scholarly journals Infectivity and antigenicity of SARS-CoV-2 B.1.617 variants

2021 ◽  
Author(s):  
Youchun Wang ◽  
Li Zhang ◽  
Qianqian Li ◽  
Jiajing Wu ◽  
Yuanling Yu ◽  
...  
Keyword(s):  
Amino Acid ◽  
Cell Fusion ◽  
Receptor Binding ◽  
Human Cells ◽  
Binding Domain ◽  
Single Amino Acid ◽  
Inactivated Vaccine ◽  
Receptor Binding Domain ◽  
Amino Acid Mutations ◽  
Cell Cell

Abstract SARS-CoV-2 has caused the COVID-19 pandemic. Recently, B.1.617 variants have been transmitted rapidly in India. The transmissibility, pathogenicity, and neutralization characteristics of these variants have received considerable interest. In this study, 22 pseudotyped viruses were constructed for B.1.617 variants and their corresponding single amino acid mutations. B.1.617 variants did not exhibit significant enhanced infectivity in human cells, but mutations T478K and E484Q in the receptor binding domain led to enhanced infectivity in mouse ACE2-overexpressing cells. Furin activities were slightly increased against B.1.617 variants and cell–cell fusion after infection of B.1.617 variants was enhanced. Furthermore, B.1.617 variants escaped neutralization by several mAbs, mainly because of mutations L452R, T478K, and E484Q in the receptor binding domain. The neutralization activities of sera from convalescent patients, inactivated vaccine-immunized volunteers, adenovirus vaccine-immunized volunteers, and SARS-CoV-2 immunized animals against pseudotyped B.1.617 variants were reduced by approximately twofold, compared with the D614G variant.

scholarly journals Ten emerging SARS-CoV-2 spike variants exhibit variable infectivity, animal tropism, and antibody neutralization

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Li Zhang ◽  
Zhimin Cui ◽  
Qianqian Li ◽  
Bo Wang ◽  
Yuanling Yu ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Amino Acid ◽  
Receptor Binding ◽  
Immune Escape ◽  
Cathepsin L ◽  
Single Amino Acid ◽  
Receptor Binding Domain ◽  
Therapeutic Antibodies ◽  
Amino Acid Mutations ◽  
Better Than

AbstractEmerging mutations in SARS-CoV-2 cause several waves of COVID-19 pandemic. Here we investigate the infectivity and antigenicity of ten emerging SARS-CoV-2 variants—B.1.1.298, B.1.1.7(Alpha), B.1.351(Beta), P.1(Gamma), P.2(Zeta), B.1.429(Epsilon), B.1.525(Eta), B.1.526-1(Iota), B.1.526-2(Iota), B.1.1.318—and seven corresponding single amino acid mutations in the receptor-binding domain using SARS-CoV-2 pseudovirus. The results indicate that the pseudovirus of most of the SARS-CoV-2 variants (except B.1.1.298) display slightly increased infectivity in human and monkey cell lines, especially B.1.351, B.1.525 and B.1.526 in Calu-3 cells. The K417N/T, N501Y, or E484K-carrying variants exhibit significantly increased abilities to infect mouse ACE2-overexpressing cells. The activities of furin, TMPRSS2, and cathepsin L are increased against most of the variants. RBD amino acid mutations comprising K417T/N, L452R, Y453F, S477N, E484K, and N501Y cause significant immune escape from 11 of 13 monoclonal antibodies. However, the resistance to neutralization by convalescent serum or vaccines elicited serum is mainly caused by the E484K mutation. The convalescent serum from B.1.1.7- and B.1.351-infected patients neutralized the variants themselves better than other SARS-CoV-2 variants. Our study provides insights regarding therapeutic antibodies and vaccines, and highlights the importance of E484K mutation.

scholarly journals Complete map of SARS-CoV-2 RBD mutations that escape the monoclonal antibody LY-CoV555 and its cocktail with LY-CoV016

2021 ◽  
Author(s):  
Tyler N. Starr ◽  
Allison J. Greaney ◽  
Adam S. Dingens ◽  
Jesse D. Bloom
Keyword(s):  
Monoclonal Antibody ◽  
Monoclonal Antibodies ◽  
Amino Acid ◽  
Receptor Binding ◽  
Binding Domain ◽  
Single Amino Acid ◽  
Receptor Binding Domain ◽  
Antigenic Evolution

