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 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.

Merging of Complementary Structural Techniques

1997 ◽  
Vol 3 (S2) ◽  
pp. 1119-1120
Author(s):  
P.L. Stewart ◽  
C.Y. Chiu ◽  
D.A. Haley
Keyword(s):  
Binding Site ◽  
Receptor Binding ◽  
Three Dimensional ◽  
Human Adenovirus ◽  
Maldi Mass Spectrometry ◽  
Fab Fragment ◽  
Receptor Binding Site ◽  
Viral Receptor ◽  
Peptide Epitope ◽  
Image Reconstruction Techniques

Cryo-electron microscopy (cryo-EM) and image reconstruction techniques provide a powerful way to study three-dimensional structures of biological complexes. As the resolution of the resulting three-dimensional reconstructions is typically in the range of 10-35 À, information from other structural techniques is often invaluable in analyzing the biological structure. We present the use of crystallographic coordinates to determine the amplitude of motion of a viral receptor binding site and molecular models to assess the degree of quaternary conformational flexibility within a multimeric protein assembly.In order to visualize the αv integrin receptor binding site on the surface of human adenovirus (150 MDa), we have reconstructed adenovirus in complex with a Fab fragment from a monoclonal antibody (DAV-1) targeted to this site. The peptide epitope of DAV-1 has been mapped by MALDI mass spectrometry to 9 residues within the penton base protein and includes the integrin binding Arg-Gly-Asp (RGD) residues.

scholarly journals The natural stilbenoid (–)-hopeaphenol inhibits cellular entry of SARS-CoV-2 USA-WA1/2020, B.1.1.7 and B.1.351 variants

2021 ◽  
Author(s):  
Ian Tietjen ◽  
Joel Cassel ◽  
Emery T. Register ◽  
Xiang Yang Zhou ◽  
Troy E. Messick ◽  
...  
Keyword(s):  
South Africa ◽  
United Kingdom ◽  
Receptor Binding ◽  
Viral Entry ◽  
Cytopathic Effect ◽  
Selective Inhibitors ◽  
The United Kingdom ◽  
Pure Compounds ◽  
The Usa

AbstractAntivirals are urgently needed to combat the global SARS-CoV-2/COVID-19 pandemic, supplement existing vaccine efforts, and target emerging SARS-CoV-2 variants of concern. Small molecules that interfere with binding of the viral spike receptor binding domain (RBD) to the host ACE2 receptor may be effective inhibitors of SARS-CoV-2 cell entry. Here we screened 512 pure compounds derived from natural products using a high-throughput RBD/ACE2 binding assay and identified (–)-hopeaphenol, a resveratrol tetramer, in addition to vatalbinoside A and vaticanol B, as potent and selective inhibitors of RBD/ACE2 binding and viral entry. For example, (–)-hopeaphenol disrupted RBD/ACE2 binding with a 50% inhibitory concentration (IC50) of 0.11 μM in contrast to an IC50 of 28.3 μM against the unrelated host ligand/receptor binding pair PD-1/PD-L1 (selectivity index = 257.3). When assessed against the USA-WA1/2020 variant, (–)-hopeaphenol also inhibited entry of a VSVΔG-GFP reporter pseudovirus expressing SARS-CoV-2 spike into ACE2-expressing Vero-E6 cells and in vitro replication of infectious virus in cytopathic effect assays (IC50 = 10.2 μM) without cytotoxicity. Notably, (–)- hopeaphenol also inhibited two emerging variants of concern originating from the United Kingdom (B.1.1.7) and South Africa (B.1.351) in both cytopathic effect and spike-containing pseudovirus assays with similar (B.1.1.7) or improved (B.1.351) efficacies over the USA- WA1/2020 variant. These results identify (–)-hopeaphenol and related stilbenoid analogues as potent and selective inhibitors of viral entry across multiple SARS-CoV-2 variants including those with increased infectivity and/or reduced susceptibility to existing vaccines.ImportanceSARS-CoV-2 antivirals are needed to supplement existing vaccine efforts and target emerging viral variants with increased infectivity or reduced susceptibility to existing vaccines. Here we show that (–)-hopeaphenol, a naturally-occurring stilbenoid compound, in addition to its analogues vatalbinoside A and vaticanol B, inhibit SARS-CoV-2 by blocking the interaction of the viral spike protein with the cellular ACE2 entry receptor. Importantly, in addition to inhibiting the early USA-WA1/2020 SARS-CoV-2 variant, hopeaphenol also inhibits emerging variants of concern including B.1.1.7 (“United Kingdom variant”) and B.1.351 (“South Africa variant”), with improved efficacy against B.1.351. (–)-Hopeaphenol therefore represents a new antiviral lead against infection from multiple SARS-CoV-2 variants.

