scholarly journals Neutralization of N501Y mutant SARS-CoV-2 by BNT162b2 vaccine-elicited sera

2021 ◽  
Author(s):  
Xuping Xie ◽  
Jing Zou ◽  
Camila R. Fontes-Garfias ◽  
Hongjie Xia ◽  
Kena A. Swanson ◽  
...  
Keyword(s):  
South Africa ◽  
United Kingdom ◽  
Angiotensin Converting Enzyme ◽  
Receptor Binding ◽  
Cell Entry ◽  
Converting Enzyme ◽  
Receptor Binding Site ◽  
Viral Receptor ◽  
Angiotensin Converting Enzyme 2 ◽  
The United Kingdom

Rapidly spreading variants of SARS-CoV-2 that have arisen in the United Kingdom and South Africa share the spike N501Y substitution, which is of particular concern because it is located in the viral receptor binding site for cell entry and increases binding to the receptor (angiotensin converting enzyme 2). We generated isogenic N501 and Y501 SARS-CoV-2. Sera of 20 participants in a previously reported trial of the mRNA-based COVID-19 vaccine BNT162b2 had equivalent neutralizing titers to the N501 and Y501 viruses.

scholarly journals Neutralization of N501Y mutant SARS-CoV-2 by BNT162b2 vaccine-elicited sera

2021 ◽  
Author(s):  
Pei-Yong Shi ◽  
Xuping Xie ◽  
Jing Zou ◽  
Camila Fontes-Garfias ◽  
Hongjie Xia ◽  
...  
Keyword(s):  
South Africa ◽  
United Kingdom ◽  
Binding Site ◽  
Receptor Binding ◽  
Cell Entry ◽  
Receptor Binding Site ◽  
Viral Receptor ◽  
The United Kingdom ◽  
Human Sera

Abstract Rapidly spreading variants of SARS-CoV-2 that have arisen in the United Kingdom and South Africa share the spike N501Y substitution, which is of particular concern because it is located in the viral receptor binding site for cell entry and increases binding to the receptor. We generated isogenic N501 and Y501 SARS-CoV-2. Twenty human sera from the mRNA-based vaccine BNT162b2 trial exhibited equivalent neutralizing titers to the N501 and Y501 viruses.

scholarly journals Coronacept – a potent immunoadhesin against SARS-CoV-2

2020 ◽  
Author(s):  
Hadas Cohen-Dvashi ◽  
Jonathan Weinstein ◽  
Michael Katz ◽  
Maayan Eilon ◽  
Yuval Mor ◽  
...  
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Angiotensin Converting Enzyme ◽  
Receptor Binding ◽  
Computational Analysis ◽  
Binding Domain ◽  
Cellular Receptor ◽  
Receptor Binding Domain ◽  
Converting Enzyme ◽  
Viral Receptor ◽  
Angiotensin Converting Enzyme 2

AbstractAngiotensin-converting enzyme 2 (ACE2) is the cellular receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Computational analysis of mammalian ACE2 orthologues suggests various residues at the interface with the viral receptor binding domain that could facilitate tighter interaction compared to the human-ACE2. Introducing several mutations to the human-ACE2 resulted with significantly augmented affinity to the viral spike complex. This modified human-ACE2 fused to an Fc portion of an antibody makes a potent immunoadhesin that effectively targets SARS-CoV-2.

scholarly journals SARS-CoV-2 Structural Analysis of Receptor Binding Domain New Variants from United Kingdom and South Africa

2021 ◽  
Vol 7 ◽  
Author(s):  
Victor Padilla-Sanchez
Keyword(s):  
South Africa ◽  
United Kingdom ◽  
Structural Analysis ◽  
Receptor Binding ◽  
Binding Domain ◽  
The Other ◽  
Receptor Binding Domain ◽  
Converting Enzyme ◽  
Spike Glycoprotein ◽  
Angiotensin Converting Enzyme 2

SARS-CoV-2 has caused more than 80 million infections and close to 2 million deaths worldwide as of January 2021. This pandemic has caused an incredible damage to humanity being it medically and/or financially halting life as we know it. If it were not enough, the current virus is changing to a more deadly form because of the mutations that are arising on its genome. Importantly, two variants have emerged in recent months, one in United Kingdom and the other in South Africa that are more infectious and escape antibody binding. These two variants have mutations in the receptor binding domain of the spike glycoprotein namely N501Y (UK, SA), K417N (SA) and E484K (SA). Here, I present a structural analysis of spike glycoprotein bound to ACE2 (angiotensin converting enzyme 2) where the mutations have been introduced in silico showing the reason why these variants bind better to ACE2 receptors.