AbstractMonoclonal antibodies and antibody cocktails are a promising therapeutic and prophylaxis for COVID-19. However, ongoing evolution of SARS-CoV-2 can render monoclonal antibodies ineffective. Here we completely map all mutations to the SARS-CoV-2 spike receptor binding domain (RBD) that escape binding by a leading monoclonal antibody, LY-CoV555, and its cocktail combination with LY-CoV016. Individual mutations that escape binding by each antibody are combined in the circulating B.1.351 and P.1 SARS-CoV-2 lineages (E484K escapes LY-CoV555, K417N/T escape LY-CoV016). Additionally, the L452R mutation in the B.1.429 lineage escapes LY-CoV555. Furthermore, we identify single amino acid changes that escape the combined LY-CoV555+LY-CoV016 cocktail. We suggest that future efforts should diversify the epitopes targeted by antibodies and antibody cocktails to make them more resilient to antigenic evolution of SARS-CoV-2.

scholarly journals Neutralization of European, South African, and United States SARS-CoV-2 mutants by a human antibody and antibody domains

2021 ◽  
Author(s):  
Zehua Sun ◽  
Andrew Kim ◽  
Michele D Sobolewski ◽  
Nathan Enick ◽  
Chuan Chen ◽  
...  
Keyword(s):  
United States ◽  
Amino Acid ◽  
Severe Acute Respiratory Syndrome ◽  
South African ◽  
Receptor Binding ◽  
Binding Domain ◽  
Human Antibody ◽  
Elisa Assay ◽  
Receptor Binding Domain ◽  
Amino Acid Mutations

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) transmission with several emerging variants remain uncontrolled in many countries, indicating the pandemic remains severe. Recent studies showed reduction of neutralization against these emerging SARS-CoV-2 variants by vaccine-elicited antibodies. Among those emerging SARS-CoV-2 variants, a panel of amino acid mutations was characterized including those in the receptor-binding domain (RBD) of the SARS-CoV-2 spike (S) glycoprotein. In the present study, we evaluated our previously identified antibody and antibody domains for binding to these RBD variants with the emerging mutations, and neutralization of pseudo typed viruses carrying spike proteins with such mutations. Our results showed that one previously identified antibody domain, ab6, can bind 32 out of 35 RBD mutants tested in an ELISA assay. All three antibodies and antibody domains can neutralize pseudo typed B.1.1.7 (UK variant), but only the antibody domain ab6 can neutralize the pseudo typed virus with the triple mutation (K417N, E484K, N501Y). This domain and its improvements have potential for therapy of infections caused by SARS-CoV-2 mutants.

scholarly journals Envelope Proteins Containing Single Amino Acid Substitutions Support a Structural Model of the Receptor-Binding Domain of Bovine Leukemia Virus Surface Protein

2002 ◽  
Vol 76 (21) ◽  
pp. 10861-10872 ◽  
Author(s):  
Elizabeth R. Johnston ◽  
Lorraine M. Albritton ◽  
Kathryn Radke
Keyword(s):  
Amino Acid ◽  
Receptor Binding ◽  
Bovine Leukemia Virus ◽  
Murine Leukemia Virus ◽  
Leukemia Virus ◽  
Binding Domain ◽  
Single Amino Acid ◽  
Receptor Binding Domain ◽  
Env Protein ◽  
Murine Leukemia

ABSTRACT Functional domains of the strikingly conserved envelope (Env) glycoproteins of bovine leukemia virus (BLV) and its close relative, human T-cell leukemia virus type 1 (HTLV-1), are still being defined. We have used BLV Env protein variants to gain insights into the structure and function of this important determinant of viral infectivity. Each of 23 different single amino acid variants found in cDNA clones of env transcripts present after short-term culture of peripheral blood mononuclear cells from BLV-infected sheep was expressed in COS-1 cells and tested for the ability to mediate cell fusion and to be cleaved to surface (SU) and transmembrane (TM) protein subunits. Of 11 Env variants that failed to induce syncytia or did so poorly, 7 contained changes in amino acids identical or chemically conserved in the HTLV-1 Env protein. These seven included the four variants that showed aberrant proteolytic cleavage and poor cell surface expression, underscoring their importance for Env structure. Ten of 12 variants that retained wild-type syncytium-inducing ability clustered in the N-terminal half of BLV SU, which forms the putative receptor-binding domain (RBD). Several variants in the RBD showed evidence of subtle misfolding, as judged by reduced binding to monoclonal antibodies recognizing conformational epitopes F, G, and H formed by the N terminus of SU. We modeled the BLV RBD by aligning putative structural elements with known elements of the ecotropic Friend murine leukemia virus RBD monomer. All the variant RBD residues but one are exposed on the surface of this BLV model. These variants as well as function-altering, antibody-reactive residues defined by other investigators group on one face of the molecular model. They are strikingly absent from the opposite face, implying that it is likely to face inward in Env complexes. This surface might interact with the C-terminal domain of SU or with an adjacent monomer in the Env oligomer. This location suggests an orientation for the monomer of ecotropic Friend murine leukemia virus RBD.

