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SARS-CoV 2 spike protein S1 subunit as an ideal target for stable vaccines: A bioinformatic study.

ABSTRACT: The Covid-19 a pandemic infectious disease and affected life across the world resulting in over 188.65 million confirmed cases across 223 countries, territories and areas with 4.06 million deaths. It is caused by a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and spike (S) protein of SARS-CoV-2, which plays a key role in the receptor recognition and cell membrane fusion process, is composed of two subunits, S1 and S2. The S1 subunit contains a receptor-binding domain (RBD) that recognizes and binds to the host receptor angiotensin-converting enzyme 2 (ACE2), while the S2 subunit mediates viral cell membrane fusion. Hence, it is a key target for developing neutralizing antibodies. Here, we have performed phylogenetic analysis and structural modeling of the SARS-CoV-2 spike glycoprotein, which is found highly conserved. The overall percent protein sequence identity from the SARS-CoV-2 spike protein sequences from the NCBI database was 99.68%. The functional domains of the S protein reveal that the S1 subunit was highly conserved (99.70%) than the S2 subunit (99.66%). Further, the 319-541 residues (RBD) of amino acids within the S1 domain were 100% similar among the spike protein. The 3D modeling of SARS-CoV-2 spike glycoprotein indicated that S protein has four domains with five protein units and the S1 subunit from 1 to 289 amino acid of domain 1 is highly conserved without any change in the ligand interaction site. This analysis clearly suggests that the S1 subunit (RBD 319-541) can be used as a target region for stable and safe vaccine development.

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PROVIDER: S-EPMC8279943 | biostudies-literature |

REPOSITORIES: biostudies-literature

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SARS-CoV-2 SPIKE PROTEIN: an optimal immunological target for vaccines.

Project description:COVID-19 has rapidly spread all over the world, progressing into a pandemic. This situation has urgently impelled many companies and public research institutes to concentrate their efforts on research for effective therapeutics. Here, we outline the strategies and targets currently adopted in developing a vaccine against SARS-CoV-2. Based on previous evidence and experience with SARS and MERS, the primary focus has been the Spike protein, considered as the ideal target for COVID-19 immunotherapies.

| S-EPMC7268185 | biostudies-literature

Deciphering the protein motion of S1 subunit in SARS-CoV-2 spike glycoprotein through integrated computational methods.

Project description:The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a major worldwide public health emergency that has infected over 8 million people. Spike glycoprotein, especially the partially open state of S1 subunit, in SARS-CoV-2 is considered vital for its infection with human host cell. However, the mechanism elucidating the transition from the closed state to the partially open state still remains unclear. In this study, we applied a series of computational methods, including Markov state model, transition path theory and random forest to analyze the S1 motion. Our results showed a promising complete conformational movement of the receptor-binding domain, from buried, partially open, to detached states. We also estimated the transition probability among these states. Based on the asymmetry in both the dynamics behavior and the accumulated alpha carbon (Cα) importance, we further suggested a relation among chains in the trimer spike protein, which leads to a deeper understanding on protein motions of the S1 subunit. Communicated by Ramaswamy H. Sarma.

| S-EPMC7484573 | biostudies-literature

Adenoviral expression of a truncated S1 subunit of SARS-CoV spike protein results in specific humoral immune responses against SARS-CoV in rats.

Project description:The causative agent of severe acute respiratory syndrome (SARS) has been identified as SARS-associated coronavirus (SARS-CoV), but the prophylactic treatment of SARS-CoV is still under investigation. We constructed a recombinant adenovirus containing a truncated N-terminal fragment of the SARS-CoV Spike (S) gene (from--45 to 1469, designated Ad-S(N)), which encoded a truncated S protein (490 amino-acid residues, a part of 672 amino-acid S1 subunit), and investigated whether this construct could induce effective immunity against SARS-CoV in Wistar rats. Rats were immunized either subcutaneously or intranasally with Ad-S(N) once a week for three consecutive weeks. Our results showed that all of the immunized animals generated humoral immunity against the SARS-CoV spike protein, and the sera of immunized rats showed strong capable of protecting from SARS-CoV infection in vitro. Histopathological examination did not find evident side effects in the immunized animals. These results indicate that an adenoviral-based vaccine carrying an N-terminal fragment of the Spike gene is able to elicit strong SARS-CoV-specific humoral immune responses in rats, and may be useful for the development of a protective vaccine against SARS-CoV infection.

| S-EPMC7114075 | biostudies-literature

Rescue of recombinant canine distemper virus that expresses S1 subunit of SARS-CoV-2 spike protein in vitro.

