scholarly journals Role of Structural and Non-Structural Proteins and Therapeutic Targets of SARS-CoV-2 for COVID-19

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 821
Author(s):  
Rohitash Yadav ◽  
Jitendra Kumar Chaudhary ◽  
Neeraj Jain ◽  
Pankaj Kumar Chaudhary ◽  
Supriya Khanra ◽  
...  
Keyword(s):  
Host Cell ◽  
Protein S ◽  
Structural Similarity ◽  
Cell Receptor ◽  
Molecular Assembly ◽  
The Body ◽  
Spike Protein ◽  
Structural Proteins ◽  
Structural Protein ◽  
Novel Coronavirus

Coronavirus belongs to the family of Coronaviridae, comprising single-stranded, positive-sense RNA genome (+ ssRNA) of around 26 to 32 kilobases, and has been known to cause infection to a myriad of mammalian hosts, such as humans, cats, bats, civets, dogs, and camels with varied consequences in terms of death and debilitation. Strikingly, novel coronavirus (2019-nCoV), later renamed as severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), and found to be the causative agent of coronavirus disease-19 (COVID-19), shows 88% of sequence identity with bat-SL-CoVZC45 and bat-SL-CoVZXC21, 79% with SARS-CoV and 50% with MERS-CoV, respectively. Despite key amino acid residual variability, there is an incredible structural similarity between the receptor binding domain (RBD) of spike protein (S) of SARS-CoV-2 and SARS-CoV. During infection, spike protein of SARS-CoV-2 compared to SARS-CoV displays 10–20 times greater affinity for its cognate host cell receptor, angiotensin-converting enzyme 2 (ACE2), leading proteolytic cleavage of S protein by transmembrane protease serine 2 (TMPRSS2). Following cellular entry, the ORF-1a and ORF-1ab, located downstream to 5′ end of + ssRNA genome, undergo translation, thereby forming two large polyproteins, pp1a and pp1ab. These polyproteins, following protease-induced cleavage and molecular assembly, form functional viral RNA polymerase, also referred to as replicase. Thereafter, uninterrupted orchestrated replication-transcription molecular events lead to the synthesis of multiple nested sets of subgenomic mRNAs (sgRNAs), which are finally translated to several structural and accessory proteins participating in structure formation and various molecular functions of virus, respectively. These multiple structural proteins assemble and encapsulate genomic RNA (gRNA), resulting in numerous viral progenies, which eventually exit the host cell, and spread infection to rest of the body. In this review, we primarily focus on genomic organization, structural and non-structural protein components, and potential prospective molecular targets for development of therapeutic drugs, convalescent plasm therapy, and a myriad of potential vaccines to tackle SARS-CoV-2 infection.

scholarly journals Dynamical asymmetry exposes 2019-nCoV prefusion spike

2020 ◽  
Author(s):  
Susmita Roy
Keyword(s):  
Host Cell ◽  
Cell Receptor ◽  
Spike Protein ◽  
The Novel ◽  
Structural Topology ◽  
Dynamic Simulations ◽  
Asymmetric Structures ◽  
Host Cell Receptor ◽  
Model Hamiltonian ◽  
Novel Coronavirus

AbstractThe novel coronavirus (2019-nCoV) spike protein is a smart molecular machine that instigates the entry of coronavirus to the host cell causing the COVID-19 pandemic. In this study, a structural-topology based model Hamiltonian of C3 symmetric trimeric spike is developed to explore its complete conformational energy landscape using molecular dynamic simulations. The study finds 2019-nCoV to adopt a unique strategy by undertaking a dynamic conformational asymmetry induced by a few unique inter-chain interactions. This results in two prevalent asymmetric structures of spike where one or two spike heads lifted up undergoing a dynamic transition likely to enhance rapid recognition of the host-cell receptor turning on its high-infectivity. The crucial interactions identified in this study are anticipated to potentially affect the efficacy of therapeutic targets.One Sentence SummaryInter-chain-interaction driven rapid symmetry breaking strategy adopted by the prefusion trimeric spike protein likely to make 2019-nCoV highly infective.

scholarly journals NOVEL CORONAVIRUS (SARS-COV-2): MOLECULAR BIOLOGY, PATHOGENESIS, PATHOBIOLOGY AND ADVANCES IN TREATMENT OF COVID-19 PATIENTS– AN UPDATE

