scholarly journals Structural modeling of 2019-novel coronavirus (nCoV) spike protein reveals a proteolytically-sensitive activation loop as a distinguishing feature compared to SARS-CoV and related SARS-like coronaviruses

2020 ◽  
Author(s):  
Javier A. Jaimes ◽  
Nicole M. André ◽  
Jean K. Millet ◽  
Gary R. Whittaker
Keyword(s):  
Receptor Binding ◽  
Structural Modeling ◽  
Spike Protein ◽  
Health Concern ◽  
Activation Loop ◽  
Public Health Concern ◽  
Amino Acid Similarity ◽  
Common Receptor ◽  
Novel Coronavirus ◽  
Structural Loop

AbstractThe 2019 novel coronavirus (2019-nCoV) is currently causing a widespread outbreak centered on Hubei province, China and is a major public health concern. Taxonomically 2019-nCoV is closely related to SARS-CoV and SARS-related bat coronaviruses, and it appears to share a common receptor with SARS-CoV (ACE-2). Here, we perform structural modeling of the 2019-nCoV spike glycoprotein. Our data provide support for the similar receptor utilization between 2019-nCoV and SARS-CoV, despite a relatively low amino acid similarity in the receptor binding module. Compared to SARS-CoV, we identify an extended structural loop containing basic amino acids at the interface of the receptor binding (S1) and fusion (S2) domains, which we predict to be proteolytically-sensitive. We suggest this loop confers fusion activation and entry properties more in line with MERS-CoV and other coronaviruses, and that the presence of this structural loop in 2019-nCoV may affect virus stability and transmission.

scholarly journals Preparedness of Healthcare Workers towards Handling COVID-19 Outbreak in the Gambia

2021 ◽  
Vol 3 ◽  
pp. 36-42
Author(s):  
Joseph W Jatta ◽  
Jean Claude Romaric Pingdwindé Ouédraogo ◽  
Yusupha Sanyang ◽  
Daniel Nebongo ◽  
Tahir Ahmed Touray ◽  
...  
Keyword(s):  
Health Facility ◽  
Healthcare Workers ◽  
The Gambia ◽  
Health Concern ◽  
The Novel ◽  
Public Health Concern ◽  
Cross Sectional Survey ◽  
Cross Sectional ◽  
Significant Difference ◽  
Novel Coronavirus

Background: The novel Coronavirus (COVID-19) outbreak that began in Wuhan, China rapidly became a public health concern and a challenge for healthcare systems globally.  In the wake of the first confirmed case in The Gambia, concerns were raised in some quarters about the health system's preparedness to handle the outbreak. Therefore, we aimed to assess health personnel's knowledge and preparedness in fighting the COVID-19 outbreak in The Gambia. Methods: A cross-sectional survey was conducted using self-administered questionnaires distributed online through social media. Descriptive, bivariate, and binary logistic analyses were done using SPSS Version 22. Results: We obtained 333 valid responses. Most participants reported that their health facility has some form of preparedness; however, only a small proportion reported enough PPEs in the health facility. About half (50.5%) showed good knowledge of COVID-19. There was a statistically significant difference among the professions regarding their reaction if they were found positive of COVID-19 (p=0.006). There was a significant association between health professions [other professions (Odds ratio [OR]=0.2, 95% Confidence interval [CI]:0.04–0 .9; p=0.038)] and overall knowledge of COVID-19. Conclusion: Our findings showed some form of preparedness towards COVID-19 among healthcare workers. However, many aspects, such as the availability of PPEs and their proper use and knowledge, need improvement. Thus, training and an adequate supply of equipment are required to better respond to upcoming COVID-19 waves and future outbreaks. Doi: 10.28991/SciMedJ-2021-03-SI-5 Full Text: PDF

scholarly journals Dynamics of the ACE2 - SARS-CoV/SARS-CoV-2 spike protein interface reveal unique mechanisms

2020 ◽  
Author(s):  
Amanat Ali ◽  
Ranjit Vijayan
Keyword(s):  
Salt Bridge ◽  
Spike Protein ◽  
Health Concern ◽  
Treatment Modalities ◽  
Receptor Binding Domain ◽  
Public Health Concern ◽  
Angiotensin Converting Enzyme 2 ◽  
Dynamics Simulations ◽  
And Function ◽  
Host Target

