HCV NS3-NS4A protease complex facilitates viral replication by cleaving and inactivating the antiviral innate immune signaling proteins MAVS and Riplet, which are essential for RIG-I activation. NS3-NS4A therefore prevents IRF3 activation and interferon induction during HCV infection. Here, we uncover an amino acid residue within the NS4A transmembrane domain that is essential for inactivation of Riplet but does not affect MAVS cleavage by NS3-NS4A. Our study reveals that Riplet is involved in a RIG-I- and MAVS-independent signaling pathway that activates IRF3 and that this pathway is normally inactivated by NS3-NS4A during HCV infection. Our study selectively uncouples these distinct regulatory mechanisms within NS3-NS4A and defines a new role for Riplet in the antiviral response to HCV. Since Riplet is known to be inhibited by other RNA viruses, such as such influenza A virus, this innate immune signaling pathway may also be important in controlling other RNA virus infections.

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Innate Immune DNA Sensing of Flaviviruses

Viruses ◽

10.3390/v12090979 ◽

2020 ◽

Vol 12 (9) ◽

pp. 979

Author(s):

Tongtong Zhu ◽

Ana Fernandez-Sesma

Keyword(s):

Innate Immune System ◽

Rna Viruses ◽

Innate Immune ◽

Host Factors ◽

Dna Sensing ◽

Antiviral Responses ◽

Sensory Pathways ◽

Sensing System ◽

Positive Sense ◽

Successful Replication

Flaviviruses are arthropod-borne RNA viruses that have been used extensively to study host antiviral responses. Often selected just to represent standard single-stranded positive-sense RNA viruses in early studies, the Flavivirus genus over time has taught us how truly unique it is in its remarkable ability to target not just the RNA sensory pathways but also the cytosolic DNA sensing system for its successful replication inside the host cell. This review summarizes the main developments on the unexpected antagonistic strategies utilized by different flaviviruses, with RNA genomes, against the host cyclic GAMP synthase (cGAS)/stimulator of interferon genes (STING) cytosolic DNA sensing pathway in mammalian systems. On the basis of the recent advancements on this topic, we hypothesize that the mechanisms of viral sensing and innate immunity are much more fluid than what we had anticipated, and both viral and host factors will continue to be found as important factors contributing to the host innate immune system in the future.

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