scholarly journals Analysis of SARS-CoV-2 Spike Protein as The Key Target in the Development of Antiviral Candidates for COVID-19 through Computational Study

2021 ◽  
Vol 5 (4) ◽  
pp. 347-352
Author(s):  
Taufik Muhammad Fakih ◽  
Mentari Luthfika Dewi
Keyword(s):  
Binding Sites ◽  
Computational Study ◽  
Docking Simulation ◽  
Competitive Inhibitor ◽  
Protein Docking ◽  
Spike Protein ◽  
Health Crisis ◽  
Angiotensin Converting Enzyme 2 ◽  
Public Health Crisis ◽  
Spike Proteins

The recent public health crisis is threatening the world with the emergence of the spread of the new coronavirus 2019 (2019-nCoV) or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This virus originates from bats and is transmitted to humans through unknown intermediate animals in Wuhan, China in December 2019. Advances in technology have opened opportunities to find candidates for natural compounds capable of preventing and controlling COVID-19 infection through inhibition of spike proteins of SARS-CoV-2. This research aims to identify, evaluate, and explore the structure of spike protein macromolecules from three coronaviruses (SARS-CoV, MERS-CoV, and SARS-CoV-2) and their effects on Angiotensin-Converting Enzyme 2 (ACE-2) using computational studies. Based on the identification of the three spike protein macromolecules, it was found that there was a similarity between the active binding sites of ACE-2. These observations were then confirmed using a protein-docking simulation to observe the interaction of the protein spike to the active site of ACE-2. SARS-COV-2 spike protein has the strongest bond to ACE-2, with an ACE score of −1341.85 kJ/mol. Therefore, some of this information from the results of this research can be used as a reference in the development of competitive inhibitor candidates for SARS-CoV-2 spike proteins for the treatment of COVID-19 infectious diseases.

scholarly journals Bioengineered probiotics to control SARS-CoV-2 infection

2020 ◽  
Vol 6 ◽  
Author(s):  
Shantibhusan Senapati ◽  
Jayalaxmi Dash ◽  
Manisha Sethi ◽  
Subhankar Chakraborty
Keyword(s):  
Virus Disease ◽  
Spike Protein ◽  
Converting Enzyme ◽  
Global Public Health ◽  
Health Crisis ◽  
Angiotensin Converting Enzyme 2 ◽  
Public Health Crisis ◽  
Biochemical Studies ◽  
Viral Outbreak ◽  
Novel Therapeutic

The outbreak of 2019 novel corona virus disease (COVID-19) is now a global public health crisis and declared as a pandemic. Several recent studies suggest that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein binds to human angiotensin-converting enzyme 2 (ACE2). The information obtained from these structural and biochemical studies provides a strong rationale to target SARS-CoV-2 spike protein and ACE2 interaction for developing therapeutics against this viral infection. Here, we propose to discuss the scope of bioengineered probiotics expressing human ACE2 as a novel therapeutic to control the viral outbreak.

scholarly journals “Molecular Masks” for ACE2 to Effectively and Safely Block SARS-CoV-2 Virus Entry

2021 ◽  
Vol 22 (16) ◽  
pp. 8963
Author(s):  
Satya Prakash Shukla ◽  
Kwang Bog Cho ◽  
Vineeta Rustagi ◽  
Xiang Gao ◽  
Xinping Fu ◽  
...  
Keyword(s):  
Virus Entry ◽  
Cell Surface Receptor ◽  
Spike Protein ◽  
Pressure Regulation ◽  
Converting Enzyme ◽  
Normal Blood Pressure ◽  
Health Crisis ◽  
Angiotensin Converting Enzyme 2 ◽  
Surface Receptor ◽  
Unique Cell