Project description:The coronavirus disease 2019 (COVID-19), as an unprecedented pandemic, has rapidly spread around the globe. Its etiological agent, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), belongs to the genus Betacoronavirus in the family Coronaviridae. The viral S1 subunit has been demonstrated to have a powerful potential in inducing protective immune responses in vivo. Since April 2020, farmed minks were frequently reported to be infected with the SARS-CoV-2 in different countries. Unfortunately, there has been no available veterinary vaccine as yet. In this study, we used reverse genetics to rescue a recombinant canine distemper virus (CDV) that could express the SARS-CoV-2 S1 subunit in vitro. The S1 subunit sequence was demonstrated to be relatively stable in the genome of recombinant CDV during twenty serial viral passages in cells. However, due to introduction of the S1 subunit sequence into CDV genome, this recombinant CDV grew more slowly than the wild-type strain did. The genomic backbone of recombinant CDV was derived from a virulence-attenuating strain (QN strain). Therefore, if able to induce immune protections in minks from canine distemper and COVID-19 infections, this recombinant would be a potential vaccine candidate for veterinary use.

| S-EPMC8312057 | biostudies-literature

Cell-Free Hemoglobin Does Not Attenuate the Effects of SARS-CoV-2 Spike Protein S1 Subunit in Pulmonary Endothelial Cells.

Project description:SARS-CoV-2 primarily infects epithelial airway cells that express the host entry receptor angiotensin-converting enzyme 2 (ACE2), which binds to the S1 spike protein on the surface of the virus. To delineate the impact of S1 spike protein interaction with the ACE2 receptor, we incubated the S1 spike protein with human pulmonary arterial endothelial cells (HPAEC). HPAEC treatment with the S1 spike protein caused disruption of endothelial barrier function, increased levels of numerous inflammatory molecules (VCAM-1, ICAM-1, IL-1β, CCL5, CXCL10), elevated mitochondrial reactive oxygen species (ROS), and a mild rise in glycolytic reserve capacity. Because low oxygen tension (hypoxia) is associated with severe cases of COVID-19, we also evaluated treatment with hemoglobin (HbA) as a potential countermeasure in hypoxic and normal oxygen environments in analyses with the S1 spike protein. We found hypoxia downregulated the expression of the ACE2 receptor and increased the critical oxygen homeostatic signaling protein, hypoxia-inducible factor (HIF-1α); however, treatment of the cells with HbA yielded no apparent change in the levels of ACE2 or HIF-1α. Use of quantitative proteomics revealed that S1 spike protein-treated cells have few differentially regulated proteins in hypoxic conditions, consistent with the finding that ACE2 serves as the host viral receptor and is reduced in hypoxia. However, in normoxic conditions, we found perturbed abundance of proteins in signaling pathways related to lysosomes, extracellular matrix receptor interaction, focal adhesion, and pyrimidine metabolism. We conclude that the spike protein alone without the rest of the viral components is sufficient to elicit cell signaling in HPAEC, and that treatment with HbA failed to reverse the vast majority of these spike protein-induced changes.

| S-EPMC8396564 | biostudies-literature

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

Project description: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.

| S-EPMC8347908 | biostudies-literature

Protection from COVID-19 disease in hamsters vaccinated with subunit SARS-CoV-2 S1 mucosal vaccines adjuvanted with different adjuvants

Project description:Introduction Adjuvant plays an important role in directing the immune responses induced by vaccines. In previous studies, we have shown that a mucosal SARS-CoV-2 S1 subunit vaccine adjuvanted with a combination of CpG, Poly I:C and IL-15 (named CP15) induced effective mucosal and systemic immunity and conferred nearly sterile protection against SARS-CoV-2 viral replication in macaque models. Methods In this study, we used a hamster model, which mimics the human scenario and reliably exhibits severe SARS-CoV-2 disease similar to hospitalized patients, to investigate the protection efficacy of the vaccines against COVID-19 disease. We compared the weight loss, viral loads (VLs), and clinical observation scores of three different vaccine regimens. All three regimens consisted of priming/boosting with S1 subunit vaccines, but adjuvanted with alum and/or CP15 administrated by either intramuscular (IM) or intranasal (IN) routes: Group 1 was adjuvanted with alum/alum administrated IM/IM; Group 2 was alum-IM/CP15-IN; and Group 3 was CP15-IM/CP15-IN. Results After challenge with SARS-CoV-2 WA strain, we found that the alum/CP15 group showed best protection against weight loss, while the CP15 group demonstrated best reduction of oral SARS-CoV-2 VLs, suggesting that the protection profiles were different. Sex differences for VL and clinical scores were observed. Humoral immunity was induced but not correlated with protection. Moreover, S1-specific binding antibody titers against beta, omicron BA.1, and BA.2 variants showed 2.6-, 4.9- and 2.8- fold reduction, respectively, compared to the Wuhan strain. Discussion Overall, the data suggested that adjuvants in subunit vaccines determine the protection profiles after SARS-CoV-2 infection and that nasal/oral mucosal immunization can protect against systemic COVID-19 disease.

