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1.
J Med Virol ; 94(6): 2479-2486, 2022 06.
Article in English | MEDLINE | ID: covidwho-1797827

ABSTRACT

The COVID-19 pandemic continues to have a threatening impact on a global scale, largely due to the emergence of newly SARS-CoV-2 variants. The Mu (PANGO lineage B.1.621), was first identified in Colombia in January 2021 and was classified as a variant of interest (VOI) in August 2021, due to a constellation of mutations that likely-mediate an unexpectedly enhanced immune resistance to inactivated vaccine-elicited antibodies. Despite recent studies suggesting that the Mu variant appears to have less infectivity than the Delta variant, here we examined the structural effect of the Mu spike protein mutations and predicted the potential impact on infectivity of the Mu variant compared with the Delta and Delta plus spike protein.


Subject(s)
COVID-19 , SARS-CoV-2 , Attention , COVID-19 Vaccines , Humans , Mutation , Pandemics , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus
2.
Int J Mol Sci ; 23(8)2022 Apr 09.
Article in English | MEDLINE | ID: covidwho-1785747

ABSTRACT

Tracing the appearance and evolution of virus variants is essential in the management of the COVID-19 pandemic. Here, we focus on SARS-CoV-2 spread in Italian patients by using viral sequences deposited in public databases and a tracing procedure which is used to monitor the evolution of the pandemic and detect the spreading, within the infected population of emergent sub-clades with a potential positive selection. Analyses of a collection of monthly samples focused on Italy highlighted the appearance and evolution of all the main viral sub-trees emerging at the end of the first year of the pandemic. It also identified additional expanding subpopulations which spread during the second year (i.e., 2021). Three-dimensional (3D) modelling of the main amino acid changes in mutated viral proteins, including ORF1ab (nsp3, nsp4, 2'-o-ribose methyltransferase, nsp6, helicase, nsp12 [RdRp]), N, ORF3a, ORF8, and spike proteins, shows the potential of the analysed structural variations to result in epistatic modulation and positive/negative selection pressure. These analyzes will be of importance to the early identification of emerging clades, which can develop into new "variants of concern" (i.e., VOC). These analyses and settings will also help SARS-CoV-2 coronet genomic centers in other countries to trace emerging worldwide variants.


Subject(s)
COVID-19 , SARS-CoV-2 , COVID-19/epidemiology , Humans , Mutation , Pandemics , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/metabolism
4.
EuropePMC; 2020.
Preprint in English | EuropePMC | ID: ppcovidwho-306875

ABSTRACT

The Coronavirus disease (COVID-19) is a new viral infection caused by severe acute respiratory coronavirus 2 (SARS-CoV-2) that was initially reported in city of Wuhan, China and afterwards spread globally. Genomic analyses revealed that SARS-CoV-2 is phylogenetically related to severe acute respiratory syndrome-like (SARS-like) Pangolin and Bat coronavirus specific isolates. In this study we focused on two proteins of Sars-CoV-2 surface: Envelope protein and Membrane protein. Sequences from Sars-CoV-2 isolates and other closely related virus were collected from the GenBank through TBlastN searches. The retrieved sequences were multiply aligned with MAFFT. The Envelope protein is identical to the counterparts from Pangolin CoV MP798 isolate and Bat CoV isolates CoVZXC21, CoVZC45 and RaTG13. However, a substitution at position 69 where an Arg replace for Glu, and a deletion in position 70 corresponding to Gly or Cys in other Envelope proteins were found. The Membrane glycoprotein appears more variable with respect to the SARS CoV proteins than the Envelope: a heterogeneity at the N-terminal position, exposed to the virus surface, was found between Pangolin CoV MP798 isolate and Bat CoV isolates CoVZXC21, CoVZC45 and RaTG13. Mutations observed on Envelope protein are drastic and may have significant implications for conformational properties and possibly for protein-protein interactions. Mutations on Membrane protein may also be relevant because this protein cooperates with the Spike during the cell attachment and entry. Therefore, these mutations may influence interaction with host cells. The mutations that have been detected in these comparative studies may reflect functional peculiarities of the Sars-CoV-2 virus and may help explaining the epizootic origin the COVID-19 epidemic.

