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1.
Front Immunol ; 12: 767347, 2021.
Article in English | MEDLINE | ID: covidwho-1528823

ABSTRACT

Infection with SARS-CoV-2 triggers the simultaneous activation of innate inflammatory pathways including the complement system and the kallikrein-kinin system (KKS) generating in the process potent vasoactive peptides that contribute to severe acute respiratory syndrome (SARS) and multi-organ failure. The genome of SARS-CoV-2 encodes four major structural proteins - the spike (S) protein, nucleocapsid (N) protein, membrane (M) protein, and the envelope (E) protein. However, the role of these proteins in either binding to or activation of the complement system and/or the KKS is still incompletely understood. In these studies, we used: solid phase ELISA, hemolytic assay and surface plasmon resonance (SPR) techniques to examine if recombinant proteins corresponding to S1, N, M and E: (a) bind to C1q, gC1qR, FXII and high molecular weight kininogen (HK), and (b) activate complement and/or the KKS. Our data show that the viral proteins: (a) bind C1q and activate the classical pathway of complement, (b) bind FXII and HK, and activate the KKS in normal human plasma to generate bradykinin and (c) bind to gC1qR, the receptor for the globular heads of C1q (gC1q) which in turn could serve as a platform for the activation of both the complement system and KKS. Collectively, our data indicate that the SARS-CoV-2 viral particle can independently activate major innate inflammatory pathways for maximal damage and efficiency. Therefore, if efficient therapeutic modalities for the treatment of COVID-19 are to be designed, a strategy that includes blockade of the four major structural proteins may provide the best option.


Subject(s)
Antigens, Viral/immunology , COVID-19/immunology , Complement System Proteins/immunology , Kallikrein-Kinin System , SARS-CoV-2/immunology , Viral Structural Proteins/immunology , Carrier Proteins/genetics , Carrier Proteins/immunology , Hemolysis , Humans , Mitochondrial Proteins/genetics , Mitochondrial Proteins/immunology , Recombinant Proteins/immunology , Viral Structural Proteins/genetics
2.
Infect Genet Evol ; 97: 105154, 2022 01.
Article in English | MEDLINE | ID: covidwho-1521408

ABSTRACT

The pandemic of COVID-19 has been haunting us for almost the past two years. Although, the vaccination drive is in full swing throughout the world, different mutations of the SARS-CoV-2 virus are making it very difficult to put an end to the pandemic. The second wave in India, one of the worst sufferers of this pandemic, can be mainly attributed to the Delta variant i.e. B.1.617.2. Thus, it is very important to analyse and understand the mutational trajectory of SARS-CoV-2 through the study of the 26 virus proteins. In this regard, more than 17,000 protein sequences of Indian SARS-CoV-2 genomes are analysed using entropy-based approach in order to find the monthly mutational trajectory. Furthermore, Hellinger distance is also used to show the difference of the mutation events between the consecutive months for each of the 26 SARS-CoV-2 protein. The results show that the mutation rates and the mutation events of the viral proteins though changing in the initial months, start stabilizing later on for mainly the four structural proteins while the non-structural proteins mostly exhibit a more constant trend. As a consequence, it can be inferred that the evolution of the new mutative configurations will eventually reduce.


Subject(s)
COVID-19/epidemiology , Genome, Viral , Mutation Rate , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/genetics , Viral Nonstructural Proteins/genetics , Viral Structural Proteins/genetics , COVID-19/virology , Entropy , Epidemiological Monitoring , Evolution, Molecular , Gene Expression , Humans , India/epidemiology , Phylogeny , SARS-CoV-2/classification , SARS-CoV-2/pathogenicity , Spike Glycoprotein, Coronavirus/metabolism , Viral Nonstructural Proteins/classification , Viral Nonstructural Proteins/metabolism , Viral Structural Proteins/classification , Viral Structural Proteins/metabolism
4.
PLoS One ; 16(8): e0254605, 2021.
Article in English | MEDLINE | ID: covidwho-1367703