Coronavirus Disease 2019 (COVID-19) remains a global health crisis, despite the development and success of vaccines in certain countries. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes COVID-19, uses its spike protein to bind to the human cell surface receptor angiotensin-converting enzyme 2 (ACE2), which allows the virus to enter the human body. Using our unique cell screening technology, we identified two ACE2-binding peptoid compounds and developed dimeric derivatives (ACE2P1D1 and ACE2P2D1) that effectively blocked spike protein-ACE2 interaction, resulting in the inhibition of SARS-CoV-2 pseudovirus entry into human cells. ACE2P1D1 and ACE2P2D1 also blocked infection by a D614G mutant pseudovirus. More importantly, these compounds do not decrease ACE2 expression nor its enzyme activity (which is important in normal blood pressure regulation), suggesting safe applicability in humans

scholarly journals High affinity binding of SARS-CoV-2 spike protein enhances ACE2 carboxypeptidase activity

2020 ◽  
Vol 295 (52) ◽  
pp. 18579-18588 ◽  
Author(s):  
Jinghua Lu ◽  
Peter D. Sun
Keyword(s):  
Spike Protein ◽  
The Novel ◽  
Global Public Health ◽  
Health Crisis ◽  
Peptide Substrates ◽  
Angiotensin Converting Enzyme 2 ◽  
High Affinity ◽  
Enzymatic Function ◽  
Biological Substrates ◽  
Entry Receptor

The novel severe acute respiratory syndrome coronavirus (SARS-CoV-2) has emerged to a pandemic and caused global public health crisis. Human angiotensin-converting enzyme 2(ACE2) was identified as the entry receptor for SARS-CoV-2. As a carboxypeptidase, ACE2 cleaves many biological substrates besides angiotensin II to control vasodilatation and vascular permeability. Given the nanomolar high affinity between ACE2 and SARS-CoV-2 spike protein, we investigated how this interaction would affect the enzymatic activity of ACE2. Surprisingly, SARS-CoV-2 trimeric spike protein increased ACE2 proteolytic activity ∼3-10 fold against model peptide substrates, such as caspase-1 substrate and Bradykinin-analog. The enhancement in ACE2 enzymatic function was mediated by the binding of SARS-CoV-2 spike RBD domain. These results highlighted the potential for SARS-CoV-2 infection to enhance ACE2 activity, which may be relevant to the cardiovascular symptoms associated with COVID-19.

scholarly journals Introduction of Two Prolines and Removal of the Polybasic Cleavage Site Lead to Higher Efficacy of a Recombinant Spike-Based SARS-CoV-2 Vaccine in the Mouse Model

mBio ◽  
2021 ◽  
Vol 12 (2) ◽  
Author(s):  
Fatima Amanat ◽  
Shirin Strohmeier ◽  
Raveen Rathnasinghe ◽  
Michael Schotsaert ◽  
Lynda Coughlan ◽  
...  
Keyword(s):  
Mouse Model ◽  
Cleavage Site ◽  
Neutralizing Antibodies ◽  
Vaccine Development ◽  
Host Cells ◽  
Spike Protein ◽  
Optimized Design ◽  
Angiotensin Converting Enzyme 2 ◽  
Viral Target ◽  
Spike Proteins

ABSTRACT The spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been identified as the prime target for vaccine development. The spike protein mediates both binding to host cells and membrane fusion and is also so far the only known viral target of neutralizing antibodies. Coronavirus spike proteins are large trimers that are relatively unstable, a feature that might be enhanced by the presence of a polybasic cleavage site in SARS-CoV-2 spike. Exchange of K986 and V987 for prolines has been shown to stabilize the trimers of SARS-CoV-1 and the Middle East respiratory syndrome coronavirus spike proteins. Here, we test multiple versions of a soluble spike protein for their immunogenicity and protective effect against SARS-CoV-2 challenge in a mouse model that transiently expresses human angiotensin-converting enzyme 2 via adenovirus transduction. Variants tested include spike proteins with a deleted polybasic cleavage site, proline mutations, or a combination thereof, besides the wild-type protein. While all versions of the protein were able to induce neutralizing antibodies, only the antigen with both a deleted cleavage site and the K986P and V987P (PP) mutations completely protected from challenge in this mouse model. IMPORTANCE A vaccine for SARS-CoV-2 is urgently needed. A better understanding of antigen design and attributes that vaccine candidates need to have to induce protective immunity is of high importance. The data presented here validate the choice of antigens that contain the PP mutations and suggest that deletion of the polybasic cleavage site may lead to a further-optimized design.

