scholarly journals Prediction of SARS-CoV-2 Omicron Variant Immunogenicity, Immune Escape and Pathogenicity, through Analysis of Spike Protein-specific Core Unique Peptides

2021 ◽  
Author(s):  
Vasileios Pierros ◽  
EVANGELOS KONTOPODIS ◽  
DIMITRIOS J. STRAVOPODIS ◽  
GEORGE TH. TSANGARIS
Keyword(s):  
Amino Acids ◽  
Immune Escape ◽  
Contact Point ◽  
Point Mutations ◽  
Spike Protein ◽  
Binding Motif ◽  
Global Awareness ◽  
Virus Binding ◽  
Viral Binding ◽  
New Variant

The recently discovered Omicron variant of the SARS-CoV-2 corona virus has raised a new, global, awareness, since it is considered as a new variant of concern from all major health organizations, including WHO and ECDC. Omicron variant is characterized by 30 amino acid changes, three small deletions and one small insertion in the Spike protein. In this study, we have identified the Core Unique Peptides (CrUPs) that reside exclusively in the Omicron variant of Spike protein and are absent from the human proteome, thus creating a new dataset of peptides named as C/H-CrUPs. Furthermore, we have analyzed their protein locations and compared them with the respective ones of Alpha and Delta SARS-CoV-2 variants. In Omicron, 115 C/H-CrUPs were generated and 119 C/H-CrUPs were lost, almost four times as many compared to the other two variants. From position 440 to position 508, at the Receptor Binding Motif (RBM), 8 mutations were detected, resulting in the construction of 28 novel C/H-CrUPs. Most importantly, in Omicron variant, new C/H-CrUPs carrying two or three mutant amino acids were produced, as a consequence of the accumulation of multiple mutations in the RBM. Remarkably, these Omicron-derived C/H-CrUPs that bear several mutated amino acids could not be recognized in any other viral Spike variant. We suggest that virus binding to the ACE2 receptor is facilitated by the herein identified C/H-CrUPs in contact point mutations and Spike-cleavage sites, while the immunoregulatory NF9 peptide is not detectably affected. Taken together, our findings indicate that Omicron variant contains intrinsic abilities to escape immune-system attack, while its mutations can mediate strong viral binding to the ACE2 receptor, leading to highly efficient fusion of the virus to the target cell. However, the intact NF9 peptide suggests that Omicron exhibits reduced pathogenicity compared to Delta variant.

scholarly journals An in silico analysis of early SARS-CoV-2 variant B.1.1.529 (Omicron) genomic sequences and their epidemiological correlates

2021 ◽  
Author(s):  
Ashutosh Kumar ◽  
Adil Asghar ◽  
Himanshu N. Singh ◽  
Muneeb A. Faiq ◽  
Sujeet Kumar ◽  
...  
Keyword(s):  
In Silico ◽  
Immune Escape ◽  
Mutational Analysis ◽  
In Silico Analysis ◽  
Spike Protein ◽  
World Health ◽  
Genomic Sequences ◽  
Binding Motif ◽  
New Variant ◽  
Silico Analysis