ABSTRACT

The re-emergence of virulent strains of the Infectious Bursal Disease Virus (IBDV) leads to significant economic losses of poultry industry in Pakistan during last few years. This disease causes the infection of bursa, which leads to major immune losses. A total number of 30 samples from five IBD outbreaks during the period of 2019-20 were collected from different areas of Faisalabad district, Pakistan and assayed by targeting the IBD virus VP2 region through RT-PCR. Among all the outbreaks, almost 80% of poultry birds were found positive for the IBDV. The bursa tissues were collected from the infected birds and histopathological examination of samples revealed severe lymphocytic depletion, infiltration of inflammatory cells, and necrosis of the bursa of Fabricius (BF). Positive samples were subjected to re-isolation and molecular characterization of IBDV. The Pakistan IBDV genes were subjected to DNA sequencing to determine the virus nucleotide sequences. The sequences of 100 Serotype-I IBDVs showing nearest homology were compared and identified with the study sequence. The construction of the phylogenetic tree for nucleotide sequences was accomplished by the neighbor-joining method in MEGA-6 with reference strains. The VP2 segment reassortment of IBDVs carrying segment A were identified as one important type of circulating strains in Pakistan. The findings indicated the molecular features of the Pakistan IBDV strains playing a role in the evolution of new strains of the virus, which will contribute to the vaccine selection and effective prevention of the disease.


Subject(s)
Birnaviridae Infections/epidemiology , Infectious bursal disease virus/pathogenicity , Poultry/virology , Vaccines/pharmacology , Animals , Birnaviridae Infections/veterinary , Birnaviridae Infections/virology , Bursa of Fabricius/pathology , Bursa of Fabricius/virology , Chickens/virology , Disease Outbreaks/veterinary , Humans , Infectious bursal disease virus/genetics , Pakistan/epidemiology , Phylogeny , Poultry Diseases/virology , Viral Structural Proteins/genetics , Viral Structural Proteins/immunology
6.
Brief Bioinform ; 22(6)2021 11 05.
Article in English | MEDLINE | ID: covidwho-1276146

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a causative agent of the coronavirus disease (COVID-19), is a part of the $\beta $-Coronaviridae family. The virus contains five major protein classes viz., four structural proteins [nucleocapsid (N), membrane (M), envelop (E) and spike glycoprotein (S)] and replicase polyproteins (R), synthesized as two polyproteins (ORF1a and ORF1ab). Due to the severity of the pandemic, most of the SARS-CoV-2-related research are focused on finding therapeutic solutions. However, studies on the sequences and structure space throughout the evolutionary time frame of viral proteins are limited. Besides, the structural malleability of viral proteins can be directly or indirectly associated with the dysfunctionality of the host cell proteins. This dysfunctionality may lead to comorbidities during the infection and may continue at the post-infection stage. In this regard, we conduct the evolutionary sequence-structure analysis of the viral proteins to evaluate their malleability. Subsequently, intrinsic disorder propensities of these viral proteins have been studied to confirm that the short intrinsically disordered regions play an important role in enhancing the likelihood of the host proteins interacting with the viral proteins. These interactions may result in molecular dysfunctionality, finally leading to different diseases. Based on the host cell proteins, the diseases are divided in two distinct classes: (i) proteins, directly associated with the set of diseases while showing similar activities, and (ii) cytokine storm-mediated pro-inflammation (e.g. acute respiratory distress syndrome, malignancies) and neuroinflammation (e.g. neurodegenerative and neuropsychiatric diseases). Finally, the study unveils that males and postmenopausal females can be more vulnerable to SARS-CoV-2 infection due to the androgen-mediated protein transmembrane serine protease 2.


Subject(s)
COVID-19/genetics , Genome, Viral/genetics , Protein Conformation , SARS-CoV-2/ultrastructure , COVID-19/virology , Coronavirus Envelope Proteins/genetics , Coronavirus Envelope Proteins/ultrastructure , Humans , Membrane Proteins/genetics , Membrane Proteins/ultrastructure , Nucleocapsid Proteins/genetics , Nucleocapsid Proteins/ultrastructure , SARS-CoV-2/genetics , SARS-CoV-2/pathogenicity , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/ultrastructure , Viral Replicase Complex Proteins/genetics , Viral Replicase Complex Proteins/ultrastructure , Viral Structural Proteins/genetics , Viral Structural Proteins/ultrastructure
7.
Crit Rev Ther Drug Carrier Syst ; 38(3): 75-115, 2021.
Article in English | MEDLINE | ID: covidwho-1236628