AbstractThe coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a major public health concern. A handful of static structures now provide molecular insights into how SARS-CoV-2 and SARS-CoV interact with its host target, which is the angiotensin converting enzyme 2 (ACE2). Molecular recognition, binding and function are dynamic processes. To evaluate this, multiple all atom molecular dynamics simulations of at least 500 ns each were performed to better understand the structural stability and interfacial interactions between the receptor binding domain of the spike protein of SARS-CoV-2 and SARS-CoV bound to ACE2. Several contacts were observed to form, break and reform in the interface during the simulations. Our results indicate that SARS-CoV and SARS-CoV-2 utilizes unique strategies to achieve stable binding to ACE2. Several differences were observed between the residues of SARS-CoV-2 and SARS-CoV that consistently interacted with ACE2. Notably, a stable salt bridge between Lys417 of SARS-CoV-2 spike protein and Asp30 of ACE2 as well as three stable hydrogen bonds between Tyr449, Gln493, and Gln498 of SARS-CoV-2 and Asp38, Glu35, and Lys353 of ACE2 were observed, which were absent in the SARS-CoV-ACE2 interface. Some previously reported residues, which were suggested to enhance the binding affinity of SARS-CoV-2, were not observed to form stable interactions in these simulations. Stable binding to the host receptor is crucial for virus entry. Therefore, special consideration should be given to these stable interactions while designing potential drugs and treatment modalities to target or disrupt this interface.

scholarly journals Computational simulations reveal the binding dynamics between human ACE2 and the receptor binding domain of SARS-CoV-2 spike protein

2020 ◽  
Author(s):  
Cecylia S. Lupala ◽  
Xuanxuan Li ◽  
Jian Lei ◽  
Hong Chen ◽  
Jianxun Qi ◽  
...  
Keyword(s):  
Receptor Binding ◽  
Genomic Analysis ◽  
Md Simulations ◽  
Binding Domain ◽  
Spike Protein ◽  
Receptor Binding Domain ◽  
Binding Modes ◽  
Angiotensin Converting Enzyme 2 ◽  
Causal Pathogen ◽  
Novel Coronavirus

AbstractA novel coronavirus (the SARS-CoV-2) has been identified in January 2020 as the causal pathogen for COVID-19 pneumonia, an outbreak started near the end of 2019 in Wuhan, China. The SARS-CoV-2 was found to be closely related to the SARS-CoV, based on the genomic analysis. The Angiotensin converting enzyme 2 protein (ACE2) utilized by the SARS-CoV as a receptor was found to facilitate the infection of SARS-CoV-2 as well, initiated by the binding of the spike protein to the human ACE2. Using homology modeling and molecular dynamics (MD) simulation methods, we report here the detailed structure of the ACE2 in complex with the receptor binding domain (RBD) of the SARS-CoV-2 spike protein. The predicted model is highly consistent with the experimentally determined complex structures. Plausible binding modes between human ACE2 and the RBD were revealed from all-atom MD simulations. The simulation data further revealed critical residues at the complex interface and provided more details about the interactions between the SARS-CoV-2 RBD and human ACE2. Two mutants mimicking rat ACE2 were modeled to study the mutation effects on RBD binding to ACE2. The simulations showed that the N-terminal helix and the K353 of the human ACE2 alter the binding modes of the CoV2-RBD to the ACE2.

scholarly journals The Covid-19 Pandemic and its Effect on the Elderly: A Review

2020 ◽  
Vol 5 (3) ◽  
Author(s):  
Maimoona Nadri ◽  
Ujala Zubair
Keyword(s):  
The Elderly ◽  
Medical Community ◽  
Health Concern ◽  
The Novel ◽  
Global Public Health ◽  
Public Health Concern ◽  
The World ◽  
Long Term Consequences ◽  
Novel Coronavirus

In 2019, the world experienced a global public health concern when the novel coronavirus originated from China and affected around fifty-seven thousand people around the world by March 2020. The quick rise in the number of cases and the death toll overwhelmed the scientific and medical community. While all the focus was driven towards finding the epidemiology, the treatment and the management, the mental health aspect of the quarantine was being overlooked. The purpose of this review is to create awareness about the long-term consequences of quarantine, with the focus on the elderly community in Pakistan. 