Background: A newly emerged SARS-CoV-2 variant B.1.1.529 has worried health policymakers worldwide due to the presence of a large number of mutations in its genomic sequence, especially in the spike protein region. World Health Organization (WHO) has designated it as a global variant of concern (VOC) and has named as Omicron. A surge in new COVID-19 cases has been reported from certain geographical locations, primarily in South Africa (SA) following the emergence of Omicron. Materials and methods: We performed an in silico analysis of the complete genomic sequences of Omicron available on GISAID (until 2021-12-6) to predict the functional impact of the mutations present in this variant on virus-host interactions in terms of viral transmissibility, virulence/lethality, and immune escape. In addition, we performed a correlation analysis of the relative proportion of the genomic sequences of specific SARS-CoV-2 variants (in the period of 01 Oct-29 Nov 2021) with the current epidemiological data (new COVID-19 cases and deaths) from SA to understand whether the Omicron has an epidemiological advantage over existing variants. Results: Compared to the current list of global VOCs/VOIs (as per WHO) Omicron bears more sequence variation, specifically in the spike protein and host receptor-binding motif (RBM). Omicron showed the closest nucleotide and protein sequence homology with Alpha variant for the complete sequence as well as for RBM. The mutations were found primarily condensed in the spike region (28-48) of the virus. Further, the mutational analysis showed enrichment for the mutations decreasing ACE2-binding affinity and RBD protein expression, in contrast, increasing the propensity of immune escape. An inverse correlation of Omicron with Delta variant was noted (r=-0.99, p< .001, 95% CI: -0.99 to -0.97) in the sequences reported from SA post-emergence of the new variant, later showing a decrease. There has been a steep rise in the new COVID-19 cases in parallel with the increase in the proportion of Omicron since the first case (74-100%), on the contrary, the incidences of new deaths have not been increased (r=-0.04, p>0.05, 95% CI =-0.52 to 0.58). Conclusions: Omicron may have greater immune escape ability than the existing VOCs/VOIs. However, there are no clear indications coming out from the predictive mutational analysis that the Omicron may have higher virulence/lethality than other variants, including Delta. The higher ability for immune escape may be a likely reason for the recent surge in Omicron cases in SA.

scholarly journals E156/G and Arg158, Phe-157/del mutation in NTD of spike protein in B.1.167.2 lineage of SARS-CoV-2 leads to immune evasion through antibody escape

2021 ◽  
Author(s):  
Armi Chaudhari ◽  
Dinesh Kumar ◽  
Dr. Madhvi Joshi ◽  
Amrutlal Patel ◽  
Prof. Chaitanya joshi
Keyword(s):  
Immune Escape ◽  
Spike Protein ◽  
Structural Basis ◽  
Virus Particles ◽  
Fitness Advantage ◽  
Pathogenic Virus ◽  
New Variant ◽  
Significant Difference ◽  
Dynamics Simulations ◽  
Immune Escape Mechanisms

New emerging variants of SARS-CoV-2 remains a persistent threat with better immune escape mechanisms and higher transmissibility across the globe. B.1.617.2 (Delta) variant first emerged from Maharashtra, India in December, 2020. This variant is classified to be a major cause and concern of the recent peak of COVID-19 in India. Cellular entry of coronaviruses largely depends on binding of the viral spike (S) proteins to host receptors and priming by host cell proteases through the contact of the droplets containing pathogenic virus particles. Our research study, explore the genomic and structural basis of this variant through computational analysis, protein modelling and molecular dynamics simulations approach and identifies the mechanism through which it is probably more pathogenically evolved with higher transmissibility as compared to the wild-type. These findings reveal the significant difference in rigidity and reducing the flexibility within N-terminal domain (NTD) of the spike protein, hence prevailing case of antibody escape. The results of the present study demonstrate the fitness advantage to the new variant which further need to be critically examined though supportive experimental biology that might help devising better therapeutics and containment of SARS-CoV-2.

scholarly journals SARS-CoV-2 Spike receptor-binding domain with a G485R mutation in complex with human ACE2

2021 ◽  
Author(s):  
Claire M. Weekley ◽  
Damian F. J. Purcell ◽  
Michael W. Parker
Keyword(s):  
Receptor Binding ◽  
Point Mutations ◽  
Direct Interaction ◽  
Binding Domain ◽  
Spike Protein ◽  
Genomic Sequencing ◽  
Binding Motif ◽  
Receptor Binding Domain ◽  
Structural Characterisation ◽  
Human Receptor

AbstractSince SARS-CoV-2 emerged in 2019, genomic sequencing has identified mutations in the viral RNA including in the receptor-binding domain of the Spike protein. Structural characterisation of the Spike carrying point mutations aids in our understanding of how these mutations impact binding of the protein to its human receptor, ACE2, and to therapeutic antibodies. The Spike G485R mutation has been observed in multiple isolates of the virus and mutation of the adjacent residue E484 to lysine is known to contribute to antigenic escape. Here, we have crystallised the SARS-CoV-2 Spike receptor-binding domain with a G485R mutation in complex with human ACE2. The crystal structure shows that while the G485 residue does not have a direct interaction with ACE2, its mutation to arginine affects the structure of the loop made by residues 480-488 in the receptor-binding motif, disrupting the interactions of neighbouring residues with ACE2 and with potential implications for antigenic escape from vaccines, antibodies and other biologics directed against SARS-CoV-2 Spike.