ABSTRACT

The outbreak of novel coronavirus (nCoV) or severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) in December 2019 in Wuhan, China, has posed an international public health emergency worldwide and forced people to be confined in their homes. This virus is of high-risk category and is declared a pandemic by the World Health Organization (WHO). The worldwide researchers and various health professionals are working together to determine the best way to stop its spread or halt this virus's spread and circumvent this pandemic condition threatening millions of human lives. The absence of definitive treatment is possible to explore to reduce virus infection and enhance patient recovery. Along with off-label medicines, plasma therapy, vaccines, the researchers exploit the various plants/herbs and their constituents to effectively treat nCoV infection. The present study aimed to present brief and most informative salient features of the numerous facts regarding the SARS-CoV-2, including the structure, genomic sequence, recent mutation, targeting possibility, and various hurdles in research progress, and off-labeled drugs, convalescent plasma therapy, vaccine and plants/herbs for the treatment of coronavirus disease-2019 (COVID-19). Results showed that off-labeled drugs such as hydroxychloroquine, dexamethasone, tocilizumab, antiviral drug (remdesivir, favipiravir), etc., give positive results and approved for use or approved for restricted use in some countries like India. Future research should focus on these possibilities that may allow the development of an effective treatment for COVID-19.


Subject(s)
Antiviral Agents/pharmacology , COVID-19 Vaccines/administration & dosage , COVID-19/drug therapy , Plant Extracts/pharmacology , SARS-CoV-2/drug effects , Angiotensin-Converting Enzyme 2/antagonists & inhibitors , Angiotensin-Converting Enzyme 2/metabolism , Antiviral Agents/therapeutic use , COVID-19/epidemiology , COVID-19/immunology , COVID-19/virology , Clinical Trials as Topic , Drug Therapy, Combination/methods , Humans , Molecular Targeted Therapy/methods , Mutation , Off-Label Use , Pandemics/prevention & control , Plant Extracts/therapeutic use , SARS-CoV-2/genetics , SARS-CoV-2/immunology , SARS-CoV-2/metabolism , Treatment Outcome , Viral Structural Proteins/antagonists & inhibitors , Viral Structural Proteins/genetics , Viral Structural Proteins/metabolism
8.
Hum Gene Ther ; 32(11-12): 541-562, 2021 06.
Article in English | MEDLINE | ID: covidwho-1216585

ABSTRACT

Severe acute respiratory syndrome (SARS) is a newly emerging infectious disease (COVID-19) caused by the novel coronavirus SARS-coronavirus 2 (CoV-2). To combat the devastating spread of SARS-CoV-2, extraordinary efforts from numerous laboratories have focused on the development of effective and safe vaccines. Traditional live-attenuated or inactivated viral vaccines are not recommended for immunocompromised patients as the attenuated virus can still cause disease via phenotypic or genotypic reversion. Subunit vaccines require repeated dosing and adjuvant use to be effective, and DNA vaccines exhibit lower immune responses. mRNA vaccines can be highly unstable under physiological conditions. On the contrary, naturally antigenic viral vectors with well-characterized structure and safety profile serve as among the most effective gene carriers to provoke immune response via heterologous gene transfer. Viral vector-based vaccines induce both an effective cellular immune response and a humoral immune response owing to their natural adjuvant properties via transduction of immune cells. Consequently, viral vectored vaccines carrying the SARS-CoV-2 spike protein have recently been generated and successfully used to activate cytotoxic T cells and develop a neutralizing antibody response. Recent progress in SARS-CoV-2 vaccines, with an emphasis on gene therapy viral vector-based vaccine development, is discussed in this review.