scholarly journals The Effects of Aβ1-42 Binding to the SARS-CoV-2 Spike Protein S1 Subunit and Angiotensin-Converting Enzyme 2

2021 ◽  
Vol 22 (15) ◽  
pp. 8226
Author(s):  
John Tsu-An Hsu ◽  
Chih-Feng Tien ◽  
Guann-Yi Yu ◽  
Santai Shen ◽  
Yi-Hsuan Lee ◽  
...  
Keyword(s):  
Angiotensin Converting Enzyme ◽  
Viral Entry ◽  
Negative Impact ◽  
Spike Protein ◽  
Infection Model ◽  
Converting Enzyme ◽  
Viral Receptor ◽  
Angiotensin Converting Enzyme 2 ◽  
People With Dementia ◽  
The Impact

Increasing evidence suggests that elderly people with dementia are vulnerable to the development of severe coronavirus disease 2019 (COVID-19). In Alzheimer’s disease (AD), the major form of dementia, β-amyloid (Aβ) levels in the blood are increased; however, the impact of elevated Aβ levels on the progression of COVID-19 remains largely unknown. Here, our findings demonstrate that Aβ1-42, but not Aβ1-40, bound to various viral proteins with a preferentially high affinity for the spike protein S1 subunit (S1) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the viral receptor, angiotensin-converting enzyme 2 (ACE2). These bindings were mainly through the C-terminal residues of Aβ1-42. Furthermore, Aβ1-42 strengthened the binding of the S1 of SARS-CoV-2 to ACE2 and increased the viral entry and production of IL-6 in a SARS-CoV-2 pseudovirus infection model. Intriguingly, data from a surrogate mouse model with intravenous inoculation of Aβ1-42 show that the clearance of Aβ1-42 in the blood was dampened in the presence of the extracellular domain of the spike protein trimers of SARS-CoV-2, whose effects can be prevented by a novel anti-Aβ antibody. In conclusion, these findings suggest that the binding of Aβ1-42 to the S1 of SARS-CoV-2 and ACE2 may have a negative impact on the course and severity of SARS-CoV-2 infection. Further investigations are warranted to elucidate the underlying mechanisms and examine whether reducing the level of Aβ1-42 in the blood is beneficial to the fight against COVID-19 and AD.

scholarly journals Mutations from bat ACE2 orthologs markedly enhance ACE2-Fc neutralization of SARS-CoV-2

2020 ◽  
Author(s):  
Huihui Mou ◽  
Brian D. Quinlan ◽  
Haiyong Peng ◽  
Yan Guo ◽  
Shoujiao Peng ◽  
...  
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Angiotensin Converting Enzyme ◽  
Converting Enzyme ◽  
Viral Receptor ◽  
S Protein ◽  
Angiotensin Converting Enzyme 2 ◽  
Binding Domains ◽  
Protein Receptor ◽  
Horseshoe Bat ◽  
Horseshoe Bats

SUMMARYThe severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) protein mediates infection of cells expressing angiotensin-converting enzyme 2 (ACE2). ACE2 is also the viral receptor of SARS-CoV (SARS-CoV-1), a related coronavirus that emerged in 2002-2003. Horseshoe bats (genus Rhinolophus) are presumed to be the original reservoir of both viruses, and a SARS-like coronavirus, RaTG13, closely related SARS-CoV-2, has been isolated from one horseshoe-bat species. Here we characterize the ability of S-protein receptor-binding domains (RBDs) of SARS-CoV-1, SARS-CoV-2, and RaTG13 to bind a range of ACE2 orthologs. We observed that the SARS-CoV-2 RBD bound human, pangolin, and horseshoe bat (R. macrotis) ACE2 more efficiently than the SARS-CoV-1 or RaTG13 RBD. Only the RaTG13 RBD bound rodent ACE2 orthologs efficiently. Five mutations drawn from ACE2 orthologs of nine Rhinolophus species enhanced human ACE2 binding to the SARS-CoV-2 RBD and neutralization of SARS-CoV-2 by an immunoadhesin form of human ACE2 (ACE2-Fc). Two of these mutations impaired neutralization of SARS-CoV-1. An ACE2-Fc variant bearing all five mutations neutralized SARS-CoV-2 five-fold more efficiently than human ACE2-Fc. These data narrow the potential SARS-CoV-2 reservoir, suggest that SARS-CoV-1 and -2 originate from distinct bat species, and identify a more potently neutralizing form of ACE2-Fc.