scholarly journals Fast forward evolution in real time: the rapid spread of SARS-CoV-2 variant of concern lineage B.1.1.7 in Saxony-Anhalt over a period of 5 months

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Markus Glaß ◽  
Danny Misiak ◽  
Claudia Misiak ◽  
Simon Müller ◽  
Alexander Rausch ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Immune Escape ◽  
Point Mutations ◽  
Clinical Signs ◽  
Relevant Information ◽  
University Hospital ◽  
Surveillance Program ◽  
Binding Motif ◽  
Whole Genome

Abstract Objectives Random mutations and recombinations are the main sources for the genetic diversity in SARS-CoV-2, with mutations in the SARS-CoV-2 spike (S) receptor binding motif (RBM) representing a high potential for the emergence of new putative variants under investigation (VUI) or variants of concern (VOC). It is of importance, to measure the different circulating SARS-CoV-2 lineages in order to establish a regional SARS-CoV-2 surveillance program. We established whole genome sequencing (WGS) of circulating SARS-CoV-2 lineages in order to establish a regional SARS-CoV-2 surveillance program. Methods We established a surveillance program for circulating SARS-CoV-2 lineages by performing whole genome sequencing (WGS) in SARS-CoV-2 isolates. Specimens were collected over a period of 5 months from three different sites. Specimens were collected from both patients suffering from COVID-19 and from outpatients without any clinical signs or symptoms; both in a tertiary university hospital, and two private laboratories within an urban area of eastern part Germany. Results Viral WGS from the 364 respiratory specimens with positive SARS-CoV-2 RT-PCR comprised 16 different SARS-CoV-2 lineages. The majority of the obtained sequences (252/364=69%) was assigned to the variant of concern (VOC) Alpha (B.1.1.7). This variant first appeared in February in our samples and quickly became the dominant virus variant. All SNP PCR results could be verified using WGS. Other VOCs found in our cohort were Beta (B.1.351, n=2) and Delta (B.1.617.2, n=1). Conclusions Lineage analysis revealed 16 different virus variants among 364 respiratory samples analyzed by WGS. The number of distinct lineages dramatically decreased over time in leaving only few variants, in particular, the VOC Alpha or B.1.1.7. By closer inspection of point mutations, we found several distinct mutations of the viral spike protein that were reported to increase affinity or enable immune escape. Within a study period of only 5 months, SARS-CoV-2 lineage B.1.1.7 became the dominant lineage in our study population. This study emphasizes the benefit of SARS-CoV-2 testing by WGS. The increasing use of WGS to sequence the entire SARS-CoV-2 genome will reveal additional VUIs and VOCs with the potential to evade the immune system and, thus, will be a promising tool for data mining of relevant information for epidemiological studies. SARS-CoV-2 lineage monitoring using WGS is an important surveillance tool for early detection of upcoming new lineages of concern.

scholarly journals The lethal triad: SARS-CoV-2 Spike, ACE2 and TMPRSS2. Mutations in host and pathogen may affect the course of pandemic

2021 ◽  
Author(s):  
Matteo Calcagnile ◽  
Patricia Forgez ◽  
Marco Alifano ◽  
Pietro Alifano
Keyword(s):  
Amino Acid ◽  
Receptor Binding ◽  
Virus Transmission ◽  
Threat Assessment ◽  
Spike Protein ◽  
Binding Motif ◽  
Lethal Triad ◽  
New Variant ◽  
South East England ◽  
And Control