Subject(s)
COVID-19 Vaccines/pharmacology , Genetic Vectors , Vaccines, Attenuated/pharmacology , Vaccines, Synthetic/pharmacology , Viral Structural Proteins/chemistry , Adenoviridae/genetics , Genetic Therapy/methods , Genetic Vectors/chemistry , Genetic Vectors/genetics , Humans , Lentivirus/genetics , SARS-CoV-2/genetics , Vaccines, DNA/pharmacology , Viral Structural Proteins/genetics , Viral Structural Proteins/metabolism
9.
J Med Virol ; 93(5): 2790-2798, 2021 May.
Article in English | MEDLINE | ID: covidwho-1196503

ABSTRACT

Coronavirus disease-2019 (COVID-19), the ongoing pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a major threat to the entire human race. It is reported that SARS-CoV-2 seems to have relatively low pathogenicity and higher transmissibility than previously outbroke SARS-CoV. To explore the reason of the increased transmissibility of SARS-CoV-2 compared with SARS-CoV, we have performed a comparative analysis on the structural proteins (spike, envelope, membrane, and nucleoprotein) of two viruses. Our analysis revealed that extensive substitutions of hydrophobic to polar and charged amino acids in spike glycoproteins of SARS-CoV2 creates an intrinsically disordered region (IDR) at the beginning of membrane-fusion subunit and intrinsically disordered residues in fusion peptide. IDR provides a potential site for proteolysis by furin and enriched disordered residues facilitate prompt fusion of the SARS-CoV2 with host membrane by recruiting molecular recognition features. Here, we have hypothesized that mutation-driven accumulation of intrinsically disordered residues in spike glycoproteins play dual role in enhancing viral transmissibility than previous SARS-coronavirus. These analyses may help in epidemic surveillance and preventive measures against COVID-19.


Subject(s)
COVID-19/epidemiology , Disease Outbreaks , Membrane Fusion/genetics , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/genetics , Amino Acid Sequence , COVID-19/transmission , COVID-19/virology , Humans , Mutation , Protein Subunits , SARS Virus/genetics , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/metabolism , Viral Structural Proteins/chemistry , Viral Structural Proteins/genetics , Viral Structural Proteins/metabolism , Virus Internalization
10.
Cells ; 10(4)2021 04 06.
Article in English | MEDLINE | ID: covidwho-1178117

ABSTRACT

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.


Subject(s)
COVID-19/therapy , COVID-19/virology , Drug Discovery , SARS-CoV-2/physiology , Viral Nonstructural Proteins/metabolism , Viral Structural Proteins/metabolism , Animals , Antibodies, Neutralizing/pharmacology , Antibodies, Neutralizing/therapeutic use , COVID-19/drug therapy , COVID-19/metabolism , Drug Design , Humans , Immunization, Passive , Molecular Targeted Therapy , SARS-CoV-2/drug effects , SARS-CoV-2/genetics , Viral Nonstructural Proteins/chemistry , Viral Nonstructural Proteins/genetics , Viral Structural Proteins/chemistry , Viral Structural Proteins/genetics , Virus Internalization/drug effects , Virus Replication/drug effects
11.
Genome ; 64(7): 665-678, 2021 Jul.
Article in English | MEDLINE | ID: covidwho-1166573

ABSTRACT

SARS-CoV-2 is mutating and creating divergent variants across the world. An in-depth investigation of the amino acid substitutions in the genomic signature of SARS-CoV-2 proteins is highly essential for understanding its host adaptation and infection biology. A total of 9587 SARS-CoV-2 structural protein sequences collected from 49 different countries are used to characterize protein-wise variants, substitution patterns (type and location), and major substitution changes. The majority of the substitutions are distinct, mostly in a particular location, and lead to a change in an amino acid's biochemical properties. In terms of mutational changes, envelope (E) and membrane (M) proteins are relatively more stable than nucleocapsid (N) and spike (S) proteins. Several co-occurrence substitutions are observed, particularly in S and N proteins. Substitution specific to active sub-domains reveals that heptapeptide repeat, fusion peptides, transmembrane in S protein, and N-terminal and C-terminal domains in the N protein are remarkably mutated. We also observe a few deleterious mutations in the above domains. The overall study on non-synonymous mutation in structural proteins of SARS-CoV-2 at the start of the pandemic indicates a diversity amongst virus sequences.