scholarly journals Gene of the month: the 2019-nCoV/SARS-CoV-2 novel coronavirus spike protein

2020 ◽  
Vol 73 (7) ◽  
pp. 366-369 ◽  
Author(s):  
Tahir S Pillay
Keyword(s):  
Receptor Binding ◽  
Transmembrane Domain ◽  
Vaccine Development ◽  
Protein S ◽  
Respiratory Illness ◽  
Spike Protein ◽  
Furin Cleavage ◽  
Furin Cleavage Site ◽  
Cellular Entry ◽  
Novel Coronavirus

The year 2020 has seen a major and sustained outbreak of a novel betacoronavirus (severe acute respiratory syndrome (SARS)-coronavirus (CoV)-2) infection that causes fever, severe respiratory illness and pneumonia, a disease called COVID-19. At the time of writing, the death toll was greater than 120 000 worldwide with more than 2 million documented infections. The genome of the CoV encodes a number of structural proteins that facilitate cellular entry and assembly of virions, of which the spike protein S appears to be critical for cellular entry. The spike protein guides the virus to attach to the host cell. The spike protein contains a receptor-binding domain (RBD), a fusion domain and a transmembrane domain. The RBD of spike protein S binds to Angiotensin Converting Enzyme 2 (ACE2) to initiate cellular entry. The spike protein of SARS-CoV-2 shows more than 90% amino acid similarity to the pangolin and bat CoVs and these also use ACE2 as a receptor. Binding of the spike protein to ACE2 exposes the cleavage sites to cellular proteases. Cleavage of the spike protein by transmembrane protease serine 2 and other cellular proteases initiates fusion and endocytosis. The spike protein contains an addition furin cleavage site that may allow it to be ‘preactivated’ and highly infectious after replication. The fundamental role of the spike protein in infectivity suggests that it is an important target for vaccine development, blocking therapy with antibodies and diagnostic antigen-based tests. This review briefly outlines the structure and function of the 2019 novel CoV/SARS-CoV-2 spike protein S.

scholarly journals COVID-19 and suicide: when crises collide

2021 ◽  
Author(s):  
Jeff Clyde G Corpuz
Keyword(s):  
Public Health ◽  
Suicide Prevention ◽  
Suicide Attempts ◽  
Population Based ◽  
Health Concern ◽  
The Novel ◽  
Public Health Concern ◽  
Sectoral Approach ◽  
The World ◽  
Novel Coronavirus

Abstract Suicide is a leading cause of death worldwide. Even before the emergence of the novel coronavirus SARS-CoV2 COVID-19 pandemic, suicide continued to be a major public health concern. Globally, someone dies by suicide every 40 s, and for each death, there are 20 more persons attempting suicide. A recently published article rightly stated the need for a ‘population-based approach’ to suicide prevention to mitigate suicide attempts. This paper further adds that there must be a stronger multi-agency or multi-sectoral approach to suicide prevention, intervention and postvention. This paper concludes with few suggestions on how to address the COVID-19-related suicide cases as the world continues to fight against the double pandemic.

scholarly journals How Does the Novel Coronavirus Interact with the Human ACE2 Enzyme? A Thermodynamic Answer

2020 ◽  
Author(s):  
Jones de Andrade ◽  
Paulo Fernando Bruno Gonçalves ◽  
Paulo Augusto Netz
Keyword(s):  
Free Energy ◽  
Protein Complexes ◽  
Minimum Free Energy ◽  
New Drugs ◽  
Host Cells ◽  
Spike Protein ◽  
Health Concern ◽  
Novel Coronavirus ◽  
Dynamics Simulations ◽  
Free Energy Of Binding