5.
EuropePMC; 2020.
Preprint in English | EuropePMC | ID: ppcovidwho-306874

ABSTRACT

The Sars-CoV-2 is the causative agent of the current coronavirus disease pandemic. To effectively fight this pathogen, it is important to understand its evolution and the mechanism of adaptation to the host. A software workflow has been utilized to scan 26,016 Sars-CoV-2 genomes available in GISAID databank to analyse the distribution and frequency of mutations in the corresponding proteomes. A filtering procedure has been applied to remove data inconsistencies and redundancies. The number of observed mutations appears proportional to protein sequence length except for ORF3a, Nucleocapsid and Nsp2 that seem to accept more mutations than expected. The most pervasive mutations of the three proteins have been reported and the most variable and conservative regions mapped onto the respective sequences. The results suggest that these proteins may have a role in the adaptation of virus to new hosts and influence its pathogenicity and replication. These considerations prompt the experimental study and characterization of the three proteins.

7.
J Med Virol ; 93(12): 6551-6556, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1530181

ABSTRACT

Lineage B.1.617+, also known as G/452R.V3 and now denoted by WHO with the Greek letters δ and κ, is a recently described SARS-CoV-2 variant under investigation first identified in October 2020 in India. As of May 2021, three sublineages labeled as B.1.617.1 (κ), B.1.617.2 (δ), and B.1.617.3 have been already identified, and their potential impact on the current pandemic is being studied. This variant has 13 amino acid changes, three in its spike protein, which are currently of particular concern: E484Q, L452R, and P681R. Here, we report a major effect of the mutations characterizing this lineage, represented by a marked alteration of the surface electrostatic potential (EP) of the receptor-binding domain (RBD) of the spike protein. Enhanced RBD-EP is particularly noticeable in the B.1.617.2 (δ) sublineage, which shows multiple replacements of neutral or negatively charged amino acids with positively charged amino acids. We here hypothesize that this EP change can favor the interaction between the B.1.617+ RBD and the negatively charged ACE2, thus conferring a potential increase in the virus transmission.


Subject(s)
COVID-19/virology , SARS-CoV-2/pathogenicity , COVID-19/transmission , Humans , Mutation , Protein Structure, Tertiary , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , Static Electricity
8.
Biomolecules ; 11(10)2021 10 10.
Article in English | MEDLINE | ID: covidwho-1463549

ABSTRACT

Among the more recently identified SARS-CoV-2 Variants of Interest (VOI) is the Lambda variant, which emerged in Peru and has rapidly spread to South American regions and the US. This variant remains poorly investigated, particularly regarding the effects of mutations on the thermodynamic parameters affecting the stability of the Spike protein and its Receptor Binding Domain. We report here an in silico study on the potential impact of the Spike protein mutations on the immuno-escape ability of the Lambda variant. Bioinformatics analysis suggests that a combination of shortening the immunogenic epitope loops and the generation of potential N-glycosylation sites may be a viable adaptation strategy, potentially allowing this emerging viral variant to escape from host immunity.


Subject(s)
Epitopes/genetics , SARS-CoV-2/genetics , Epitopes/immunology , Humans , SARS-CoV-2/immunology
10.
Sci Signal ; 14(690)2021 07 06.
Article in English | MEDLINE | ID: covidwho-1299215

ABSTRACT

Inorganic polyphosphates (polyPs) are linear polymers composed of repeated phosphate (PO4 3-) units linked together by multiple high-energy phosphoanhydride bonds. In addition to being a source of energy, polyPs have cytoprotective and antiviral activities. Here, we investigated the antiviral activities of long-chain polyPs against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In molecular docking analyses, polyPs interacted with several conserved amino acid residues in angiotensin-converting enzyme 2 (ACE2), the host receptor that facilitates virus entry, and in viral RNA-dependent RNA polymerase (RdRp). ELISA and limited proteolysis assays using nano- LC-MS/MS mapped polyP120 binding to ACE2, and site-directed mutagenesis confirmed interactions between ACE2 and SARS-CoV-2 RdRp and identified the specific amino acid residues involved. PolyP120 enhanced the proteasomal degradation of both ACE2 and RdRp, thus impairing replication of the British B.1.1.7 SARS-CoV-2 variant. We thus tested polyPs for functional interactions with the virus in SARS-CoV-2-infected Vero E6 and Caco2 cells and in primary human nasal epithelial cells. Delivery of a nebulized form of polyP120 reduced the amounts of viral positive-sense genomic and subgenomic RNAs, of RNA transcripts encoding proinflammatory cytokines, and of viral structural proteins, thereby presenting SARS-CoV-2 infection in cells in vitro.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , Polyphosphates/pharmacology , SARS-CoV-2/drug effects , Administration, Inhalation , Amino Acid Sequence , Angiotensin-Converting Enzyme 2/chemistry , Angiotensin-Converting Enzyme 2/metabolism , Animals , Antiviral Agents/administration & dosage , Antiviral Agents/chemistry , COVID-19/metabolism , COVID-19/virology , Caco-2 Cells , Chlorocebus aethiops , Coronavirus RNA-Dependent RNA Polymerase/chemistry , Coronavirus RNA-Dependent RNA Polymerase/genetics , Coronavirus RNA-Dependent RNA Polymerase/metabolism , Cytokines/metabolism , HEK293 Cells , Host Microbial Interactions/drug effects , Host Microbial Interactions/genetics , Host Microbial Interactions/physiology , Humans , In Vitro Techniques , Models, Biological , Molecular Docking Simulation , Nebulizers and Vaporizers , Polyphosphates/administration & dosage , Polyphosphates/chemistry , Proteasome Endopeptidase Complex/metabolism , Protein Interaction Domains and Motifs , Proteolysis/drug effects , RNA, Viral/genetics , RNA, Viral/metabolism , SARS-CoV-2/genetics , SARS-CoV-2/physiology , Sequence Homology, Amino Acid , Signal Transduction/drug effects , Vero Cells , Virus Replication/drug effects
11.
Expert Rev Mol Diagn ; 21(6): 547-562, 2021 06.
Article in English | MEDLINE | ID: covidwho-1182936