Subject(s)
SARS-CoV-2/chemistry , Viral Structural Proteins/chemistry , Viral Structural Proteins/genetics , Amino Acid Substitution , Amino Acids/chemistry , Coronavirus Envelope Proteins/chemistry , Coronavirus Envelope Proteins/genetics , Coronavirus Nucleocapsid Proteins/chemistry , Coronavirus Nucleocapsid Proteins/genetics , Humans , Mutation , Mutation Rate , Phosphoproteins/chemistry , Phosphoproteins/genetics , SARS-CoV-2/genetics , SARS-CoV-2/isolation & purification , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , Viral Matrix Proteins/chemistry , Viral Matrix Proteins/genetics
12.
PLoS One ; 16(2): e0247396, 2021.
Article in English | MEDLINE | ID: covidwho-1090539

ABSTRACT

Among various delivery systems for vaccine and drug delivery, cell-penetrating peptides (CPPs) have been known as a potent delivery system because of their capability to penetrate cell membranes and deliver some types of cargoes into cells. Several CPPs were found in the proteome of viruses such as Tat originated from human immunodeficiency virus-1 (HIV-1), and VP22 derived from herpes simplex virus-1 (HSV-1). In the current study, a wide-range of CPPs was identified in the proteome of SARS-CoV-2, a new member of coronaviruses family, using in silico analyses. These CPPs may play a main role for high penetration of virus into cells and infection of host. At first, we submitted the proteome of SARS-CoV-2 to CellPPD web server that resulted in a huge number of CPPs with ten residues in length. Afterward, we submitted the predicted CPPs to C2Pred web server for evaluation of the probability of each peptide. Then, the uptake efficiency of each peptide was investigated using CPPred-RF and MLCPP web servers. Next, the physicochemical properties of the predicted CPPs including net charge, theoretical isoelectric point (pI), amphipathicity, molecular weight, and water solubility were calculated using protparam and pepcalc tools. In addition, the probability of membrane binding potential and cellular localization of each CPP were estimated by Boman index using APD3 web server, D factor, and TMHMM web server. On the other hand, the immunogenicity, toxicity, allergenicity, hemolytic potency, and half-life of CPPs were predicted using various web servers. Finally, the tertiary structure and the helical wheel projection of some CPPs were predicted by PEP-FOLD3 and Heliquest web servers, respectively. These CPPs were divided into: a) CPP containing tumor homing motif (RGD) and/or tumor penetrating motif (RXXR); b) CPP with the highest Boman index; c) CPP with high half-life (~100 hour) in mammalian cells, and d) CPP with +5.00 net charge. Based on the results, we found a large number of novel CPPs with various features. Some of these CPPs possess tumor-specific motifs which can be evaluated in cancer therapy. Furthermore, the novel and potent CPPs derived from SARS-CoV-2 may be used alone or conjugated to some sequences such as nuclear localization sequence (NLS) for vaccine and drug delivery.


Subject(s)
COVID-19 Vaccines/chemistry , Cell-Penetrating Peptides/chemistry , Computational Biology , Computer Simulation , Drug Delivery Systems , Proteome , SARS-CoV-2/chemistry , Animals , COVID-19 , COVID-19 Vaccines/genetics , COVID-19 Vaccines/metabolism , Cell-Penetrating Peptides/genetics , Cell-Penetrating Peptides/metabolism , HIV-1/chemistry , HIV-1/genetics , Herpesvirus 1, Human/chemistry , Herpesvirus 1, Human/genetics , Humans , SARS-CoV-2/genetics , SARS-CoV-2/metabolism , Viral Structural Proteins/chemistry , Viral Structural Proteins/genetics , tat Gene Products, Human Immunodeficiency Virus/chemistry , tat Gene Products, Human Immunodeficiency Virus/genetics
13.
Viruses ; 13(1)2020 12 22.
Article in English | MEDLINE | ID: covidwho-1025054

ABSTRACT

Viruses belonging to the Coronaviridae family have a single-stranded positive-sense RNA with a poly-A tail. The genome has a length of ~29.9 kbps, which encodes for genes that are essential for cell survival and replication. Different evolutionary constraints constantly influence the codon usage bias (CUB) of different genes. A virus optimizes its codon usage to fit the host environment on which it savors. This study is a comprehensive analysis of the CUB for the different genes encoded by viruses of the Coronaviridae family. Different methods including relative synonymous codon usage (RSCU), an Effective number of codons (ENc), parity plot 2, and Neutrality plot, were adopted to analyze the factors responsible for the genetic evolution of the Coronaviridae family. Base composition and RSCU analyses demonstrated the presence of A-ended and U-ended codons being preferred in the 3rd codon position and are suggestive of mutational selection. The lesser ENc value for the spike 'S' gene suggests a higher bias in the codon usage of this gene compared to the other structural genes. Parity plot 2 and neutrality plot analyses demonstrate the role and the extent of mutational and natural selection towards the codon usage pattern. It was observed that the structural genes of the Coronaviridae family analyzed in this study were at the least under 84% influence of natural selection, implying a major role of natural selection in shaping the codon usage.