2020 ◽  
Vol 8 (6) ◽  
pp. 683-708
Author(s):  
Sonam Tripathi ◽  
◽  
Megha Katare Pandey ◽  
Yashpal Singh Malik ◽  
Muhammad Bilal ◽  
...  
Keyword(s):  
The Body ◽  
Control Measures ◽  
Structural Proteins ◽  
Receptor Protein ◽  
Whole Genome ◽  
Structural Protein ◽  
Coding Region ◽  
Sequence Alignments ◽  
Novel Coronavirus ◽  
Bat Coronavirus

The novel coronavirus (CoV), earlier named 2019-nCoV, and later as severe acute respiratory syndrome coronavirus - 2 (SARS-CoV-2) has now created havoc and panic across the globe by its severe ongoing pandemic. This virus has to date as of 23rd November 2020, killed nearly 1.4 million persons out of more than 59 million confirmed positive cases, while spreading rapidly in more than 215 countries and territories. Taxonomically, SARS-CoV-2 has been characterized in genus Betacoronavirus, which contains non-segmented positive-sense, single-stranded (ss) RNA genome of 30 kb. The first two open reading frames (ORFs), ORF1a and ORF1b, of SARS-CoV-2, encode 16 non-structural proteins (nsp1-nsp16), whereas other ORFs encodes four main structural proteins (sp) [spike (s) by ORF2, envelope (E) by ORF4, membrane (M) by ORF5, nucleoprotein (N) by ORF9], and accessory proteins essential for the virus fitness, pathogenesis and host immunity evasion. Sequence alignments of SARS-CoV-2 with genomes of various coronaviruses showed 58% identity in the non-structural protein (nsp)-coding region, 43% with the structural protein (sp)-coding region and 54% with the whole genome. The full-length genome sequence of the 2019-nCoV sample showed only up to 79.60% similarity with SARS CoV, but up to 96% similarity with bat coronavirus (bat coronavirus RaTG13). This gives strong evidence that 2019-nCoV has originated from the bat. The genomic and evolutionary evidence of another coronavirus species from pangolins also show higher similarity to SARS-CoV at the whole-genome level. Apart from RaTG13, Pangolin-CoV is the most closely related CoV to SARS-CoV-2. During infection, the viral S protein interacts with the receptor protein of the human cell membrane, known as angiotensin-converting enzyme II (ACE2). Presently, SARS-CoV-2 vaccines and drugs are not available, for which researchers are trying hard to develop to tackle rising tide of COVID-19- pandemic. Early diagnosis, contact tracing, strict prevention and control measures, biosecurity, personal biosafety, disinfection and sanitization practices, social distancing are aiding in prevention with SARS-CoV-2 infection. Boosting immunity by intaking the balanced and nutritious food, nutraceuticals, herbs, and following physical exercises along with avoiding stress conditions enhance the fighting power of the body against SARS-CoV-2 infection and limiting the severity of COVID-19. The present article describes salient knowledge on SARS-CoV-2 structure, genomic organization, pathogenesis, pathobiology, and advances and progress being made to treat COVID-19 patients.

scholarly journals An Overview of Spike Surface Glycoprotein in Severe Acute Respiratory Syndrome–Coronavirus

2021 ◽  
Vol 8 ◽  
Author(s):  
Muthu Kumaradoss Kathiravan ◽  
Srimathi Radhakrishnan ◽  
Vigneshwaran Namasivayam ◽  
Senthilkumar Palaniappan
Keyword(s):  
Host Cell ◽  
Viral Infections ◽  
Cell Receptor ◽  
Surface Glycoprotein ◽  
Structural Proteins ◽  
Viral Fusion ◽  
Single Chain ◽  
S Protein ◽  
Protease Enzyme ◽  
Novel Coronavirus