scholarly journals Possible Transmission Flow of SARS-CoV-2 Based on ACE2 Features

Molecules ◽  
2020 ◽  
Vol 25 (24) ◽  
pp. 5906
Author(s):  
Sk. Sarif Hassan ◽  
Shinjini Ghosh ◽  
Diksha Attrish ◽  
Pabitra Pal Choudhury ◽  
Alaa A. A. Aljabali ◽  
...  
Keyword(s):  
Amino Acids ◽  
Severe Acute Respiratory Syndrome ◽  
Angiotensin Converting Enzyme ◽  
Receptor Binding ◽  
Comprehensive Analysis ◽  
Cellular Receptor ◽  
Receptor Binding Domain ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2 ◽  
Protein Receptor

Angiotensin-converting enzyme 2 (ACE2) is the cellular receptor for the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) that is engendering the severe coronavirus disease 2019 (COVID-19) pandemic. The spike (S) protein receptor-binding domain (RBD) of SARS-CoV-2 binds to the three sub-domains viz. amino acids (aa) 22–42, aa 79–84, and aa 330–393 of ACE2 on human cells to initiate entry. It was reported earlier that the receptor utilization capacity of ACE2 proteins from different species, such as cats, chimpanzees, dogs, and cattle, are different. A comprehensive analysis of ACE2 receptors of nineteen species was carried out in this study, and the findings propose a possible SARS-CoV-2 transmission flow across these nineteen species.

scholarly journals A Multifunctional Peptide From Bacillus Fermented Soybean for Effective Inhibition of SARS-CoV-2 S1 Receptor Binding Domain and Modulation of Toll Like Receptor 4: A Molecular Docking Study

2021 ◽  
Vol 8 ◽  
Author(s):  
Srichandan Padhi ◽  
Samurailatpam Sanjukta ◽  
Rounak Chourasia ◽  
Rajendra K. Labala ◽  
Sudhir P. Singh ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Angiotensin Converting Enzyme ◽  
Receptor Binding ◽  
In Silico ◽  
Receptor Binding Domain ◽  
Converting Enzyme ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Angiotensin Converting Enzyme 2 ◽  
Fermented Soybean

Fermented soybean products are traditionally consumed and popular in many Asian countries and the northeastern part of India. To search for potential agents for the interruption of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Spike glycoprotein 1 (S1) and human angiotensin-converting enzyme 2 (ACE2) receptor interactions, the in silico antiviral prospective of peptides identified from the proteome of kinema was investigated. Soybean was fermented using Bacillus licheniformis KN1G, Bacillus amyloliquefaciens KN2G and two different strains of Bacillus subtilis (KN2B and KN2M). The peptides were screened in silico for possible antiviral activity using two different web servers (AVPpred and meta-iAVP), and binding interactions of selected 44 peptides were further explored against the receptor-binding domain (RBD) of the S1 protein (PDB ID: 6M0J) by molecular docking using ZDOCK. The results showed that a peptide ALPEEVIQHTFNLKSQ (P13) belonging to B. licheniformis KN1G fermented kinema was able to make contacts with the binding motif of RBD by blocking specific residues designated as critical (GLN493, ASN501) in the binding of human angiotensin-converting enzyme 2 (ACE2) cell receptor. The selected peptide was also observed to have a significant affinity towards human toll like receptor 4 (TLR4)/Myeloid Differentiation factor 2 (MD2) (PDB ID: 3FXI) complex known for its essential role in cytokine storm. The energy properties of the docked complexes were analyzed through the Generalized Born model and Solvent Accessibility method (MM/GBSA) using HawkDock server. The results showed peptidyl amino acids GLU5, GLN8, PHE11, and LEU13 contributed most to P13-RBD binding. Similarly, ARG90, PHE121, LEU61, PHE126, and ILE94 were appeared to be significant in P13-TLR4/MD2 complex. The findings of the study suggest that the peptides from fermented soy prepared using B. licheniformis KN1G have better potential to be used as antiviral agents. The specific peptide ALPEEVIQHTFNLKSQ could be synthesized and used in combination with experimental studies to validate its effect on SARS-CoV-2-hACE2 interaction and modulation of TLR4 activity. Subsequently, the protein hydrolysate comprising these peptides could be used as prophylaxis against viral diseases, including COVID-19.