ABSTRACT

Introduction: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has pushed the scientific community to undertake intense research efforts. Understanding SARS-CoV-2 biology is necessary to discover therapeutic or preventive strategies capable of containing the pandemic. Knowledge of the structural characteristics of the virus genome and proteins is essential to find targets for therapies and immunological interventions.Areas covered: This review covers different areas of expertise, genomic analysis of circulating strains, structural biology, viral mutations, molecular diagnostics, disease, and vaccines. In particular, the review is focused on the molecular approaches and modern clinical strategies used in these fields.Expert opinion: Molecular approaches to SARS-CoV-2 pandemic have been critical to shorten time for new diagnostic, therapeutic and prevention strategies. In this perspective, the entire scientific community is moving in the same direction. Vaccines, together with the development of new drugs to treat the disease, represent the most important strategy to protect human from viral disease and prevent further spread. In this regard, new molecular technologies have been successfully implemented. The use of a novel strategy of communication is suggested for a better diffusion to the broader public of new data and results.


Subject(s)
COVID-19 Nucleic Acid Testing/methods , COVID-19 Vaccines/pharmacology , COVID-19/epidemiology , SARS-CoV-2/genetics , Animals , COVID-19/etiology , Genome, Viral , Humans , Mutation , Phylogeny , SARS-CoV-2/isolation & purification , Viral Proteins/chemistry , Viral Proteins/genetics
12.
Int J Biol Macromol ; 170: 820-826, 2021 Feb 15.
Article in English | MEDLINE | ID: covidwho-996949

ABSTRACT

In this study, analysis of changes of SARS-CoV-2 ORF3a protein during pandemic is reported. ORF3a, a conserved coronavirus protein, is involved in virus replication and release. A set of 70,752 high-quality SARS-CoV-2 genomes available in GISAID databank at the end of August 2020 have been scanned. All ORF3a mutations in the virus genomes were grouped according to the collection date interval and over the entire data set. The considered intervals were: start of collection-February, March, April, May, June, July and August 2020. The top five most frequent variants were examined within each collection interval. Overall, seventeen variants have been isolated. Ten of the seventeen mutant sites occur within the transmembrane (TM) domain of ORF3a and are in contact with the central pore or side tunnels. The other variant sites are in different places of the ORF3a structure. Within the entire sample, the five most frequent mutations are V13L, Q57H, Q57H + A99V, G196V and G252V. The same analysis identified 28 sites identically conserved in all the genome isolates. These sites are possibly involved in stabilization of monomer, dimer, tetramerization and interaction with other cellular components. The results here reported can be helpful to understand virus biology and to design new therapeutic strategies.