<p>The SARS-CoV-2 coronavirus pandemic is certainly the most important public health concern today. Until now there are no vaccines or treatments available, despite intensive international efforts. One of the targets for new drugs is the Coronavirus Spike Protein, responsible for its binding and entry into the host cells. The Receptor Binding Domain (RBD) found at the Spike Protein recognizes the human angiotensin-converting enzyme 2 (hACE2). The present in silico study discuss structural and thermodynamic aspects of the protein complexes involving the RBD’s from the 2002 SARS-CoV and 2019 SARS-CoV-2 with the hACE2. Molecular docking and molecular dynamics simulations of the complexes and isolated proteins were performed, providing insights on their detailed pattern of interactions, and estimating the free energy of binding. The obtained results support previous studies indicating that the chemical affinity of the new SARS-CoV-2 for the hACE2 enzyme virus is much higher than the 2002 SARS-CoV. The herein calculated Gibbs free energy of binding to the hACE2 enzyme is, depending on the technique, from 5.11 kcal/mol to 8.39 kcal/mol more negative in the case of the new coronavirus’ RBD. In addition, within each employed technique, this free energy is consistently 61±2% stronger for SARS-CoV-2 than for SARS-CoV. This work presents a chemical reason for the difficulty in treating the SARS-CoV-2 virus using drugs targeting its Spike Protein, as well as helps to explain its infectivity, while defining a minimum free energy of binding for new drugs to be designed against this disease.<br></p>

scholarly journals Mutations, Recombination and Insertion in the Evolution of 2019-nCoV

2020 ◽  
Author(s):  
Aiping Wu ◽  
Peihua Niu ◽  
Lulan Wang ◽  
Hangyu Zhou ◽  
Xiang Zhao ◽  
...  
Keyword(s):  
Receptor Binding ◽  
Cleavage Site ◽  
Comprehensive Analysis ◽  
Spike Protein ◽  
Genomic Sequences ◽  
Receptor Binding Domain ◽  
Genome Sequences ◽  
Systematic Analysis ◽  
Amino Acid Insertion ◽  
Novel Coronavirus

AbstractBackgroundThe 2019 novel coronavirus (2019-nCoV or SARS-CoV-2) has spread more rapidly than any other betacoronavirus including SARS-CoV and MERS-CoV. However, the mechanisms responsible for infection and molecular evolution of this virus remained unclear.MethodsWe collected and analyzed 120 genomic sequences of 2019-nCoV including 11 novel genomes from patients in China. Through comprehensive analysis of the available genome sequences of 2019-nCoV strains, we have tracked multiple inheritable SNPs and determined the evolution of 2019-nCoV relative to other coronaviruses.ResultsSystematic analysis of 120 genomic sequences of 2019-nCoV revealed co-circulation of two genetic subgroups with distinct SNPs markers, which can be used to trace the 2019-nCoV spreading pathways to different regions and countries. Although 2019-nCoV, human and bat SARS-CoV share high homologous in overall genome structures, they evolved into two distinct groups with different receptor entry specificities through potential recombination in the receptor binding regions. In addition, 2019-nCoV has a unique four amino acid insertion between S1 and S2 domains of the spike protein, which created a potential furin or TMPRSS2 cleavage site.ConclusionsOur studies provided comprehensive insights into the evolution and spread of the 2019-nCoV. Our results provided evidence suggesting that 2019-nCoV may increase its infectivity through the receptor binding domain recombination and a cleavage site insertion.One Sentence SummaryNovel 2019-nCoV sequences revealed the evolution and specificity of betacoronavirus with possible mechanisms of enhanced infectivity.

scholarly journals In silico elucidation revealed SARS CoV and MERS CoV Drug Compounds could be Potential Therapeutic Candidates against Post Fusion Core (S2) Protein of Novel Coronavirus (2019-nCov)

2020 ◽  
Author(s):  
Zainab Ayaz ◽  
Bibi Zainab ◽  
Arshad Mehmood Abbasi
Keyword(s):  
Membrane Fusion ◽  
Host Cell ◽  
Receptor Binding ◽  
Active Sites ◽  
Binding Capacity ◽  
Host Cells ◽  
Spike Protein ◽  
World Health ◽  
Drug Compounds ◽  
Novel Coronavirus

