scholarly journals Investigation of ACE2 N-terminal fragments binding to SARS-CoV-2 Spike RBD

2020 ◽  
Author(s):  
G. Zhang ◽  
S. Pomplun ◽  
A. R. Loftis ◽  
X. Tan ◽  
A. Loas ◽  
...  
Keyword(s):  
Protein S ◽  
Human Cells ◽  
Designer Drugs ◽  
Structural Determinants ◽  
Pure Material ◽  
Variable Binding ◽  
Health Crisis ◽  
Binding Behavior ◽  
Novel Coronavirus ◽  
Dynamics Simulations

AbstractCoronavirus disease 19 (COVID-19) is an emerging global health crisis. With over 7 million confirmed cases to date, this pandemic continues to expand, spurring research to discover vaccines and therapies. SARS-CoV-2 is the novel coronavirus responsible for this disease. It initiates entry into human cells by binding to angiotensin-converting enzyme 2 (ACE2) via the receptor binding domain (RBD) of its spike protein (S). Disrupting the SARS-CoV-2-RBD binding to ACE2 with designer drugs has the potential to inhibit the virus from entering human cells, presenting a new modality for therapeutic intervention. Peptide-based binders are an attractive solution to inhibit the RBD-ACE2 interaction by adequately covering the extended protein contact interface. Using molecular dynamics simulations based on the recently solved cryo-EM structure of ACE2 in complex with SARS-CoV-2-RBD, we observed that the ACE2 peptidase domain (PD) α1 helix is important for binding SARS-CoV-2-RBD. Using automated fast-flow peptide synthesis, we chemically synthesized a 23-mer peptide fragment of the ACE2 PD α1 helix (SBP1) composed entirely of proteinogenic amino acids. Chemical synthesis of SBP1 was complete in 1.5 hours, and after work up and isolation >20 milligrams of pure material was obtained. Bio-layer interferometry (BLI) revealed that SBP1 associates with micromolar affinity to insect-derived SARS-CoV-2-RBD protein obtained from Sino Biological. Association of SBP1 was not observed to an appreciable extent to HEK cell-expressed SARS-CoV-2-RBD proteins and insect-derived variants acquired from other vendors. Moreover, competitive BLI assays showed SBP1 does not outcompete ACE2 binding to Sino Biological insect-derived SARS-CoV-2-RBD. Further investigations are ongoing to gain insight into the molecular and structural determinants of the variable binding behavior to different SARS-CoV-2-RBD protein variants.

scholarly journals Static all-atom energetic mappings of the SARS-Cov-2 spike protein and dynamic stability analysis of “Up” versus “Down” protomer states

PLoS ONE ◽  
2020 ◽  
Vol 15 (11) ◽  
pp. e0241168 ◽  
Author(s):  
Michael H. Peters ◽  
Oscar Bastidas ◽  
Daniel S. Kokron ◽  
Christopher E. Henze
Keyword(s):  
Noncovalent Interactions ◽  
Single Point ◽  
Protein S ◽  
Spike Protein ◽  
Single Point Mutation ◽  
Binding Behavior ◽  
Neighboring Chain ◽  
Domain Interactions ◽  
Interchain Interactions ◽  
Dynamics Simulations