scholarly journals Structural and functional ramifications of antigenic drift in recent SARS-CoV-2 variants

Science ◽  
2021 ◽  
pp. eabh1139
Author(s):  
Meng Yuan ◽  
Deli Huang ◽  
Chang-Chun D. Lee ◽  
Nicholas C. Wu ◽  
Abigail M. Jackson ◽  
...  
Keyword(s):  
South Africa ◽  
Binding Site ◽  
Receptor Binding ◽  
Neutralizing Antibodies ◽  
Antigenic Drift ◽  
Spike Protein ◽  
Binding Modes ◽  
Next Generation ◽  
Wild Type ◽  
Receptor Binding Site

Neutralizing antibodies (nAbs) elicited against the receptor-binding site (RBS) of the spike protein of wild-type SARS-CoV-2 are generally less effective against recent variants of concern. RBS residues E484, K417 and N501 are mutated in variants first described in South Africa (B.1.351) and Brazil (P.1). We analyzed their effects on ACE2 binding and K417N and E484K mutations on nAbs isolated from COVID-19 patients. Binding and neutralization of the two most frequently elicited antibody families (IGHV3-53/3-66 and IGHV1-2), which can both bind the RBS in alternate binding modes, are abrogated by K417N, E484K, or both. These effects can be structurally explained by their extensive interactions with RBS nAbs. However, nAbs to the more conserved, cross-neutralizing CR3022 and S309 sites were largely unaffected. The results have implications for next-generation vaccines and antibody therapies.

scholarly journals Viral Receptor-Binding Site Antibodies with Diverse Germline Origins

Cell ◽  
2015 ◽  
Vol 161 (5) ◽  
pp. 1026-1034 ◽  
Author(s):  
Aaron G. Schmidt ◽  
Matthew D. Therkelsen ◽  
Shaun Stewart ◽  
Thomas B. Kepler ◽  
Hua-Xin Liao ◽  
...  
Keyword(s):  
Binding Site ◽  
Receptor Binding ◽  
Receptor Binding Site ◽  
Viral Receptor

scholarly journals RIC in COVID-19—a Clinical Trial to Investigate Whether Remote Ischemic Conditioning (RIC) Can Prevent Deterioration to Critical Care in Patients with COVID-19

2021 ◽  
Author(s):  
Sean M. Davidson ◽  
Kishal Lukhna ◽  
Diana A. Gorog ◽  
Alan D. Salama ◽  
Alejandro Rosell Castillo ◽  
...  
Keyword(s):  
South Africa ◽  
Clinical Trial ◽  
United Kingdom ◽  
Inflammatory Cytokines ◽  
In Vitro Cytotoxicity ◽  
Cytokine Storm ◽  
Remote Ischemic Conditioning ◽  
Ischemic Conditioning ◽  
The United Kingdom

Abstract Purpose Coronavirus disease 19 (COVID-19) has, to date, been diagnosed in over 130 million persons worldwide and is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Several variants of concern have emerged including those in the United Kingdom, South Africa, and Brazil. SARS-CoV-2 can cause a dysregulated inflammatory response known as a cytokine storm, which can progress rapidly to acute respiratory distress syndrome (ARDS), multi-organ failure, and death. Suppressing these cytokine elevations may be key to improving outcomes. Remote ischemic conditioning (RIC) is a simple, non-invasive procedure whereby a blood pressure cuff is inflated and deflated on the upper arm for several cycles. “RIC in COVID-19” is a pilot, multi-center, randomized clinical trial, designed to ascertain whether RIC suppresses inflammatory cytokine production. Methods A minimum of 55 adult patients with diagnosed COVID-19, but not of critical status, will be enrolled from centers in the United Kingdom, Brazil, and South Africa. RIC will be administered daily for up to 15 days. The primary outcome is the level of inflammatory cytokines that are involved in the cytokine storm that can occur following SARS-CoV-2 infection. The secondary endpoint is the time between admission and until intensive care admission or death. The in vitro cytotoxicity of patient blood will also be assessed using primary human cardiac endothelial cells. Conclusions The results of this pilot study will provide initial evidence on the ability of RIC to suppress the production of inflammatory cytokines in the setting of COVID-19. Trial Registration NCT04699227, registered January 7th, 2021.