Subject(s)
Codon Usage , Codon , Coronaviridae/genetics , Selection, Genetic , Viral Structural Proteins/genetics , Algorithms , Base Composition , Biological Evolution , Evolution, Molecular , Humans , Models, Genetic , Mutation
14.
Theranostics ; 11(4): 1690-1702, 2021.
Article in English | MEDLINE | ID: covidwho-1013521

ABSTRACT

The global outbreak of a novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) highlighted a requirement for two pronged clinical interventions such as development of effective vaccines and acute therapeutic options for medium-to-severe stages of "coronavirus disease 2019" (COVID-19). Effective vaccines, if successfully developed, have been emphasized to become the most effective strategy in the global fight against the COVID-19 pandemic. Basic research advances in biotechnology and genetic engineering have already provided excellent progress and groundbreaking new discoveries in the field of the coronavirus biology and its epidemiology. In particular, for the vaccine development the advances in characterization of a capsid structure and identification of its antigens that can become targets for new vaccines. The development of the experimental vaccines requires a plethora of molecular techniques as well as strict compliance with safety procedures. The research and clinical data integrity, cross-validation of the results, and appropriated studies from the perspective of efficacy and potently side effects have recently become a hotly discussed topic. In this review, we present an update on latest advances and progress in an ongoing race to develop 52 different vaccines against SARS-CoV-2. Our analysis is focused on registered clinical trials (current as of November 04, 2020) that fulfill the international safety and efficacy criteria in the vaccine development. The requirements as well as benefits and risks of diverse types of SARS-CoV-2 vaccines are discussed including those containing whole-virus and live-attenuated vaccines, subunit vaccines, mRNA vaccines, DNA vaccines, live vector vaccines, and also plant-based vaccine formulation containing coronavirus-like particle (VLP). The challenges associated with the vaccine development as well as its distribution, safety and long-term effectiveness have also been highlighted and discussed.


Subject(s)
COVID-19 Vaccines , COVID-19/epidemiology , Drug Development/trends , Pandemics/prevention & control , SARS-CoV-2/immunology , Antigens, Viral/genetics , Antigens, Viral/immunology , COVID-19/prevention & control , COVID-19/transmission , COVID-19/virology , Clinical Trials as Topic/statistics & numerical data , Drug Approval , Drug Development/statistics & numerical data , Humans , Patient Safety , SARS-CoV-2/genetics , Time Factors , Treatment Outcome , Viral Structural Proteins/genetics , Viral Structural Proteins/immunology
15.
J Mol Biol ; 433(2): 166725, 2021 01 22.
Article in English | MEDLINE | ID: covidwho-947287

ABSTRACT

The unprecedented scale of the ongoing COVID-19 pandemic has catalyzed an intense effort of the global scientific community to unravel different aspects of the disease in a short time. One of the crucial aspects of these developments is the determination of more than three hundred experimental structures of SARS-CoV-2 proteins in the last few months. These include structures of viral non-structural, structural, and accessory proteins and their complexes determined by either X-ray diffraction or cryo-electron microscopy. These structures elucidate the intricate working of different components of the viral machinery at the atomic level during different steps of the viral life cycle, including attachment to the host cell, viral genome replication and transcription, and genome packaging and assembly of the virion. Some of these proteins are also potential targets for drug development against the disease. In this review, we discuss important structural features of different SARS-CoV-2 proteins with their function, and their potential as a target for therapeutic interventions.