The SARS-CoV-2 virion responsible for the current world-wide pandemic COVID-19 has a characteristic Spike protein (S) on its surface that embellishes both a prefusion state and fusion state. The prefusion Spike protein (S) is a large trimeric protein where each protomer may be in a so-called Up state or Down state, depending on the configuration of its receptor binding domain (RBD) within its distal, prefusion S1 domain. The Up state is believed to allow binding of the virion to ACE-2 receptors on human epithelial cells, whereas the Down state is believed to be relatively inactive or reduced in its binding behavior. We have performed detailed all-atom, dominant energy landscape mappings for noncovalent interactions (charge, partial charge, and van der Waals) of the SARS-CoV-2 Spike protein in its static prefusion state based on two recent and independent experimental structure publications. We included both interchain interactions and intrachain (domain) interactions in our mappings in order to determine any telling differences (different so-called “glue” points) between residues in the Up and Down state protomers. The S2 proximal, fusion domain demonstrated no appreciable energetic differences between Up and Down protomers, including interchain as well as each protomer’s intrachain, S1-S2 interactions. However, the S1 domain interactions across neighboring protomers, which include the RBD-NTD cross chain interactions, showed significant energetic differences between Up-Down and Down-Down neighboring protomers. This included, for example, a key RBD residue ARG357 in the Up-Down interaction and a three residue sequence ALA520-PRO521-ALA522, associated with a turn structure in the RBD of the Up state protomer, acting as a stabilizing interaction with the NTD of its neighbor protomer. Additionally, our intra chain dominant energy mappings within each protomer, identified a significant “glue” point or possible “latch” for the Down state protomer between the S1 subdomain, SD1, and the RBD domain of the same protomer that was completely missing in the Up state protomer analysis. Ironically, this dominant energetic interaction in the Down state protomer involved the backbone atoms of the same three residue sequence ALA520-PRO521-ALA522 of the RBD with the amino acid R-group of GLN564 in the SD1 domain. Thus, this same three residue sequence acts as a stabilizer of the RBD in the Up conformation through its interactions with its neighboring NTD chain and a kind of latch in the Down state conformation through its interactions with its own SD1 domain. The dominant interaction energy residues identified here are also conserved across reported variations of SARS-CoV-2, as well as the closely related virions SARS-Cov and the bat corona virus RatG13. We conducted preliminary molecular dynamics simulations across 0.1 μ seconds to see if this latch provided structural stability and indeed found that a single point mutation (Q564G) resulted in the latch releasing transforming the protomer from the Down to the Up state conformation. Full trimeric Spike protein studies of the same mutation across all protomers, however, did not exhibit latch release demonstrating the critical importance of interchain interactions across the S1 domain, including RBD-NTD neighboring chain interactions. Therapies aimed at disrupting these noncovalent interactions could be a viable route for the physico-chemical mitigation of this deadly virion.

Coronavirus: Towards controlling of the pandemic - Indian scenario

2020 ◽  
Vol 11 (SPL1) ◽  
pp. 462-468
Author(s):  
Latika kothari ◽  
Sanskruti Wadatkar ◽  
Roshni Taori ◽  
Pavan Bajaj ◽  
Diksha Agrawal
Keyword(s):  
Control Measures ◽  
The Novel ◽  
Medical Treatments ◽  
Health Crisis ◽  
The Public ◽  
Infection Control Measures ◽  
The Social ◽  
Asking Questions ◽  
The Government ◽  
Novel Coronavirus

Coronavirus disease 2019 (COVID-19) is a communicable infection caused by the novel coronavirus resulting in severe acute respiratory syndrome coronavirus 2 (SARS-CoV). It was recognized to be a health crisis for the general population of international concern on 30th January 2020 and conceded as a pandemic on 11th March 2020. India is taking various measures to fight this invisible enemy by adopting different strategies and policies. To stop the COVID-19 from spreading, the Home Affairs Ministry and the health ministry, of India, has issued the nCoV 19 guidelines on travel. Screening for COVID-19 by asking questions about any symptoms, recent travel history, and exposure. India has been trying to get testing kits available. The government of India has enforced various laws like the social distancing, Janata curfew, strict lockdowns, screening door to door to control the spread of novel coronavirus. In this pandemic, innovative medical treatments are being explored, and a proper vaccine is being hunted to deal with the situation. Infection control measures are necessary to prevent the virus from further spreading and to help control the current situation. Thus, this review illustrates and explains the criteria provided by the government of India to the awareness of the public to prevent the spread of COVID-19.

scholarly journals The two redox states of the human NEET proteins’ [2Fe–2S] clusters

2021 ◽  
Vol 26 (7) ◽  
pp. 763-774
Author(s):  
Ke Zuo ◽  
Henri-Baptiste Marjault ◽  
Kara L. Bren ◽  
Giulia Rossetti ◽  
Rachel Nechushtai ◽  
...  
Keyword(s):  
Protein S ◽  
Spectroscopic Studies ◽  
Reduced Form ◽  
Rieske Protein ◽  
Kinetic Measurements ◽  
Redox States ◽  
Extra Electron ◽  
Dynamics Simulations ◽  
Reduced State