The novel coronavirus originated in December 2019 in Hubei, China. This contagious disease named as COVID-19 resulted in a massive expansion within 6 months by spreading to more than 213 countries. Despite the availability of antiviral drugs for the treatment of various viral infections, it was concluded by the WHO that there is no medicine to treat novel CoV, SARS-CoV-2. It has been confirmed that SARS-COV-2 is the most highly virulent human coronavirus and occupies the third position following SARS and MERS with the highest mortality rate. The genetic assembly of SARS-CoV-2 is segmented into structural and non-structural proteins, of which two-thirds of the viral genome encodes non-structural proteins and the remaining genome encodes structural proteins. The most predominant structural proteins that make up SARS-CoV-2 include spike surface glycoproteins (S), membrane proteins (M), envelope proteins (E), and nucleocapsid proteins (N). This review will focus on one of the four major structural proteins in the CoV assembly, the spike, which is involved in host cell recognition and the fusion process. The monomer disintegrates into S1 and S2 subunits with the S1 domain necessitating binding of the virus to its host cell receptor and the S2 domain mediating the viral fusion. On viral infection by the host, the S protein is further cleaved by the protease enzyme to two major subdomains S1/S2. Spike is proven to be an interesting target for developing vaccines and in particular, the RBD-single chain dimer has shown initial success. The availability of small molecules and peptidic inhibitors for host cell receptors is briefly discussed. The development of new molecules and therapeutic druggable targets for SARS-CoV-2 is of global importance. Attacking the virus employing multiple targets and strategies is the best way to inhibit the virus. This article will appeal to researchers in understanding the structural and biological aspects of the S protein in the field of drug design and discovery.

scholarly journals Hepatitis C Virus E2—Host Cell Receptor, HSPA5, Binding Site Prediction

2020 ◽  
Author(s):  
Alaa Elgohary ◽  
Abdo Elfiky
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Host Cell ◽  
Cyclic Peptide ◽  
Causative Factor ◽  
Cell Receptor ◽  
Binding Mode ◽  
Structural Protein ◽  
The Unfolded Protein Response

Hepatitis C Virus (HCV) is the main causative factor for liver cirrhosis and the development of liver cancer, with a confirmed ~ 180 million infections worldwide. E2 is an HCV structural protein responsible for virus entry to the host cell. Heat Shock Protein A5 (HSPA5), also termed BiP and GRP78, is the master regulator of the unfolded protein response mechanism, where it mainly localizes in the lumen of the Endoplasmic Reticulum (ER) in normal conditions. Under the stress of HCV infection or carcinogenesis, HSPA5 is upregulated. Consequently, HSPA5 escapes the ER retention localization and translocates to the cytoplasm and plasma membrane. Pep42, a cyclic peptide that was reported to target explicitly cell-surface HSPA5 in vivo. Owing to the high sequence and structural conservation between the C554-C566 region of HCV E2 and the Pep42, then we propose that the HCV E2 C554-C566 region could be the recognition site. The motivation of this work is to predict the possible binding mode between HCV E2 and HSPA5 by implementing molecular docking to test such proposed binding. Docking results reveal the high potent binding of the HCV E2 C554-C566 region to HSPA5 substrate-binding domain β (SBDβ). Moreover, the full-length HCV E2 also exhibits high binding potency to HSPA5 SBDβ. Defining the binding mode between HCV E2 and HSPA5 is of significance, so one can interfere with such binding and reducing the viral infection.

scholarly journals Genetic Manipulation of Arterivirus Alternative mRNA Leader-Body Junction Sites Reveals Tight Regulation of Structural Protein Expression

2000 ◽  
Vol 74 (24) ◽  
pp. 11642-11653 ◽  
Author(s):  
Alexander O. Pasternak ◽  
Alexander P. Gultyaev ◽  
Willy J. M. Spaan ◽  
Eric J. Snijder
Keyword(s):  
Rna Structure ◽  
The Body ◽  
Equine Arteritis Virus ◽  
Site Directed Mutagenesis ◽  
Structural Proteins ◽  
Limiting Factors ◽  
Progeny Virus ◽  
Structural Protein ◽  
Sequence Element ◽  
Conserved Sequence

ABSTRACT To express its structural proteins, the arterivirus Equine arteritis virus (EAV) produces a nested set of six subgenomic (sg) RNA species. These RNA molecules are generated by a mechanism of discontinuous transcription, during which a common leader sequence, representing the 5′ end of the genomic RNA, is attached to the bodies of the sg RNAs. The connection between the leader and body parts of an mRNA is formed by a short, conserved sequence element termed the transcription-regulating sequence (TRS), which is present at the 3′ end of the leader as well as upstream of each of the structural protein genes. With the exception of RNA3, only one body TRS was previously assumed to be used to join the leader and body of each EAV sg RNA. Here we show that for the synthesis of two other sg RNAs, RNA4 and RNA5, alternative leader-body junction sites that differ substantially in transcriptional activity are used. By site-directed mutagenesis of an EAV infectious cDNA clone, the alternative TRSs used to generate RNA3, -4, and -5 were inactivated, which strongly influenced the corresponding RNA levels and the production of infectious progeny virus. The relative amounts of RNA produced from alternative TRSs differed significantly and corresponded to the relative infectivities of the virus mutants. This strongly suggested that the structural proteins that are expressed from these RNAs are limiting factors during the viral life cycle and that the discontinuous step in sg RNA synthesis is crucial for the regulation of their expression. On the basis of a theoretical analysis of the predicted RNA structure of the 3′ end of the EAV genome, we propose that the local secondary RNA structure of the body TRS regions is an important factor in the regulation of the discontinuous step in EAV sg mRNA synthesis.