scholarly journals Highly ACE2 Expression in Pancreas May Cause Pancreas Damage After SARS-CoV-2 Infection

2020 ◽  
Author(s):  
Furong Liu ◽  
Xin Long ◽  
Wenbin Zou ◽  
Minghao Fang ◽  
Wenjuan Wu ◽  
...  
Keyword(s):  
Clinical Work ◽  
Pancreatic Injury ◽  
Exocrine Glands ◽  
Global Public Health ◽  
Rna Seq ◽  
Health Crisis ◽  
Angiotensin Converting Enzyme 2 ◽  
Public Health Crisis ◽  
Public Datasets ◽  
Possible Cause

AbstractThe ongoing outbreak of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) started in the end of 2019 in China has triggered a global public health crisis. Previous studies have shown that SARS-CoV-2 infects cells by binding angiotensin-converting enzyme 2 (ACE2), which is the same as SARS-CoV. The expression and distribution of ACE2 in the pancreas are unknown. At the same time, the injury of pancreas after SARS-CoV-2 infection has not been concerned. Here, we collected public datasets (bulk RNA-seq and single-cell RNA-seq) to indicate the expression and the distribution of ACE2 in pancreas (in both exocrine glands and islets). And further, clinical data including mild and severe patients with COVID-19 demonstrated there existed mild pancreatitis. In the 67 severe cases, 11 patients (16.41%) showed elevated levels of both amylase and lipase, and 5 patients (7.46%) showed imaging alterations. Only one patient (1.85%) showed elevated levels of both amylase and lipase in 54 mild cases, without imaging changes. Our study revealed the phenomenon and possible cause of mild pancreatic injury in patients with COVID-19. This suggests that pancreatitis after SARS-CoV-2 infection should also be paid attention in clinical work.

scholarly journals Crude Heparin Preparations Unveil the Presence of Structurally Diverse Oversulfated Contaminants

Molecules ◽  
2019 ◽  
Vol 24 (16) ◽  
pp. 2988
Author(s):  
Aline Mendes ◽  
Maria C. Z. Meneghetti ◽  
Marcelly Valle Palladino ◽  
Giselle Zenker Justo ◽  
Guilherme L. Sassaki ◽  
...  
Keyword(s):  
Public Health ◽  
Binding Sites ◽  
Heparin Binding ◽  
Global Public Health ◽  
Health Crisis ◽  
Public Health Crisis ◽  
The Past ◽  
Oversulfated Chondroitin Sulfate ◽  
Heparin Preparation ◽  
Ongoing Concern

Nowadays, pharmaceutical heparin is purified from porcine and bovine intestinal mucosa. In the past decade there has been an ongoing concern about the safety of heparin, since in 2008, adverse effects associated with the presence of an oversulfated chondroitin sulfate (OSCS) were observed in preparations of pharmaceutical porcine heparin, which led to the death of patients, causing a global public health crisis. However, it has not been clarified whether OSCS has been added to the purified heparin preparation, or whether it has already been introduced during the production of the raw heparin. Using a combination of different analytical methods, we investigate both crude and final heparin products and we are able to demonstrate that the sulfated contaminants are intentionally introduced in the initial steps of heparin preparation. Furthermore, the results show that the oversulfated compounds are not structurally homogeneous. In addition, we show that these contaminants are able to bind to cells in using well known heparin binding sites. Together, the data highlights the importance of heparin quality control even at the initial stages of its production.