scholarly journals Cooperative multivalent receptor binding promotes exposure of the SARS-CoV-2 fusion machinery core

2021 ◽  
Author(s):  
Alexander J Pak ◽  
Alvin Yu ◽  
Zunlong Ke ◽  
John Briggs ◽  
Gregory A Voth
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Angiotensin Converting Enzyme ◽  
Membrane Fusion ◽  
Receptor Binding ◽  
Coarse Grained ◽  
Viral Fusion ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2 ◽  
Viral Binding ◽  
Molecular Events

The molecular events that permit the spike glycoprotein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to bind, fuse, and enter cells are important to understand for both fundamental and therapeutic reasons. Spike proteins consist of S1 and S2 domains, which recognize angiotensin-converting enzyme 2 (ACE2) receptors and contain the viral fusion machinery, respectively. Ostensibly, the binding of spike trimers to ACE2 receptors promotes the preparation of the fusion machinery by dissociation of the S1 domains. We report the development and use of coarse-grained models and simulations to investigate the dynamical mechanisms involved in viral binding and exposure of the S2 trimeric core. We show that spike trimers cooperatively bind to multiple ACE2 dimers. The multivalent interaction cyclically and processively induces S1 dissociation, thereby exposing the S2 core containing the fusion machinery. Our simulations thus reveal an important concerted interaction between spike trimers and ACE2 dimers that primes the virus for membrane fusion and entry.

scholarly journals Phenolic compounds disrupt spike-mediated receptor-binding and entry of SARS-CoV-2 pseudo-virions

PLoS ONE ◽  
2021 ◽  
Vol 16 (6) ◽  
pp. e0253489
Author(s):  
Anna Goc ◽  
Waldemar Sumera ◽  
Matthias Rath ◽  
Aleksandra Niedzwiecki
Keyword(s):  
Phenolic Compounds ◽  
Angiotensin Converting Enzyme ◽  
Receptor Binding ◽  
Cathepsin L ◽  
Converting Enzyme ◽  
Cellular Mechanisms ◽  
Angiotensin Converting Enzyme 2 ◽  
Viral Attachment ◽  
Cellular Entry ◽  
Transmembrane Serine Protease

In the pursuit of suitable and effective solutions to SARS-CoV-2 infection, we investigated the efficacy of several phenolic compounds in controlling key cellular mechanisms involved in its infectivity. The way the SARS-CoV-2 virus infects the cell is a complex process and comprises four main stages: attachment to the cognate receptor, cellular entry, replication and cellular egress. Since, this is a multi-part process, it creates many opportunities to develop effective interventions. Targeting binding of the virus to the host receptor in order to prevent its entry has been of particular interest. Here, we provide experimental evidence that, among 56 tested polyphenols, including plant extracts, brazilin, theaflavin-3,3’-digallate, and curcumin displayed the highest binding with the receptor-binding domain of spike protein, inhibiting viral attachment to the human angiotensin-converting enzyme 2 receptor, and thus cellular entry of pseudo-typed SARS-CoV-2 virions. Both, theaflavin-3,3’-digallate at 25 μg/ml and curcumin above 10 μg/ml concentration, showed binding with the angiotensin-converting enzyme 2 receptor reducing at the same time its activity in both cell-free and cell-based assays. Our study also demonstrates that brazilin and theaflavin-3,3’-digallate, and to a still greater extent, curcumin, decrease the activity of transmembrane serine protease 2 both in cell-free and cell-based assays. Similar pattern was observed with cathepsin L, although only theaflavin-3,3’-digallate showed a modest diminution of cathepsin L expression at protein level. Finally, each of these three compounds moderately increased endosomal/lysosomal pH. In conclusion, this study demonstrates pleiotropic anti-SARS-CoV-2 efficacy of specific polyphenols and their prospects for further scientific and clinical investigations.

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