AbstractVariants of SARS-CoV-2 have been identified rapidly after the beginning of pandemic. One of them, involving the spike protein and called D614G, represents a substantial percentage of currently isolated strains. While research on this variant was ongoing worldwide, on December 20th 2020 the European Centre for Disease Prevention and Control reported a Threat Assessment Brief describing the emergence of a new variant of SARS-CoV-2, named B.1.1.7, harboring multiple mutations mostly affecting the Spike protein. This viral variant has been recently associated with a rapid increase in COVID-19 cases in South East England, with alarming implications for future virus transmission rates. Specifically, of the nine amino acid replacements that characterize the Spike in the emerging variant, four are found in the region between the Fusion Peptide and the RBD domain (namely the already known D614G, together with A570D, P681H, T716I), and one, N501Y, is found in the Spike Receptor Binding Domain – Receptor Binding Motif (RBD-RBM). In this study, by using in silico biology, we provide evidence that these amino acid replacements have dramatic effects on the interactions between SARS-CoV-2 Spike and the host ACE2 receptor or TMPRSS2, the protease that induces the fusogenic activity of Spike. Mostly, we show that these effects are strongly dependent on ACE2 and TMPRSS2 polymorphism, suggesting that dynamics of pandemics are strongly influenced not only by virus variation but also by host genetic background.

scholarly journals The Comparison of SARS-CoV-2, SARS-CoV, and MERS-CoV Genome and Spike Protein Variations

2021 ◽  
Vol 3 (1) ◽  
pp. 38
Author(s):  
Choirun Nita Fikriani ◽  
I Kade Karisma Gita Ardana ◽  
Dwi Listyorini
Keyword(s):  
Receptor Binding ◽  
Protein Sequence ◽  
Respiratory Infections ◽  
Genome Structure ◽  
Spike Protein ◽  
Target Cells ◽  
Binding Motif ◽  
Data Mining Approach ◽  
New Variant ◽  
Using Data

SARS-CoV-2 is a virus that has caused COVID-19 pandemic. This virus is a new variant of the SARS-CoV virus and also closely related to MERS-CoV, which caused similar acute respiratory infections. All these viruses recognize target cells by binding to the Receptor Binding Domain (RBD) on Spike protein with receptors. This study aimed to determine the SARS-CoV-2, MERS-CoV, and SARS-CoV genome structure, Spike protein sequence differences, and variations of RBD’s Receptor Binding Motif (RBM). This research was using data mining approach. Genome sequences were downloaded from NCBI, except for Indonesian samples were downloaded from GISAID. Genomic structures, Spike sequence, and RBD structure were analyzed using Bioedit, followed by protein modelling using SwissModel and PyMol applications. The result showed that the SARS-CoV-2, MERS-CoV, and SARS-CoV genome shared the same genes yet in different numbers and length. SARS-CoV-2 Spike protein sequence was quite similar to SARS-CoV Spike protein, but very different to the Spike protein of MERS-CoV. There were variations of RBD’s RBM structure due to the mutations occurred among these viruses. It is suggested that these differences may increase the affinity between SARS-CoV-2 Spike protein to its hACE2 receptor which caused SARS-CoV-2 becomes more infective and spread wider than SARS-CoV and MERS-CoV, in turn. This result expected to be basic information for the development of SARS-CoV-2 introduction inhibition agent and spreading prevention.

scholarly journals Design of a companion bioinformatic tool to detect the emergence and geographical distribution of SARS-CoV-2 Spike protein genetic variants

2020 ◽  
Vol 18 (1) ◽  
Author(s):  
Alice Massacci ◽  
Eleonora Sperandio ◽  
Lorenzo D’Ambrosio ◽  
Mariano Maffei ◽  
Fabio Palombo ◽  
...  
Keyword(s):  
Receptor Binding ◽  
Consensus Sequence ◽  
Cell Epitope ◽  
Vaccine Design ◽  
Binding Domain ◽  
Spike Protein ◽  
Antibody Activity ◽  
Binding Motif ◽  
Receptor Binding Domain ◽  
The Impact