scholarly journals Rapid SARS-CoV-2 Detection Using Electrochemical Immunosensor

Sensors ◽  
2021 ◽  
Vol 21 (2) ◽  
pp. 390
Author(s):  
Biljana Mojsoska ◽  
Sylvester Larsen ◽  
Dorte Aalund Olsen ◽  
Jonna Skov Madsen ◽  
Ivan Brandslund ◽  
...  
Keyword(s):  
Treatment Options ◽  
Surface Protein ◽  
Electrochemical Immunosensor ◽  
Spike Protein ◽  
The Novel ◽  
Label Free ◽  
Detection Range ◽  
Health Crisis ◽  
Public Health Crisis ◽  
Novel Coronavirus

The outbreak of the coronavirus disease (COVID-19) pandemic caused by the novel coronavirus (SARS-CoV-2) has been declared an international public health crisis. It is essential to develop diagnostic tests that can quickly identify infected individuals to limit the spread of the virus and assign treatment options. Herein, we report a proof-of-concept label-free electrochemical immunoassay for the rapid detection of SARS-CoV-2 virus via the spike surface protein. The assay consists of a graphene working electrode functionalized with anti-spike antibodies. The concept of the immunosensor is to detect the signal perturbation obtained from ferri/ferrocyanide measurements after binding of the antigen during 45 min of incubation with a sample. The absolute change in the [Fe(CN)6]3−/4− current upon increasing antigen concentrations on the immunosensor surface was used to determine the detection range of the spike protein. The sensor was able to detect a specific signal above 260 nM (20 µg/mL) of subunit 1 of recombinant spike protein. Additionally, it was able to detect SARS-CoV-2 at a concentration of 5.5 × 105 PFU/mL, which is within the physiologically relevant concentration range. The novel immunosensor has a significantly faster analysis time than the standard qPCR and is operated by a portable device which can enable on-site diagnosis of infection.

scholarly journals ACE2 peptide fragment interacts with several sites on the SARS-CoV-2 spike protein S1

2021 ◽  
Author(s):  
Aleksei Kuznetsov ◽  
Piret Arukuusk ◽  
Heleri Heike Härk ◽  
Erkki Juronen ◽  
Ülo Langel ◽  
...  
Keyword(s):  
Binding Sites ◽  
Peptide Binding ◽  
Inhibitory Effect ◽  
Spike Protein ◽  
Receptor Binding Domain ◽  
Peptide Fragment ◽  
Dissociation Kinetics ◽  
Angiotensin Converting Enzyme 2 ◽  
Significant Inhibitory Effect ◽  
Kinetics Of

Abstract The influence of the peptide QAKTFLDKFNHEAEDLFYQ on the kinetics of the SARS-CoV-2 spike protein S1 binding to angiotensin-converting enzyme 2 (ACE2) was studied to model the interaction of the virus with its host cell. This peptide corresponds to the sequence 24–42 of the ACE2 α1 domain, which is the binding site for the S1 protein. The on-rate and off-rate of S1-ACE2 complex formation were measured in the presence of various peptide concentrations using Bio-Layer Interferometry (BLI). The formation of the S1-ACE2 complex was inhibited when the S1 protein was preincubated with the peptide, however, no significant inhibitory effect was observed in the absence of preincubation. Dissociation kinetics revealed that the peptide remained bound to the S1-ACE2 complex and stabilized this complex. This suggestion was confirmed by computational mapping of the S1 protein surface for peptide binding that revealed two additional sites, located at some distance from the receptor binding domain of S1. These additional binding sites may affect the interaction between the peptide, the S1 protein, and ACE2.

scholarly journals Molecular mechanism of evolution and human infection with the novel coronavirus (2019-nCoV)

2020 ◽  
Author(s):  
Jiahua He ◽  
Huanyu Tao ◽  
Yumeng Yan ◽  
Sheng-You Huang ◽  
Yi Xiao
Keyword(s):  
Free Energy ◽  
Molecular Mechanisms ◽  
Vaccine Development ◽  
Binding Free Energy ◽  
Protein Docking ◽  
Human Infection ◽  
Host Cells ◽  
Spike Protein ◽  
Temperature Sensitive ◽  
Health Crisis