Subject(s)
COVID-19/virology , SARS-CoV-2/chemistry , SARS-CoV-2/genetics , Viral Proteins/chemistry , Coronavirus 3C Proteases/chemistry , Coronavirus 3C Proteases/genetics , Cryoelectron Microscopy , Genome, Viral , Humans , Life Cycle Stages/genetics , Models, Molecular , Protein Conformation , Viral Nonstructural Proteins/chemistry , Viral Nonstructural Proteins/genetics , Viral Proteins/genetics , Viral Regulatory and Accessory Proteins/chemistry , Viral Regulatory and Accessory Proteins/genetics , Viral Structural Proteins/chemistry , Viral Structural Proteins/genetics , Virus Replication
16.
Molecules ; 25(23)2020 Nov 25.
Article in English | MEDLINE | ID: covidwho-945888

ABSTRACT

A serious pandemic has been caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The interaction between spike surface viral protein (Sgp) and the angiotensin-converting enzyme 2 (ACE2) cellular receptor is essential to understand the SARS-CoV-2 infectivity and pathogenicity. Currently, no drugs are available to treat the infection caused by this coronavirus and the use of antimicrobial peptides (AMPs) may be a promising alternative therapeutic strategy to control SARS-CoV-2. In this study, we investigated the in silico interaction of AMPs with viral structural proteins and host cell receptors. We screened the antimicrobial peptide database (APD3) and selected 15 peptides based on their physicochemical and antiviral properties. The interactions of AMPs with Sgp and ACE2 were performed by docking analysis. The results revealed that two amphibian AMPs, caerin 1.6 and caerin 1.10, had the highest affinity for Sgp proteins while interaction with the ACE2 receptor was reduced. The effective AMPs interacted particularly with Arg995 located in the S2 subunits of Sgp, which is key subunit that plays an essential role in viral fusion and entry into the host cell through ACE2. Given these computational findings, new potentially effective AMPs with antiviral properties for SARS-CoV-2 were identified, but they need experimental validation for their therapeutic effectiveness.


Subject(s)
Angiotensin-Converting Enzyme 2/chemistry , COVID-19/drug therapy , SARS-CoV-2/chemistry , Spike Glycoprotein, Coronavirus/chemistry , Amphibian Proteins/chemistry , Amphibian Proteins/therapeutic use , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/therapeutic use , Antimicrobial Cationic Peptides/chemistry , Antimicrobial Cationic Peptides/therapeutic use , Antiviral Agents/chemistry , Antiviral Agents/therapeutic use , Binding Sites/genetics , COVID-19/genetics , COVID-19/virology , Computer Simulation , Humans , Pandemics , Pore Forming Cytotoxic Proteins/chemistry , Pore Forming Cytotoxic Proteins/therapeutic use , Protein Binding/genetics , SARS-CoV-2/pathogenicity , Spike Glycoprotein, Coronavirus/therapeutic use , Viral Structural Proteins/chemistry , Viral Structural Proteins/genetics , Viral Structural Proteins/therapeutic use
17.
Viruses ; 12(4)2020 04 20.
Article in English | MEDLINE | ID: covidwho-771435

ABSTRACT

Viral outbreaks of varying frequencies and severities have caused panic and havoc across the globe throughout history. Influenza, small pox, measles, and yellow fever reverberated for centuries, causing huge burden for economies. The twenty-first century witnessed the most pathogenic and contagious virus outbreaks of zoonotic origin including severe acute respiratory syndrome coronavirus (SARS-CoV), Ebola virus, Middle East respiratory syndrome coronavirus (MERS-CoV) and Nipah virus. Nipah is considered one of the world's deadliest viruses with the heaviest mortality rates in some instances. It is known to cause encephalitis, with cases of acute respiratory distress turning fatal. Various factors contribute to the onset and spread of the virus. All through the infected zone, various strategies to tackle and enhance the surveillance and awareness with greater emphasis on personal hygiene has been formulated. This review discusses the recent outbreaks of Nipah virus in Malaysia, Bangladesh and India, the routes of transmission, prevention and control measures employed along with possible reasons behind the outbreaks, and the precautionary measures to be ensured by private-public undertakings to contain and ensure a lower incidence in the future.