scholarly journals Potent sialic acid inhibitors that target influenza A virus hemagglutinin

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Yu-Jen Chang ◽  
Cheng-Yun Yeh ◽  
Ju-Chien Cheng ◽  
Yu-Qi Huang ◽  
Kai-Cheng Hsu ◽  
...  
Keyword(s):  
Sialic Acid ◽  
Antiviral Activity ◽  
Binding Site ◽  
Influenza A Virus ◽  
Receptor Binding ◽  
Influenza A ◽  
The United States ◽  
Ligand Complex ◽  
Receptor Binding Site ◽  
Computational Strategy

AbstractEradicating influenza A virus (IAV) is difficult, due to its genetic drift and reassortment ability. As the infectious cycle is initiated by the influenza glycoprotein, hemagglutinin (HA), which mediates the binding of virions to terminal sialic acids moieties, HA is a tempting target of anti-influenza inhibitors. However, the complexity of the HA structure has prevented delineation of the structural characterization of the HA protein–ligand complex. Our computational strategy efficiently analyzed > 200,000 records of compounds held in the United States National Cancer Institute (NCI) database and identified potential HA inhibitors, by modeling the sialic acid (SA) receptor binding site (RBS) for the HA structure. Our modeling revealed that compound NSC85561 showed significant antiviral activity against the IAV H1N1 strain with EC50 values ranging from 2.31 to 2.53 µM and negligible cytotoxicity (CC50 > 700 µM). Using the NSC85561 compound as the template to generate 12 derivatives, robust bioassay results revealed the strongest antiviral efficacies with NSC47715 and NSC7223. Virtual screening clearly identified three SA receptor binding site inhibitors that were successfully validated in experimental data. Thus, our computational strategy has identified SA receptor binding site inhibitors against HA that show IAV-associated antiviral activity.

scholarly journals A cross-sectional survey assessing the influence of theoretically informed behavioural factors on hand hygiene across seven countries during the COVID-19 pandemic

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
K. A. Schmidtke ◽  
K. G. Drinkwater
Keyword(s):  
South Africa ◽  
Saudi Arabia ◽  
United Kingdom ◽  
Hand Hygiene ◽  
Behaviour Change ◽  
Surface Cleaning ◽  
Behaviour Change Techniques ◽  
Cross Sectional ◽  
Surface Areas ◽  
The United Kingdom

Abstract Background Human hygiene behaviours influence the transmission of infectious diseases. Changing maladaptive hygiene habits has the potential to improve public health. Parents and teachers can play an important role in disinfecting surface areas and in helping children develop healthful handwashing habits. The current study aims to inform a future intervention that will help parents and teachers take up this role using a theoretically and empirically informed behaviour change model called the Capabilities-Opportunities-Motivations-Behaviour (COM-B) model. Methods A cross-sectional online survey was designed to measure participants’ capabilities, opportunities, and motivations to [1] increase their children’s handwashing with soap and [2] increase their cleaning of surface areas. Additional items captured how often participants believed their children washed their hands. The final survey was administered early in the coronavirus pandemic (May and June 2020) to 3975 participants from Australia, China, India, Indonesia, Saudi Arabia, South Africa, and the United Kingdom. Participants self-identified as mums, dads, or teachers of children 5 to 10 years old. ANOVAs analyses were used to compare participant capabilities, opportunities, and motivations across countries for handwashing and surface disinfecting. Multiple regressions analyses were conducted for each country to assess the predictive relationship between the COM-B components and children’s handwashing. Results The ANOVA analyses revealed that India had the lowest levels of capability, opportunity, and motivation, for both hand hygiene and surface cleaning. The regression analyses revealed that for Australia, Indonesia, and South Africa, the capability component was the only significant predictor of children’s handwashing. For India, capability and opportunity were significant. For the United Kingdom, capability and motivation were significant. Lastly, for Saudi Arabia all components were significant. Conclusions The discussion explores how the Behaviour Change Wheel methodology could be used to guide further intervention development with community stakeholders in each country. Of the countries assessed, India offers the greatest room for improvement, and behaviour change techniques that influence people’s capability and opportunities should be prioritised there.

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