scholarly journals Immunological and mutational analysis of SARS-CoV-2 structural proteins from Asian countries

2021 ◽  
Vol 8 (5) ◽  
pp. 4367-4390
Author(s):  
Deepak Kumar Jha ◽  
Niti Yashvardhini ◽  
Amit Kumar
Keyword(s):  
Envelope Protein ◽  
Mutational Analysis ◽  
Viral Evolution ◽  
Point Mutations ◽  
High Rate ◽  
World Health ◽  
Structural Proteins ◽  
Structural Protein ◽  
Health Crisis ◽  
Novel Coronavirus

Introduction: The emergence of a novel coronavirus, SARS-CoV-2, an etiolating agent of coronavirus disease (COVID-19), has become a pandemic of global concern. Considering the huge number of morbidity and mortality worldwide, the World Health Organization, on 11th March 2020, has announced an unprecedented public health crisis. This virus is a member of plus sense RNA viruses that can show a high rate of mutations. The ongoing multiple mutations in the structural proteins of coronavirus drive viral evolution, enabling them to evade the host immunity and rapidly acquire drug resistance against COVID-19. In the present study, we focused mainly on the prevalence of mutations in the four types of structural proteins like S (spike), E (envelope), M (membrane), and N (nucleocapsid) that are required for the assembly of a complete virion particle. Further, we estimated the antigenicity and allergenicity of these structural proteins to design and develop a potentially good candidate vaccine against SARS-CoV-2. Methods: In the present in silico study, envelope protein was found highly antigenic followed by nucleocapsid, membrane, and spike protein of SARS-CoV-2. Results: Consequently, in this study, we detected 987 mutations from 729 sequences of Asia in October 2020 and compared them with China's 1st Wuhan isolate sequence as a reference. Spike showed the highest mutations with 807 point mutations among the four structural proteins, followed by nucleocapsid with 151 mutations, while envelope showed 19 and membrane only 10 point mutations. Conclusion: Taken together, our study revealed, variation occurring in the structural protein of SARS-CoV-2 might be altering their structure and functions, and envelope protein appears to be a promising vaccine candidate to curb coronavirus infections.

scholarly journals TOPICS ON MOLECULAR CHARACTERIZATION OF THE NOVEL CORONAVIRUS SPECIES SARS-CoV-2

2020 ◽  
Vol 7 (1) ◽  
pp. 043-048
Author(s):  
Bruna Letícia Domingues Molinari
Keyword(s):  
New York ◽  
New York City ◽  
Viral Genome ◽  
Protein S ◽  
Public Health Issue ◽  
Controlled Environment ◽  
The Novel ◽  
Structural Protein ◽  
Novel Coronavirus

Since December 2019, a new coronavirus species named SARS-CoV-2 has been related to thousands of cases of severe respiratory disease worldwide, been considered a public health issue. Molecular comparisons between isolates from SARS-CoV-2 and other coronavirus species showed identity levels around 79% with the human strain SARS-CoV. However, sequence homology analysis showed that the most closely related known viruses with SARS-CoV-2 are two bat SL-CoVs (~89%), revealing similar evolutionary relationships and evidences that bats can act as reservoirs of SARS-CoV-2. Despite this, viral RNA has been detected in two dogs and two cats belonging to SARS-CoV-2 infected owners, in Hong Kong and Belgium, and in one tiger maintained at the Bronx Zoo in New York City. Additionally, ferrets and cats are found to be highly susceptible to SARS-CoV-2 in an experiment carried out in a controlled environment. However, there is no evidence of these animals acting as reservoirs of the virus. Despite the high genetic identity found among SARS-CoV-2 strains, mutations have been identified, mostly in the structural protein S gene, but until now, there is no enough evidence to relate specific mutation in the viral genome to a higher number of infected patients or death.