AbstractThe NEET proteins constitute a unique class of [2Fe–2S] proteins. The metal ions bind to three cysteines and one histidine. The proteins’ clusters exist in two redox states; the oxidized protein (containing two FeIII ions) can transfer the cluster to apo-acceptor protein(s), while the reduced form (containing one ferrous ion) remains bound to the protein frame. Here, we perform in silico and in vitro studies on human NEET proteins in both reduced and oxidized forms. Quantum chemical calculations on all available human NEET proteins structures suggest that reducing the cluster weakens the Fe–NHis and Fe–SCys bonds, similar to what is seen in other Fe–S proteins (e.g., ferredoxin and Rieske protein). We further show that the extra electron in the [2Fe–2S]+ clusters of one of the NEET proteins (mNT) is localized on the His-bound iron ion, consistently with our previous spectroscopic studies. Kinetic measurements demonstrate that the mNT [2Fe–2S]+ is released only by an increase in temperature. Thus, the reduced state of human NEET proteins [2Fe–2S] cluster is kinetically inert. This previously unrecognized kinetic inertness of the reduced state, along with the reactivity of the oxidized state, is unique across all [2Fe–2S] proteins. Finally, using a coevolutionary analysis, along with molecular dynamics simulations, we provide insight on the observed allostery between the loop L2 and the cluster region. Specifically, we show that W75, R76, K78, K79, F82 and G85 in the latter region share similar allosteric characteristics in both redox states. Graphic abstract

scholarly journals 2019 novel coronavirus disease with secondary ischemic stroke: two case reports

BMC Neurology ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Bin Fu ◽  
Yun Chen ◽  
Ping Li
Keyword(s):  
Ischemic Stroke ◽  
Acute Ischemic Stroke ◽  
Clinical Laboratory ◽  
Case Reports ◽  
Small Vessel ◽  
Vessel Occlusion ◽  
Aged Patients ◽  
Health Crisis ◽  
Physical Examinations ◽  
Novel Coronavirus

Abstract Background The COVID-19 pandemic, which broke out in Wuhan in 2019, has become the global health crisis of our time. Elderly patients with certain fundamental diseases are more likely to develop severe cases. The secondary lesion following viral infection have only rarely been reported. Case presentation We here report two cases of coronavirus-infected pneumonia with acute ischemic stroke in middle-aged patients. In both COVID-19 cases, neurological physical examinations showed normal results before infection. Lymphocytopenia, accompanied by elevated cytokines and D-dimers, were found from serum clinical laboratory examination at admission. Dysarthria and limb muscle weakness are initial manifestations, occurring one week after infect-causative pathogen, SARS-CoV-2. The head CT and head/neck arterial CTA showed small-vessel occlusion. The patients were diagnosed with coronavirus diseases with secondary acute ischemic stroke. They were treated with tirofiban and followed up with daily aspirin and atorvastatin. Conclusions These cases suggested that secondary ischemic stroke, mainly manifested as small-vessel occlusion, should be considered for COVID-19 patients and diagnosed and treated promptly.

scholarly journals Persistent SARS-CoV-2-positive over 4 months in a COVID-19 patient with CHB

Open Medicine ◽  
2021 ◽  
Vol 16 (1) ◽  
pp. 749-753
Author(s):  
Wenyuan Li ◽  
Beibei Huang ◽  
Qiang Shen ◽  
Shouwei Jiang ◽  
Kun Jin ◽  
...  
Keyword(s):  
The Novel ◽  
Chain Reaction ◽  
Health Crisis ◽  
Public Health Crisis ◽  
Oxygen Inhalation ◽  
New Strategy ◽  
Polymerase Chain ◽  
Novel Coronavirus ◽  
Specific Symptoms

Abstract In recent months, the novel coronavirus disease 2019 (COVID-19) pandemic has become a major public health crisis with takeover more than 1 million lives worldwide. The long-lasting existence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has not yet been reported. Herein, we report a case of SARS-CoV-2 infection with intermittent viral polymerase chain reaction (PCR)-positive for >4 months after clinical rehabilitation. A 35-year-old male was diagnosed with COVID-19 pneumonia with fever but without other specific symptoms. The treatment with lopinavir-ritonavir, oxygen inhalation, and other symptomatic supportive treatment facilitated recovery, and the patient was discharged. However, his viral PCR test was continually positive in oropharyngeal swabs for >4 months after that. At the end of June 2020, he was still under quarantine and observation. The contribution of current antivirus therapy might be limited. The prognosis of COVID-19 patients might be irrelevant to the virus status. Thus, further investigation to evaluate the contagiousness of convalescent patients and the mechanism underlying the persistent existence of SARS-CoV-2 after recovery is essential. A new strategy of disease control, especially extending the follow-up period for recovered COVID-19 patients, is necessary to adapt to the current situation of pandemic.