Subject(s)
COVID-19/virology , Mutation , SARS-CoV-2/genetics , Viroporin Proteins/genetics , Amino Acid Sequence , COVID-19/epidemiology , Conserved Sequence , Databases, Genetic , Evolution, Molecular , Genome, Viral , Humans , Models, Molecular , Pandemics , Protein Structure, Quaternary , Proteome/genetics , SARS-CoV-2/chemistry , SARS-CoV-2/physiology , Time Factors , Viroporin Proteins/chemistry , Viroporin Proteins/physiology
13.
J Med Virol ; 92(10): 2232-2237, 2020 10.
Article in English | MEDLINE | ID: covidwho-935129

ABSTRACT

Italy is the first western country suffering heavy severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission and disease impact after coronavirus disease-2019 pandemia started in China. Even though the presence of mutations on spike glycoprotein and nucleocapsid in Italian isolates has been reported, the potential impact of these mutations on viral transmission has not been evaluated. We have compared SARS-CoV-2 genome sequences from Italian patients with virus sequences from Chinese patients. We focussed upon three nonsynonymous mutations of genes coding for S(one) and N (two) viral proteins present in Italian isolates and absent in Chinese ones, using various bioinformatics tools. Amino acid analysis and changes in three-dimensional protein structure suggests the mutations reduce protein stability and, particularly for S1 mutation, the enhanced torsional ability of the molecule could favor virus binding to cell receptor(s). This theoretical interpretation awaits experimental and clinical confirmation.


Subject(s)
COVID-19/epidemiology , COVID-19/transmission , Coronavirus Nucleocapsid Proteins/chemistry , Genome, Viral , Pandemics , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/chemistry , Amino Acid Substitution , COVID-19/pathology , COVID-19/virology , China/epidemiology , Coronavirus Nucleocapsid Proteins/genetics , Evolution, Molecular , Humans , Italy/epidemiology , Models, Molecular , Molecular Epidemiology , Mutation , Phosphoproteins/chemistry , Phosphoproteins/genetics , Phylogeny , Protein Conformation, alpha-Helical , Protein Conformation, beta-Strand , SARS-CoV-2/classification , Severity of Illness Index , Spike Glycoprotein, Coronavirus/genetics , Travel , Virus Replication
14.
SSRN; 2020.
Preprint | SSRN | ID: ppcovidwho-748

ABSTRACT

Background: SARS-2-CoV is a new coronavirus that has spread globally, infecting more than 150000 people, and being declared pandemic by the WHO. We provide here

15.
J Med Virol ; 92(6): 584-588, 2020 06.
Article in English | MEDLINE | ID: covidwho-685102

ABSTRACT

Last December 2019, a new virus, named novel Coronavirus (COVID-2019) causing many cases of severe pneumonia was reported in Wuhan, China. The virus knowledge is limited and especially about COVID-2019 pathogenesis. The Open Reading Frame 1ab (ORF1ab) of COVID-2019 has been analyzed to evidence the presence of mutation caused by selective pressure on the virus. For selective pressure analysis fast-unconstrained Bayesian approximation (FUBAR) was used. Homology modelling has been performed by SwissModel and HHPred servers. The presence of transmembrane helical segments in Coronavirus ORF1ab non structural protein 2 (nsp2) and nsp3 was tested by TMHMM, MEMSAT, and MEMPACK tools. Three-dimensional structures have been analyzed and displayed using PyMOL. FUBAR analysis revealed the presence of potential sites under positive selective pressure (P < .05). Position 723 in the COVID-2019 has a serine instead a glycine residue, while at aminoacidic position 1010 a proline instead an isoleucine. Significant (P < .05) pervasive negative selection in 2416 sites (55%) was found. The positive selective pressure could account for some clinical features of this virus compared with severe acute respiratory syndrome (SARS) and Bat SARS-like CoV. The stabilizing mutation falling in the endosome-associated-protein-like domain of the nsp2 protein could account for COVID-2019 high ability of contagious, while the destabilizing mutation in nsp3 proteins could suggest a potential mechanism differentiating COVID-2019 from SARS. These data could be helpful for further investigation aimed to identify potential therapeutic targets or vaccine strategy, especially in the actual moment when the epidemic is ongoing and the scientific community is trying to enrich knowledge about this new viral pathogen.


Subject(s)
Betacoronavirus/genetics , SARS Virus/genetics , Viral Nonstructural Proteins/chemistry , Viral Proteins/chemistry , Betacoronavirus/pathogenicity , COVID-19 , Coronavirus Infections/virology , Female , Gene Expression , Humans , Male , Models, Molecular , Mutation , Pandemics , Pneumonia, Viral/virology , Polyproteins , Protein Conformation, alpha-Helical , Protein Conformation, beta-Strand , Protein Interaction Domains and Motifs , SARS Virus/pathogenicity , SARS-CoV-2 , Selection, Genetic , Structural Homology, Protein , Viral Nonstructural Proteins/genetics , Viral Nonstructural Proteins/metabolism , Viral Proteins/genetics , Viral Proteins/metabolism
16.
Biomed Res Int ; 2020: 4389089, 2020.
Article in English | MEDLINE | ID: covidwho-618728