scholarly journals Host-cell recognition through GRP78 is enhanced in the new UK variant of SARS-CoV-2, in silico 

2021 ◽  
Author(s):  
Abdo A Elfiky ◽  
Ibrahim M Ibrahim
Keyword(s):  
Host Cell ◽  
Cell Receptor ◽  
Spike Protein ◽  
Cell Recognition ◽  
Receptor Binding Domain ◽  
Host Cell Receptor ◽  
Mutant Variant ◽  
New Variant ◽  
The Uk ◽  
Host Cell Recognition

Abstract New SARS-CoV-2 variant VUI 202012/01 started in the UK and currently spreading in Europe and Australia during the last few days. The new variant bears about nine mutations in the spike protein (Δ69-70, Δ145, N501Y, A570D, D614G, P681H, T716I, S982A, and D1118H). The N501Y lies in the receptor-binding domain (RBD) of the spike and interacts with the host-cell receptor ACE2 responsible for viral recognition and entry. We tried to simulate the system of ACE2-SARS-CoV-2 spike RBD in the wildtype and mutated isoform of the RBD (N501Y). Additionally, the GRP78 association with the ACE2-SARS-CoV-2 spike RBD is modeled at the presence of this mutant variant of the viral spike.

scholarly journals Elucidating Interactions Between SARS-CoV-2 Trimeric Spike Protein and ACE2 Using Homology Modeling and Molecular Dynamics Simulations

2021 ◽  
Vol 8 ◽  
Author(s):  
Sugunadevi Sakkiah ◽  
Wenjing Guo ◽  
Bohu Pan ◽  
Zuowei Ji ◽  
Gokhan Yavas ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Homology Modeling ◽  
Molecular Dynamics Simulations ◽  
Host Cell ◽  
Tertiary Structure ◽  
Cell Receptor ◽  
Host Cells ◽  
Spike Protein ◽  
Receptor Protein ◽  
Dynamics Simulations

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19). As of October 21, 2020, more than 41.4 million confirmed cases and 1.1 million deaths have been reported. Thus, it is immensely important to develop drugs and vaccines to combat COVID-19. The spike protein present on the outer surface of the virion plays a major role in viral infection by binding to receptor proteins present on the outer membrane of host cells, triggering membrane fusion and internalization, which enables release of viral ssRNA into the host cell. Understanding the interactions between the SARS-CoV-2 trimeric spike protein and its host cell receptor protein, angiotensin converting enzyme 2 (ACE2), is important for developing drugs and vaccines to prevent and treat COVID-19. Several crystal structures of partial and mutant SARS-CoV-2 spike proteins have been reported; however, an atomistic structure of the wild-type SARS-CoV-2 trimeric spike protein complexed with ACE2 is not yet available. Therefore, in our study, homology modeling was used to build the trimeric form of the spike protein complexed with human ACE2, followed by all-atom molecular dynamics simulations to elucidate interactions at the interface between the spike protein and ACE2. Molecular Mechanics Poisson-Boltzmann Surface Area (MMPBSA) and in silico alanine scanning were employed to characterize the interacting residues at the interface. Twenty interacting residues in the spike protein were identified that are likely to be responsible for tightly binding to ACE2, of which five residues (Val445, Thr478, Gly485, Phe490, and Ser494) were not reported in the crystal structure of the truncated spike protein receptor binding domain (RBD) complexed with ACE2. These data indicate that the interactions between ACE2 and the tertiary structure of the full-length spike protein trimer are different from those between ACE2 and the truncated monomer of the spike protein RBD. These findings could facilitate the development of drugs and vaccines to prevent SARS-CoV-2 infection and combat COVID-19.

scholarly journals Gene of the month: the 2019-nCoV/SARS-CoV-2 novel coronavirus spike protein

2020 ◽  
Vol 73 (7) ◽  
pp. 366-369 ◽  
Author(s):  
Tahir S Pillay
Keyword(s):  
Receptor Binding ◽  
Transmembrane Domain ◽  
Vaccine Development ◽  
Protein S ◽  
Respiratory Illness ◽  
Spike Protein ◽  
Furin Cleavage ◽  
Furin Cleavage Site ◽  
Cellular Entry ◽  
Novel Coronavirus

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.

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