Abstract Novel coronavirus (2019-nCoV), since its emergence from Wuhan China in December 31, 2019 is still uncontrolled and has raised attention around the globe. According to World health organization, up to March 20, 2020, globally 209,839 confirmed cases of COVID-19 have been reported along with 8778 deaths. 2019-nCoV is likely to be a recombinant of different coronaviruses such as SARS CoV and MERS CoV. Recent developments revealed that glycosylated spike (S) protein of 2019-nCov is contributing significantly in facilitating 2019- nCov infection in human body. The subunit (S1) of spike protein facilitates 2019-nCov binding with host cells’ receptors, while S2 subunit (post fusion core of 2019-nCov) is a key factor in fusion of 2019-nCov with host cell membrane and subsequent inoculation of its DNA in to the host cell. Therefore, in coronavirus infection, membrane fusion and receptor binding are critical. And if active sites of 2019-nCov spike protein S2 (post fusion core of 2019-nCov) are blocked, this may reduce COVID-19 infections in human. We use clustering based drug-drug interaction (DDI) networks and drug repositioning approach based on modularity to inhibit the membrane fusion and receptor binding capacity of 2019-nCov. About 150 drug compounds effective against SARS-CoV and MERS-CoV were retrieved, and screened on the basis of Lipinski rule of five. Clusters and strongly interacted DDI networks were generated in accordance to their modularity class, average path length and density. Promising drug candidates were then filtered by toxicity indicator and molecular docking. Our finding reveals that ZINC000029038525 and ZINC000029129064 drug compounds have significant binding potential with active sites of post fusion core of 2019-nCov ‘S2’ subunit and may inhibit membrane fusion and receptor binding capacity of 2019-nCov. Therefore, these drug compounds alone or in amalgamation could be strong and more effective therapeutic candidates against 2019-nCov infections.

scholarly journals V367F mutation in SARS-CoV-2 spike RBD emerging during the early transmission phase enhances viral infectivity through increased human ACE2 receptor binding affinity

2021 ◽  
Author(s):  
Junxian Ou ◽  
Zhonghua Zhou ◽  
Ruixue Dai ◽  
Jing Zhang ◽  
Shan Zhao ◽  
...  
Keyword(s):  
Binding Affinity ◽  
Receptor Binding ◽  
Spike Protein ◽  
Receptor Binding Domain ◽  
Critical Determinant ◽  
Evolutionary Trajectory ◽  
Receptor Binding Affinity ◽  
Protein Receptor ◽  
Novel Coronavirus ◽  
Transmission Phase

The current pandemic of COVID-19 is caused by a novel coronavirus SARS-CoV-2. The SARS-CoV-2 spike protein receptor-binding domain (RBD) is the critical determinant of viral tropism and infectivity. To investigate whether naturally occurring RBD mutations during the early transmission phase have altered the receptor binding affinity and infectivity, firstly we analyzed in silico the binding dynamics between SARS-CoV-2 RBD mutants and the human ACE2 receptor. Among 32,123 genomes of SARS-CoV-2 isolates (January through March, 2020), 302 non-synonymous RBD mutants were identified and clustered into 96 mutant types. The six dominant mutations were analyzed applying molecular dynamics simulations (MDS). The mutant type V367F continuously circulating worldwide displayed higher binding affinity to human ACE2 due to the enhanced structural stabilization of the RBD beta-sheet scaffold. The MDS also indicated that it would be difficult for bat SARS-like CoV to infect humans. However, the pangolin CoV is potentially infectious to humans. The increased infectivity of V367 mutants was further validated by performing receptor-ligand binding ELISA, surface plasmon resonance, and pseudotyped virus assays. Phylogenetic analysis of the genomes of V367F mutants showed that during the early transmission phase, most V367F mutants clustered more closely with the SARS-CoV-2 prototype strain than the dual-mutation variants (V367F + D614G) which may derivate from recombination. The analysis of critical RBD mutations provides further insights into the evolutionary trajectory of early SARS-CoV-2 variants of zoonotic origin under negative selection pressure and supports the continuing surveillance of spike mutations to aid in the development of new COVID-19 drugs and vaccines. Importance A novel coronavirus SARS-CoV-2 has caused the pandemic of COVID-19. The origin of SARS-CoV-2 was associated with zoonotic infections. The spike protein receptor-binding domain (RBD) is identified as the critical determinant of viral tropism and infectivity. Thus, whether the mutations in the RBD of the circulating SARS-CoV-2 isolates have altered the receptor binding affinity and made them more infectious, has been the research hotspot. Given that SARS-CoV-2 is a novel coronavirus, the significance of our research is in identifying and validating the RBD mutant types emerging during the early transmission phase and increasing human ACE2 receptor binding affinity and infectivity. Our study provides insights into the evolutionary trajectory of early SARS-CoV-2 variants of zoonotic origin. The continuing surveillance of RBD mutations with increased human ACE2 affinity in human or other animals is critical to the development of new COVID-19 drugs and vaccines against these variants during the sustained COVID-19 pandemic.

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