scholarly journals Genetic Variation and Evolution of the 2019 Novel Coronavirus

2021 ◽  
pp. 1-13
Author(s):  
Salvatore Dimonte ◽  
Muhammed Babakir-Mina ◽  
Taib Hama-Soor ◽  
Salar Ali
Keyword(s):  
Amino Acid ◽  
Receptor Binding ◽  
Rapid Evolution ◽  
Single Amino Acid ◽  
Angiotensin Converting Enzyme 2 ◽  
New Type ◽  
Amino Acid Mutations ◽  
Host Infection ◽  
Human Coronaviruses ◽  
Novel Coronavirus

<b><i>Introduction:</i></b> SARS-CoV-2 is a new type of coronavirus causing a pandemic severe acute respiratory syndrome (SARS-2). Coronaviruses are very diverting genetically and mutate so often periodically. The natural selection of viral mutations may cause host infection selectivity and infectivity. <b><i>Methods:</i></b> This study was aimed to indicate the diversity between human and animal coronaviruses through finding the rate of mutation in each of the spike, nucleocapsid, envelope, and membrane proteins. <b><i>Results:</i></b> The mutation rate is abundant in all 4 structural proteins. The most number of statistically significant amino acid mutations were found in spike receptor-binding domain (RBD) which may be because it is responsible for a corresponding receptor binding in a broad range of hosts and host selectivity to infect. Among 17 previously known amino acids which are important for binding of spike to angiotensin-converting enzyme 2 (ACE2) receptor, all of them are conservative among human coronaviruses, but only 3 of them significantly are mutated in animal coronaviruses. A single amino acid aspartate-454, that causes dissociation of the RBD of the spike and ACE2, and F486 which gives the strength of binding with ACE2 remain intact in all coronaviruses. <b><i>Discussion/Conclusion:</i></b> Observations of this study provided evidence of the genetic diversity and rapid evolution of SARS-CoV-2 as well as other human and animal coronaviruses.

ReaxFF-based molecular dynamics simulation of the interaction between plasma ROS and the receptor-binding domain of the spike protein in the capsid protein of SARS-CoV-2

2021 ◽  
Author(s):  
Huichao Wang ◽  
Tong Zhao ◽  
Shuhui Yang ◽  
Liang Zou ◽  
Xiaolong Wang ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Amino Acid ◽  
Capsid Protein ◽  
Receptor Binding ◽  
Hydrogen Abstraction ◽  
Binding Domain ◽  
Spike Protein ◽  
Receptor Binding Domain ◽  
Amino Acid Residues ◽  
Global Epidemic

Abstract Under the severe situation of the current global epidemic, researchers have been working hard to find a reliable way to suppress the infection of the virus and prevent the spread of the epidemic. Studies have shown that the recognition and binding of human angiotensin-converting enzyme 2 (ACE2) by the receptor-binding domain (BRD) of spike protein on the surface of SARS-CoV-2 is a crucial step for SARS-CoV-2 to invade human receptor cells, and blocking this process can inhibit the virus from invading human normal cells. Plasma treatment can disrupt the structure of the RBD and effectively block the binding process. However, the mechanism by which plasma blocks the recognition and binding between the two is not clear. In this study, reaction process between reactive oxygen species (ROS) in plasma and the molecular model of RBD was simulated using a reactive molecular dynamics method. The results showed that the destruction of RBD molecule by ROS was triggered by hydrogen abstraction reactions. O and OH abstracted H atoms from RBD, while the H atoms of H2O2 and HO2 were abstracted by RBD. The hydrogen abstraction resulted in the breakage of C-H, N-H, O-H and C=O bonds and the formation of C=C, C=N bonds. The addition reaction of OH increased the number of O-H bonds and caused the formation of C-O, N-O and O-H bonds. The dissociation of N-H bonds led to the destruction of the original structure of peptide bonds and amino acid residues, change the type of amino acid residues, and caused the conversion of N-C and N=C, C=O and C-O. The simulation partially elucidated the microscopic mechanism of the interaction between ROS in plasma and the capsid protein of SARS-CoV-2, providing theoretical support for the control of SARS-CoV-2 infection by plasma, a contribution to overcoming the global epidemic problem.