Subject(s)
Encephalitis, Viral/epidemiology , Encephalitis, Viral/transmission , Henipavirus Infections/epidemiology , Henipavirus Infections/transmission , Nipah Virus/classification , Animals , Bangladesh/epidemiology , Chiroptera/virology , Disease Outbreaks , Encephalitis, Viral/prevention & control , Henipavirus Infections/prevention & control , Humans , India/epidemiology , Infection Control , Malaysia/epidemiology , Nipah Virus/genetics , Viral Structural Proteins/genetics
18.
Infect Genet Evol ; 85: 104517, 2020 11.
Article in English | MEDLINE | ID: covidwho-737519

ABSTRACT

The present study aimed to predict a novel chimeric vaccine by simultaneously targeting four major structural proteins via the establishment of ancestral relationship among different strains of coronaviruses. Conserved regions from the homologous protein sets of spike glycoprotein, membrane protein, envelope protein and nucleocapsid protein were identified through multiple sequence alignment. The phylogeny analyses of whole genome stated that four proteins reflected the close ancestral relation of SARS-CoV-2 to SARS-COV-1 and bat coronavirus. Numerous immunogenic epitopes (both T cell and B cell) were generated from the common fragments which were further ranked on the basis of antigenicity, transmembrane topology, conservancy level, toxicity and allergenicity pattern and population coverage analysis. Top putative epitopes were combined with appropriate adjuvants and linkers to construct a novel multiepitope subunit vaccine against COVID-19. The designed constructs were characterized based on physicochemical properties, allergenicity, antigenicity and solubility which revealed the superiority of construct V3 in terms safety and efficacy. Essential molecular dynamics and normal mode analysis confirmed minimal deformability of the refined model at molecular level. In addition, disulfide engineering was investigated to accelerate the stability of the protein. Molecular docking study ensured high binding affinity between construct V3 and HLA cells, as well as with different host receptors. Microbial expression and translational efficacy of the constructs were checked using pET28a(+) vector of E. coli strain K12. However, the in vivo and in vitro validation of suggested vaccine molecule might be ensured with wet lab trials using model animals for the implementation of the presented data.


Subject(s)
Epitopes, B-Lymphocyte/genetics , Epitopes, T-Lymphocyte/genetics , SARS-CoV-2/classification , Vaccines, Subunit/genetics , Viral Structural Proteins/genetics , Epitopes, B-Lymphocyte/immunology , Epitopes, T-Lymphocyte/immunology , Escherichia coli/genetics , Escherichia coli/growth & development , Evolution, Molecular , Genome, Viral , Humans , Models, Molecular , Molecular Docking Simulation , Molecular Dynamics Simulation , Phylogeny , Protein Conformation , SARS-CoV-2/genetics , SARS-CoV-2/immunology , Vaccines, Subunit/chemistry , Vaccines, Subunit/metabolism , Viral Structural Proteins/chemistry , Viral Structural Proteins/immunology , Viral Vaccines/chemistry , Viral Vaccines/genetics , Viral Vaccines/metabolism
19.
Genomics ; 112(5): 3226-3237, 2020 09.
Article in English | MEDLINE | ID: covidwho-597640

ABSTRACT

A global emergency due to the COVID-19 pandemic demands various studies related to genes and genomes of the SARS-CoV2. Among other important proteins, the role of accessory proteins are of immense importance in replication, regulation of infections of the coronavirus in the hosts. The largest accessory protein in the SARS-CoV2 genome is ORF3a which modulates the host response to the virus infection and consequently it plays an important role in pathogenesis. In this study, an attempt is made to decipher the conservation of nucleotides, dimers, codons and amino acids in the ORF3a genes across thirty-two genomes of Indian patients. ORF3a gene possesses single and double point mutations in Indian SARS-CoV2 genomes suggesting the change of SARS-CoV2's virulence property in Indian patients. We find that the parental origin of the ORF3a gene over the genomes of SARS-CoV2 and Pangolin-CoV is same from the phylogenetic analysis based on conservation of nucleotides and so on. This study highlights the accumulation of mutation on ORF3a in Indian SARS-CoV2 genomes which may provide the designing therapeutic approach against SARS-CoV2.


Subject(s)
Betacoronavirus/genetics , Conserved Sequence , Coronavirus Infections/virology , Mutation , Pneumonia, Viral/virology , Viral Regulatory and Accessory Proteins/genetics , Animals , Base Sequence , Biological Evolution , COVID-19 , Chiroptera/virology , Coronavirus Infections/veterinary , Eutheria/virology , Genome, Viral , Genomics , Humans , India , Pandemics , Phylogeny , SARS-CoV-2 , Viral Regulatory and Accessory Proteins/chemistry , Viral Structural Proteins/chemistry , Viral Structural Proteins/genetics , Viroporin Proteins
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