| S-EPMC10067881 | biostudies-literature

SARS-CoV-2 S Omicron Spike B.1.1.529

Project description: Not available

| EMPIAR-10947 | biostudies-other

SARS-CoV-2 Spike Glycoprotein S1 Induces Neuroinflammation in BV-2 Microglia.

Project description:In addition to respiratory complications produced by SARS-CoV-2, accumulating evidence suggests that some neurological symptoms are associated with the disease caused by this coronavirus. In this study, we investigated the effects of the SARS-CoV-2 spike protein S1 stimulation on neuroinflammation in BV-2 microglia. Analyses of culture supernatants revealed an increase in the production of TNF-α, IL-6, IL-1β and iNOS/NO. S1 also increased protein levels of phospho-p65 and phospho-IκBα, as well as enhanced DNA binding and transcriptional activity of NF-κB. These effects of the protein were blocked in the presence of BAY11-7082 (1 µM). Exposure of S1 to BV-2 microglia also increased the protein levels of NLRP3 inflammasome and enhanced caspase-1 activity. Increased protein levels of p38 MAPK was observed in BV-2 microglia stimulated with the spike protein S1 (100 ng/ml), an action that was reduced in the presence of SKF 86,002 (1 µM). Results of immunofluorescence microscopy showed an increase in TLR4 protein expression in S1-stimulated BV-2 microglia. Furthermore, pharmacological inhibition with TAK 242 (1 µM) and transfection with TLR4 small interfering RNA resulted in significant reduction in TNF-α and IL-6 production in S1-stimulated BV-2 microglia. These results have provided the first evidence demonstrating S1-induced neuroinflammation in BV-2 microglia. We propose that induction of neuroinflammation by this protein in the microglia is mediated through activation of NF-κB and p38 MAPK, possibly as a result of TLR4 activation. These results contribute to our understanding of some of the mechanisms involved in CNS pathologies of SARS-CoV-2.

| S-EPMC8551352 | biostudies-literature

SARS-CoV-2 spike protein S1 subunit induces potent neutralizing responses in mice and is effective against Delta and Omicron variants.

Project description:SARS-CoV-2, the virus responsible for the COVID-19 pandemic, belongs to the betacoronavirus genus. This virus has a high mutation rate, which rapidly evolves into new variants with different properties, such as increased transmissibility or immune evasion. Currently, the most prevalent global SARS-CoV-2 variant is Omicron, which is more transmissible than previous variants. Current available vaccines may be less effective against some currently existing SARS-CoV-2 variants, including the Omicron variant. The S1 subunit of the spike protein of SARS-CoV-2 has been a major target for COVID-19 vaccine development. It plays a crucial role in the virus's entry into host cells and is the primary target for neutralizing antibodies. In this study, the S1 subunit of the spike protein of SARS-CoV-2 was engineered and produced at a high level in Nicotiana benthamiana plant. The expression level of the recombinant S1 protein was greater than the 0.5-g/kg fresh weight, and the purification yield was at least ~0.3 g of pure protein/kg of plant biomass, which would make a plant-produced S1 antigen an ideal vaccine candidate for commercialization. Purified, the plant-produced SARS-CoV-2 S1 protein exhibited significantly higher binding to the SARS-CoV-2 receptor, angiotensin-converting enzyme 2 (ACE2). Moreover, we also show that recombinant S1 protein/antigen-elicited antibodies can neutralize the Delta or Omicron variants. Collectively, our results demonstrate that a plant-produced S1 antigen could be a promising vaccine candidate against SARS-CoV-2 variants including Omicron.

| S-EPMC10682712 | biostudies-literature

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