Abstract Background Tracking the genetic variability of Severe Acute Respiratory Syndrome CoronaVirus 2 (SARS-CoV-2) is a crucial challenge. Mainly to identify target sequences in order to generate robust vaccines and neutralizing monoclonal antibodies, but also to track viral genetic temporal and geographic evolution and to mine for variants associated with reduced or increased disease severity. Several online tools and bioinformatic phylogenetic analyses have been released, but the main interest lies in the Spike protein, which is the pivotal element of current vaccine design, and in the Receptor Binding Domain, that accounts for most of the neutralizing the antibody activity. Methods Here, we present an open-source bioinformatic protocol, and a web portal focused on SARS-CoV-2 single mutations and minimal consensus sequence building as a companion vaccine design tool. Furthermore, we provide immunogenomic analyses to understand the impact of the most frequent RBD variations. Results Results on the whole GISAID sequence dataset at the time of the writing (October 2020) reveals an emerging mutation, S477N, located on the central part of the Spike protein Receptor Binding Domain, the Receptor Binding Motif. Immunogenomic analyses revealed some variation in mutated epitope MHC compatibility, T-cell recognition, and B-cell epitope probability for most frequent human HLAs. Conclusions This work provides a framework able to track down SARS-CoV-2 genomic variability.

scholarly journals EBNA3C Coactivation with EBNA2 Requires a SUMO Homology Domain

2004 ◽  
Vol 78 (1) ◽  
pp. 367-377 ◽  
Author(s):  
Adam Rosendorff ◽  
Diego Illanes ◽  
Gregory David ◽  
Jeffrey Lin ◽  
Elliott Kieff ◽  
...  
Keyword(s):  
Amino Acids ◽  
Gene Activation ◽  
Point Mutations ◽  
Nuclear Body ◽  
Nuclear Bodies ◽  
Nuclear Antigen ◽  
Barr Virus ◽  
Epstein Barr ◽  
Necessary And Sufficient ◽  
Regulated Promoters

ABSTRACT Epstein-Barr virus (EBV) nuclear antigen 3C (EBNA3C) is critical for EBV immortalization of infected B lymphocytes and can coactivate the EBV LMP1 promoter with EBNA2. EBNA3C amino acids 365 to 545 are necessary and sufficient for coactivation and are required for SUMO-1 and SUMO-3 interaction. We found that EBNA3C but not EBNA3CΔ343-545 colocalized with SUMO-1 in nuclear bodies and was modified by SUMO-2, SUMO-3, and SUMO-1. EBNA3C amino acids 545 to 628 and amino acids 30 to 365 were also required for EBNA3C sumolation and nuclear body localization but were dispensable for coactivation, indicating that EBNA3C sumolation is not required for coactivation. Furthermore, EBNA3C amino acids 476 to 992 potently coactivated with EBNA2 but EBNA3C amino acids 516 to 922 lacked activity, indicating that amino acids 476 to 515 are critical for coactivation. EBNA3C amino acids 476 to 515 include DDDVIEV507-513, which are similar to SUMO-1 EEDVIEV84-90. EBNA3C m1 and m2 point mutations, DDD507-509 mutated to AAA and DVIEVID509-513 mutated to AVIAVIA, respectively, diminished SUMO-1 and SUMO-3 interaction in directed yeast two-hybrid and glutathione S-transferase pulldown assays. Furthermore, EBNA3C m1 and m2 did not coactivate the LMP1 promoter with EBNA2. Overexpression of wild-type SUMO-1, SUMO-3, and the SUMO-conjugating enzyme UBC9 coactivated the LMP1 promoter with EBNA2. Since EBNA2 activation is dependent on p300/CBP, the possible effect of EBNA3C on p300-mediated transcription was assayed. EBNA3C potentiated transcription of p300 fused to a heterologous DNA binding domain, whereas EBNA3C m1 and m2 did not. All of these data are consistent with a model in which EBNA3C upregulates EBNA2-mediated gene activation by binding to a sumolated repressor and inhibiting repressive effects on p300/CBP and other transcription factor(s) at EBNA2-regulated promoters.