Construction and immunogenic studies of a mFc fusion receptor binding domain (RBD) of spike protein as a subunit vaccine against SARS-CoV-2 infection

2020 ◽  
Vol 56 (61) ◽  
pp. 8683-8686 ◽  
Author(s):  
Xiaoxiao Qi ◽  
Bixia Ke ◽  
Qian Feng ◽  
Deying Yang ◽  
Qinghai Lian ◽  
...  
Keyword(s):  
Amino Acid ◽  
Fusion Protein ◽  
Receptor Binding ◽  
Neutralizing Antibodies ◽  
Subunit Vaccine ◽  
Binding Domain ◽  
Spike Protein ◽  
Receptor Binding Domain ◽  
Humoral And Cellular Immunity ◽  
A Subunit

Herein, we report that a recombinant fusion protein, containing a 457 amino acid SARS-CoV-2 receptor binding domain and a mouse IgG1 Fc domain, could induce highly potent neutralizing antibodies and stimulate humoral and cellular immunity in mice.

scholarly journals Receptor Binding Domain of Escherichia coli F18 Fimbrial Adhesin FedF Can Be both Efficiently Secreted and Surface Displayed in a Functional Form in Lactococcus lactis

2004 ◽  
Vol 70 (4) ◽  
pp. 2061-2071 ◽  
Author(s):  
Agneta Lindholm ◽  
Andreas Smeds ◽  
Airi Palva
Keyword(s):  
Escherichia Coli ◽  
Amino Acid ◽  
Receptor Binding ◽  
Intestinal Epithelial Cells ◽  
Surface Display ◽  
Cell Surface Display ◽  
Binding Domain ◽  
Intestinal Epithelial ◽  
Receptor Binding Domain ◽  
Amino Acid Residues

ABSTRACT Adherence of F18 fimbrial Escherichia coli to porcine intestinal epithelial cells is mediated by the adhesin (FedF) of F18 fimbriae. In a previous study, we demonstrated the specificity of the amino acid residues between 60 and 109 as the receptor binding domain of FedF. In this study, different expression, secretion, and anchoring systems for the receptor binding domain of the FedF adhesin in Lactococcus lactis were evaluated. Two partially overlapping receptor binding domains (42 and 62 amino acid residues) were expressed as fusions with L. lactis subsp. cremoris protein PrtP for evaluation of secretion efficiency. To evaluate the cell surface display of these FedF-PrtP fusions, they were further combined with different lengths of PrtP spacers fused with either the L. lactis AcmA anchor or the PrtP cell wall binding domain. An HtrA-defective L. lactis NZ9000 mutant was constructed to determine its effect on the level of secreted or anchored fusion proteins. Recombinant L. lactis clones secreting the receptor binding domain of F18 fimbriae as a fusion with the H domains of L. lactis protein PrtP were first constructed by using two different signal peptides. FedF-PrtP fusions, directed by the signal sequence of L. brevis SlpA, were throughout found to be secreted at significantly higher quantities than corresponding fusions with the signal peptide of L. lactis Usp45. In the surface display systems tested, the L. lactis AcmA anchor performed significantly better, particularly in the L. lactis NZ9000ΔhtrA strain, compared to the L. lactis PrtP anchor region. Of the cell surface display constructs with the AcmA anchor, only those with the longest PrtP spacer regions resulted in efficient binding of recombinant L. lactis cells to porcine intestinal epithelial cells. These results confirmed that it is possible to efficiently produce the receptor binding domain of the F18 adhesin in a functionally active form in L. lactis.

scholarly journals SARS-CoV-2, an evolutionary perspective of interaction with human ACE2 reveals undiscovered amino acids necessary for complex stability

2020 ◽  
Author(s):  
Vinicio Armijos-Jaramillo ◽  
Justin Yeager ◽  
Claire Muslin ◽  
Yunierkis Perez-Castillo
Keyword(s):  
Receptor Binding ◽  
Evolutionary Dynamics ◽  
Hot Spot ◽  
Critical Role ◽  
Human Cells ◽  
Binding Domain ◽  
Host Cells ◽  
Spike Protein ◽  
Receptor Binding Domain ◽  
Salt Bridges

AbstractThe emergence of SARS-CoV-2 has resulted in more than 200,000 infections and nearly 9,000 deaths globally so far. This novel virus is thought to have originated from an animal reservoir, and acquired the ability to infect human cells using the SARS-CoV cell receptor hACE2. In the wake of a global pandemic it is essential to improve our understanding of the evolutionary dynamics surrounding the origin and spread of a novel infectious disease. One way theory predicts selection pressures should shape viral evolution is to enhance binding with host cells. We first assessed evolutionary dynamics in select betacoronavirus spike protein genes to predict where these genomic regions are under directional or purifying selection between divergent viral lineages at various scales of relatedness. With this analysis, we determine a region inside the receptor-binding domain with putative sites under positive selection interspersed among highly conserved sites, which are implicated in structural stability of the viral spike protein and its union with human receptor hACE2. Next, to gain further insights into factors associated with coronaviruses recognition of the human host receptor, we performed modeling studies of five different coronaviruses and their potential binding to hACE2. Modeling results indicate that interfering with the salt bridges at hot spot 353 could be an effective strategy for inhibiting binding, and hence for the prevention of coronavirus infections. We also propose that a glycine residue at the receptor binding domain of the spike glycoprotein can have a critical role in permitting bat variants of the coronaviruses to infect human cells.

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