scholarly journals Role of Structural and Non-Structural Proteins and Therapeutic Targets of SARS-CoV-2 for COVID-19

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 821
Author(s):  
Rohitash Yadav ◽  
Jitendra Kumar Chaudhary ◽  
Neeraj Jain ◽  
Pankaj Kumar Chaudhary ◽  
Supriya Khanra ◽  
...  
Keyword(s):  
Host Cell ◽  
Protein S ◽  
Structural Similarity ◽  
Cell Receptor ◽  
Molecular Assembly ◽  
The Body ◽  
Spike Protein ◽  
Structural Proteins ◽  
Structural Protein ◽  
Novel Coronavirus

Coronavirus belongs to the family of Coronaviridae, comprising single-stranded, positive-sense RNA genome (+ ssRNA) of around 26 to 32 kilobases, and has been known to cause infection to a myriad of mammalian hosts, such as humans, cats, bats, civets, dogs, and camels with varied consequences in terms of death and debilitation. Strikingly, novel coronavirus (2019-nCoV), later renamed as severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), and found to be the causative agent of coronavirus disease-19 (COVID-19), shows 88% of sequence identity with bat-SL-CoVZC45 and bat-SL-CoVZXC21, 79% with SARS-CoV and 50% with MERS-CoV, respectively. Despite key amino acid residual variability, there is an incredible structural similarity between the receptor binding domain (RBD) of spike protein (S) of SARS-CoV-2 and SARS-CoV. During infection, spike protein of SARS-CoV-2 compared to SARS-CoV displays 10–20 times greater affinity for its cognate host cell receptor, angiotensin-converting enzyme 2 (ACE2), leading proteolytic cleavage of S protein by transmembrane protease serine 2 (TMPRSS2). Following cellular entry, the ORF-1a and ORF-1ab, located downstream to 5′ end of + ssRNA genome, undergo translation, thereby forming two large polyproteins, pp1a and pp1ab. These polyproteins, following protease-induced cleavage and molecular assembly, form functional viral RNA polymerase, also referred to as replicase. Thereafter, uninterrupted orchestrated replication-transcription molecular events lead to the synthesis of multiple nested sets of subgenomic mRNAs (sgRNAs), which are finally translated to several structural and accessory proteins participating in structure formation and various molecular functions of virus, respectively. These multiple structural proteins assemble and encapsulate genomic RNA (gRNA), resulting in numerous viral progenies, which eventually exit the host cell, and spread infection to rest of the body. In this review, we primarily focus on genomic organization, structural and non-structural protein components, and potential prospective molecular targets for development of therapeutic drugs, convalescent plasm therapy, and a myriad of potential vaccines to tackle SARS-CoV-2 infection.

Volatility transmission across international markets amid COVID 19 pandemic

2021 ◽  
Vol ahead-of-print (ahead-of-print) ◽  
Author(s):  
Hechem Ajmi ◽  
Nadia Arfaoui ◽  
Karima Saci
Keyword(s):  
Crude Oil ◽  
International Markets ◽  
The Novel ◽  
Data Set ◽  
Health Crisis ◽  
Content Type ◽  
Volatility Transmission ◽  
Oil Markets ◽  
Novel Coronavirus ◽  
Death Cases

Purpose This paper aims to investigate the volatility transmission across stocks, gold and crude oil markets before and during the novel coronavirus (COVID-19) crisis. Design/methodology/approach A multivariate vector autoregression (VAR)-Baba, Engle, Kraft and Kroner generalized autoregressive conditional heteroskedasticity model (BEKK-GARCH) is used to assess volatility transmission across the examined markets. The sample is divided as follows. The first period ranging from 02/01/2019 to 10/03/2020 defines the pre-COVID-19 crisis. The second period is from 11/03/2020 to 05/10/2020, representing the COVID-19 crisis period. Then, a robustness test is used using exponential GARCH models after including an exogenous variable capturing the growth of COVID-19 confirmed death cases worldwide with the aim to test the accuracy of the VAR-BEKK-GARCH estimated results. Findings Results indicate that the interconnectedness among the examined market has been intensified during the COVID-19 crisis, proving the lack of hedging opportunities. It is also found that stocks and Gold markets lead the crude oil market especially during the COVID-19 crisis, which explains the freefall of the crude oil price during the health crisis. Similarly, results show that Gold is most likely to act as a diversifier rather than a hedging tool during the current health crisis. Originality/value Although the recent studies in the field focused on analyzing the relationships between different markets during the first quarter of 2020, this study considers a larger data set with the aim to assess the volatility transmission across the examined international markets Amid the COVID-19 crisis, while it shows the most significant impact on various financial markets compared to other diseases.