Receptor and Molecular Mechanism of AGGF1 Signaling in Endothelial Cell Functions and Angiogenesis

2021 ◽  
Author(s):  
Jingjing Wang ◽  
Huixin Peng ◽  
Ayse Anil Timur ◽  
Vinay Pasupuleti ◽  
Yufeng Yao ◽  
...  
Keyword(s):  
Amino Acids ◽  
Endothelial Cell ◽  
Neutralizing Antibodies ◽  
Molecular Mechanisms ◽  
Capillary Tube ◽  
Therapeutic Angiogenesis ◽  
Angiogenic Factor ◽  
Single Amino Acid ◽  
Binding Motif ◽  
Cell Functions

Objective: Angiogenic factor AGGF1 (angiogenic factor and G-patch and FHA [Forkhead-associated] domain 1) promotes angiogenesis as potently as VEGFA (vascular endothelial growth factor A) and regulates endothelial cell (EC) proliferation, migration, specification of multipotent hemangioblasts and venous ECs, hematopoiesis, and vascular development and causes vascular disease Klippel-Trenaunay syndrome when mutated. However, the receptor for AGGF1 and the underlying molecular mechanisms remain to be defined. Approach and Results: Using functional blocking studies with neutralizing antibodies, we identified α5β1 as the receptor for AGGF1 on ECs. AGGF1 interacts with α5β1 and activates FAK (focal adhesion kinase), Src, and AKT. Functional analysis of 12 serial N-terminal deletions and 13 C-terminal deletions by every 50 amino acids mapped the angiogenic domain of AGGF1 to a domain between amino acids 604-613 (FQRDDAPAS). The angiogenic domain is required for EC adhesion and migration, capillary tube formation, and AKT activation. The deletion of the angiogenic domain eliminated the effects of AGGF1 on therapeutic angiogenesis and increased blood flow in a mouse model for peripheral artery disease. A 40-mer or 15-mer peptide containing the angiogenic domain blocks AGGF1 function, however, a 15-mer peptide containing a single amino acid mutation from −RDD- to −RGD- (a classical RGD integrin-binding motif) failed to block AGGF1 function. Conclusions: We have identified integrin α5β1 as an EC receptor for AGGF1 and a novel AGGF1-mediated signaling pathway of α5β1-FAK-Src-AKT for angiogenesis. Our results identify an FQRDDAPAS angiogenic domain of AGGF1 crucial for its interaction with α5β1 and signaling.

Compared with SARS-CoV2 wild type's spike protein, the SARS-CoV2 omicron's receptor binding motif has adopted a more SARS-CoV1 and/or bat/civet-like structure.

2021 ◽  
Author(s):  
Michael O. Glocker ◽  
Kwabena F. M. Opuni ◽  
Hans-Juergen Thiesen
Keyword(s):  
Free Energy ◽  
Receptor Binding ◽  
Free Energy Calculations ◽  
Viral Fitness ◽  
Spike Protein ◽  
Receptor Protein ◽  
Binding Motif ◽  
Energy Calculations ◽  
Selection Processes ◽  
Protein Receptor

Our study focuses on free energy calculations of SARS-Cov2 spike protein receptor binding motives (RBMs) from wild type and variants-of-concern with particular emphasis on currently emerging SARS- CoV2 omicron variants of concern (VOC). Our computational free energy analysis underlines the occurrence of positive selection processes that specify omicron host adaption and bring changes on the molecular level into context with clinically relevant observations. Our free energy calculations studies regarding the interaction of omicron's RBM with human ACE2 shows weaker binding to ACE2 than alpha's, delta's, or wild type's RBM. Thus, less virus is predicted to be generated in time per infected cell. Our mutant analyses predict with focus on omicron variants a reduced spike-protein binding to ACE2--receptor protein possibly enhancing viral fitness / transmissibility and resulting in a delayed induction of danger signals as trade-off. Finally, more virus is produced but less per cell accompanied with delayed Covid-19 immunogenicity and pathogenicity. Regarding the latter, more virus is assumed to be required to initiate inflammatory immune responses.

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