AbstractSince December, 2019, an outbreak of pneumonia caused by the new coronavirus (2019-nCoV) has hit the city of Wuhan in the Hubei Province. With the continuous development of the epidemic, it has become a national public health crisis and calls for urgent antiviral treatments or vaccines. The spike protein on the coronavirus envelope is critical for host cell infection and virus vitality. Previous studies showed that 2019-nCoV is highly homologous to human SARS-CoV and attaches host cells though the binding of the spike receptor binding domain (RBD) domain to the angiotensin-converting enzyme II (ACE2). However, the molecular mechanisms of 2019-nCoV binding to human ACE2 and evolution of 2019-nCoV remain unclear. In this study, we have extensively studied the RBD-ACE2 complex, spike protein, and free RBD systems of 2019-nCoV and SARS-CoV using protein-protein docking and molecular dynamics (MD) simulations. It was shown that the RBD-ACE2 binding free energy for 2019-nCoV is significantly lower than that for SARS-CoV, which is consistent with the fact that 2019-nCoV is much more infectious than SARS-CoV. In addition, the spike protein of 2019-nCoV shows a significantly lower free energy than that of SARS-CoV, suggesting that 2019-nCoV is more stable and able to survive a higher temperature than SARS-CoV. This may also provide insights into the evolution of 2019-nCoV because SARS-like coronaviruses are thought to have originated in bats that are known to have a higher body-temperature than humans. It was also revealed that the RBD of 2019-nCoV is much more flexible especially near the binding site and thus will have a higher entropy penalty upon binding ACE2, compared to the RBD of SARS-CoV. That means that 2019-nCoV will be much more temperature-sensitive in terms of human infection than SARS-CoV. With the rising temperature, 2019-nCoV is expected to decrease its infection ability much faster than SARS-CoV, and get controlled more easily. The present findings are expected to be helpful for the disease prevention and control as well as drug and vaccine development of 2019-nCoV.

scholarly journals In silico studies on milk derived peptides as potential inhibitors against SARS CoV-2 spike protein receptor binding domain

2021 ◽  
Author(s):  
Sutanu Mukhopadhyay ◽  
Anasua Sarkar
Keyword(s):  
Receptor Binding ◽  
Computational Study ◽  
Protein Docking ◽  
Binding Domain ◽  
Spike Protein ◽  
Receptor Protein ◽  
Extensive Literature ◽  
Receptor Binding Domain ◽  
Peptide Docking ◽  
In Silico Studies

Abstract COVID-19 (Corona Virus Infected Diseases-19) is caused by a strain of coronavirus called SARS-CoV-2 (Severe acute respiratory syndrome coronavirus 2). There’s no permanent diagnosis available till date to combat the disease. The viral infection in humans is initiated by binding of RBD (receptor binding domain) of spike protein to human angiotensin-converting enzyme 2 (hACE2) receptor protein. In this computational study, milk-derived peptides are screened against Receptor Binding Domain (RBD) of spike protein of the virus. Milk is considered as one of the most nutrient-rich liquid foods having several antibacterial and antiviral activities. Milk derived peptides including Casein and Whey derived peptides are known to have profound anti-viral and immunomodulatory activities. After extensive literature search, some peptides having anti-viral activities against different viruses, are shortlisted for this study and their three-dimensional structures are modelled for protein-peptide docking against SARS-CoV-2 spike protein RBD. After performing protein-peptide docking and protein-protein docking using different servers such as HPEPDOCK, FIREDOCK, HADDOCK, HDOCK, it has been observed that in presence of the peptides, the interaction between spike RBD and hACE2 has been reasonably decreased, which implies that milk-derived peptides can be potential peptide-inhibitors against the RBD of the virus along with other medications. Further studies on milk-derived peptides should be performed to develop peptide drugs based on milk-derived peptides.

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