scholarly journals Viability of Bacillus subtilis Cells in Airborne Bioaerosols on Face Masks

Atmosphere ◽  
2021 ◽  
Vol 12 (11) ◽  
pp. 1496
Author(s):  
Eun-Hee Lee ◽  
Yunsoo Chang ◽  
Seung-Woo Lee
Keyword(s):  
Bacillus Subtilis ◽  
World Health ◽  
The Novel ◽  
Fine Dust ◽  
Health Crisis ◽  
Viable Cells ◽  
Mask Material ◽  
Novel Coronavirus ◽  
Health Organization ◽  
Sand Dust

The coronavirus disease 2019 (COVID-19) pandemic is a general health crisis and has irreversible impacts on human societies. Globally, all people are at risk of being exposed to the novel coronavirus through transmission of airborne bioaerosols. Public health actions, such as wearing a mask, are highly recommended to reduce the transmission of infectious diseases. The appropriate use of masks is necessary for effectively preventing the transmission of airborne bioaerosols. The World Health Organization (WHO) suggests washing fabric masks or throwing away disposable masks after they are used. However, people often use masks more than once without washing or disposing them. The prolonged use of a single mask might—as a result of the user habitually touching the mask—promote the spread of pathogens from airborne bioaerosols that have accumulated on the mask. Therefore, it is necessary to evaluate how long the living components of bioaerosols can be viable on the masks. Here, we evaluated the viability of airborne Bacillus subtilis (B. subtilis) in bioaerosols filtered on woven and anti-droplet (non-woven) face masks. As a simulation of being simultaneously exposed to sand dust and bioaerosols, the viability rates of bioaerosols that had accumulated on masks were also tested against fine dust and airborne droplets containing bacteria. The bioaerosols survived on the masks immediately after the masks were used to filter the bioaerosols, and the bacteria significantly proliferated after one day of storage. Thereafter, the number of viable cells in the filtered bioaerosols gradually decreased over time, and the viability of B. subtilis in bioaerosols on the masks varied, depending on the mask material used (woven or non-woven). Despite the reduction in viability, bioaerosols containing living components were still found in both woven and anti-droplet masks even after six days of storage and it took nine days not to have found them on masks. The number of viable cells in bioaerosols on masks significantly decreased upon exposure of the masks to fine dust. The results of this study should provide useful information on how to appropriately use masks to increase their duration of effectiveness against bioaerosols.

scholarly journals Human IFITM3 restricts Chikungunya virus and Mayaro virus infection and is susceptible to virus-mediated counteraction

2020 ◽  
Author(s):  
Sergej Franz ◽  
Thomas Zillinger ◽  
Fabian Pott ◽  
Christiane Schüler ◽  
Sandra Dapa ◽  
...  
Keyword(s):  
Virus Infection ◽  
Influenza A ◽  
Chikungunya Virus ◽  
Protein S ◽  
Human Cells ◽  
Structural Protein ◽  
Infected Cells ◽  
Mayaro Virus ◽  
The Impact

AbstractInterferon-induced transmembrane (IFITM) proteins restrict infection by enveloped viruses through interfering with membrane fusion and virion internalisation. The role of IFITM proteins during alphaviral infection of human cells and viral counteraction strategies remain largely unexplored. Here, we characterized the impact of IFITM proteins and variants on entry and spread of Chikungunya virus (CHIKV) and Mayaro virus (MAYV) in human cells, and provide first evidence for a CHIKV-mediated antagonism of IFITM proteins. IFITM1, 2 and 3 restricted infection at the level of alphavirus glycoprotein-mediated entry, both in the context of direct infection and during cell-to-cell transmission. Relocalization of normally endosomal IFITM3 to the plasma membrane resulted in the loss of its antiviral activity. rs12252-C, a naturally occurring variant of IFITM3 that has been proposed to associate with severe influenza in humans, restricted CHIKV, MAYV and influenza A virus infection as efficiently as wild-type IFITM3. Finally, all antivirally active IFITM variants displayed reduced cell surface levels in CHIKV-infected cells involving a posttranscriptional process mediated by one or several non-structural protein(s) of CHIKV.

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