ABSTRACT

The Coronavirus Disease 2019 (COVID-19) is a new viral infection caused by the severe acute respiratory coronavirus 2 (SARS-CoV-2). Genomic analyses have revealed that SARS-CoV-2 is related to Pangolin and Bat coronaviruses. In this report, a structural comparison between the Sars-CoV-2 Envelope and Membrane proteins from different human isolates with homologous proteins from closely related viruses is described. The analyses here reported show the high structural similarity of Envelope and Membrane proteins to the counterparts from Pangolin and Bat coronavirus isolates. However, the comparisons have also highlighted structural differences specific of Sars-CoV-2 proteins which may be correlated to the cross-species transmission and/or to the properties of the virus. Structural modelling has been applied to map the variant sites onto the predicted three-dimensional structure of the Envelope and Membrane proteins.


Subject(s)
Betacoronavirus/chemistry , Coronavirus Infections/virology , Pneumonia, Viral/virology , Viral Envelope Proteins/chemistry , Viral Matrix Proteins/chemistry , Alphacoronavirus/chemistry , Alphacoronavirus/classification , Alphacoronavirus/genetics , Amino Acid Sequence , Animals , Betacoronavirus/classification , Betacoronavirus/genetics , COVID-19 , Chiroptera/virology , Coronaviridae/chemistry , Coronaviridae/classification , Coronaviridae/genetics , Coronavirus Envelope Proteins , Eutheria/virology , Humans , Models, Molecular , Pandemics , Protein Conformation , SARS-CoV-2 , Sequence Homology, Amino Acid , Species Specificity , Structural Homology, Protein , Viral Envelope Proteins/genetics , Viral Matrix Proteins/genetics
17.
J Infect ; 81(1): e24-e27, 2020 07.
Article in English | MEDLINE | ID: covidwho-47836

ABSTRACT

BACKGROUND: SARS-CoV-2 is a new coronavirus that has spread globally, infecting more than 150000 people, and being declared pandemic by the WHO. We provide here bio-informatic, evolutionary analysis of 351 available sequences of its genome with the aim of mapping genome structural variations and the patterns of selection. METHODS: A Maximum likelihood tree has been built and selective pressure has been investigated in order to find any mutation developed during the SARS-CoV-2 epidemic that could potentially affect clinical evolution of the infection. FINDING: We have found in more recent isolates the presence of two mutations affecting the Non-Structural Protein 6 (NSP6) and the Open Reding Frame10 (ORF 10) adjacent regions. Amino acidic change stability analysis suggests both mutations could confer lower stability of the protein structures. INTERPRETATION: One of the two mutations, likely developed within the genome during virus spread, could affect virus intracellular survival. Genome follow-up of SARS-CoV-2 spread is urgently needed in order to identify mutations that could significantly modify virus pathogenicity.


Subject(s)
Betacoronavirus/genetics , Capsid Proteins/genetics , Coronavirus Infections/virology , Mutation , Pneumonia, Viral/virology , Autophagy , COVID-19 , Coronavirus Nucleocapsid Proteins , Evolution, Molecular , Gene Expression Regulation, Viral , Genome, Viral , Humans , Likelihood Functions , Models, Molecular , Open Reading Frames , Pandemics , Protein Conformation , SARS-CoV-2
18.
Chemotherapy ; 2020.
Article in English | WHO COVID, ELSEVIER | ID: covidwho-38684

ABSTRACT

Background: In late December 2019, Chinese health authorities reported an outbreak of pneumonia of unknown origin in Wuhan, Hubei Province. Summary: A few days later, the genome of a novel coronavirus was released (http://viro-logical.org/t/novel-2019-coronavirus-genome/319; Wuhan-Hu-1, GenBank accession No. MN908947) and made publicly available to the scientific community. This novel coronavirus was provisionally named 2019-nCoV, now SARS-CoV-2 according to the Coronavirus Study Group of the International Committee on Taxonomy of Viruses. SARS-CoV-2 belongs to the Coronaviridae family, Betacoronavirus genus, subgenus Sarbecovirus. Since its discovery, the virus has spread globally, causing thousands of deaths and having an enormous impact on our health systems and economies. In this review, we summarize the current knowledge about the epidemiology, phylogenesis, homology modeling, and molecular diagnostics of SARS-CoV-2. Key Messages: Phylogenetic analysis is essential to understand viral evolution, whereas homology modeling is important for vaccine strategies and therapies. Highly sensitive and specific diagnostic assays are key to case identification, contact tracing, identification of the animal source, and implementation of control measures.

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