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The life cycle of SARS-CoV in host cells.Severe acute respiratory syndrome-coronavirus (SARS-CoV) enters target cells through an endosomal pathway113, 121, 125, 126, 127. S protein first binds to the cellular receptor angiotensin-converting enzyme 2 (ACE2)129, and the ACE2–virus complex is then translocated to endosomes, where S protein is cleaved by the endosomal acid proteases (cathepsin L)105 to activate its fusion activity. The viral genome is released and translated into viral replicase polyproteins pp1a and 1ab, which are then cleaved into small products by viral proteinases. Subgenomic negative-strand templates are synthesized from discontinuous transcription on the plus-strand genome and serve as templates for mRNA synthesis. The full-length negative-strand template is made as a template for genomic RNA. Viral nucleocapsids are assembled from genomic RNA and N protein in the cytoplasm, followed by budding into the lumen of the ERGIC (endoplasmic reticulum (ER)–Golgi intermediate compartment)128. Virions are then released from the cell through exocytosis.
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Severe acute respiratory syndrome (SARS) is a newly emerging infectious disease caused by a novel coronavirus, SARS-coronavirus (SARS-CoV). The SARS-CoV spike (S) protein is composed of two subunits; the S1 subunit contains a receptor-binding domain that engages with the host cell receptor angiotensin-converting enzyme 2 and the S2 subunit mediates...
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... contact. After the virus enters into the body, it binds to primary target cells that express abundant virus receptor, the angiotensin-converting enzyme 2 (ACE2), including pneumocytes and enterocytes in the respiratory system. The virus enters and replicates in these cells. The matured virions are then released to infect new target cells121 (FIG. 1). SARS-CoV can also infect mucosal cells of intestines, tubular epithelial cells of kidneys, epithelial cells of renal tubules, cerebral neurons and immune cells122,123. Infectious viral particles in patients with SARS can be excreted through respiratory secretions, stool, urine and sweat. SARS-CoV infection damages lung tissues owing ...
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1. A SARS vaccine was produced based on recombinant native full-length Spike-protein trimers (triSpike) and efficient establishment of a vaccination procedure in rodents. 2. Antibody-mediated enhancement of SARS-CoV infection with anti-SARS-CoV Spike immune-serum was observed in vitro. 3. Antibody-mediated infection of SARS-CoV triggers entry into...
Raccoon dog is one of the suspected intermediate hosts of severe acute respiratory syndrome coronavirus (SARS-CoV). In this study, the angiotensin-converting enzyme 2 (ACE2) gene of raccoon dog (rdACE2) was cloned and sequenced. The amino acid sequence of rdACE2 has identities of 99.3, 89.2, 83.9 and 80.4 % to ACE2 proteins from dog, masked palm ci...
The spike (S) protein of the severe acute respiratory syndrome coronavirus (SARS-CoV) is responsible for host cell attachment and fusion of the viral and host cell membranes. Within S the receptor binding domain (RBD) mediates the interaction with angiotensin-converting enzyme 2 (ACE2), the SARS-CoV host cell receptor. Both S and the RBD are highly...
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... However, dominant immunogenic epitopes are found on the S1 subunit, as this is the peripheral fragment of the enveloped S glycoprotein, and in the pre-fusion state, it is the main target of the immune response responsible for induction of high levels of antibodies [89]. In particular, the receptorbinding domain of IBV S may contain prime vaccine candidates, due to their ability to induce strong immune responses, as illustrated with other coronaviruses [35,90,91], and immunization with the entire RBD (19-237 aa) of IBV S might be an alternative vaccination. The HVR1 (38-67 aa) of IBV S contains a neutralising epitope at 24-61 aa [18,21,67,80]. ...
The avian coronavirus, infectious bronchitis virus (IBV), is an economically important infectious disease affecting chickens, with a diverse range of serotypes found globally. The major surface protein, spike (S), has high diversity between serotypes, and amino acid differences in the S1 sub-unit are thought to be responsible for poor cross-protection afforded by vaccination. Here, we attempt to address this, by using epitope mapping technology to identify shared and serotype-specific immunogenic epitopes of the S glycoprotein of three major circulating strains of IBV, M41, QX, and 4/91, via CLIPS peptide arrays based on peptides from the S1 sub-units. The arrays were screened with sera from chickens immunised with recombinant IBV, based on Beau-R backbone expressing heterologous S, generated in two independent vaccination/challenge trials. The screening of sera from rIBV vaccination experiments led to the identification of 52 immunogenic epitopes on the S1 of M41, QX, and 4/91. The epitopes were assigned into six overlapping epitope binding regions. Based on accessibility and location in the hypervariable regions of S, three sequences, 25YVYYYQSAFRPPNGWHLQGGAYAVVNSTN54, 67TVGVIKDVYNQSVASI82, and 83AMTVPPAGMSWSVS96, were selected for further investigation, and synthetic peptide mimics were recognised by polyclonal sera. These epitopes may have the potential to contribute towards a broader cross-protective IBV vaccine.
... envelop (E), and spike (S) proteins, respectively (17)(18)(19)(20). The S protein is highly immunogenic and plays a crucial role in initiating viral infection through the recognition of its receptor, the angiotensin converting enzyme 2 (ACE2), expressed by the host cell (21)(22)(23). The S protein is common to SARS-CoV and SARS-CoV-2, with approximately 24.5% of non-conserved amino acid sequences (24,25). ...
... A CT scan is reported to have a high sensitivity (97%) but poor specificity (25%) when compared to RT-PCR for COVID-19 diagnosis [11]. This is ascribed to the fact that the CT appearance in COVID-19 overlaps with the appearance of other viral pneumonia, similar to influenza viruses, para influenza virus, respiratory syncytial virus, adenovirus, human metapneumovirus, rhinovirus, etc. [12][13][14]. ...
Introduction: Reverse transcription-polymerase chain reaction (RT-PCR) is used as a standard test for the diagnosis of SARS-CoV-2 viral RNA from nasopharyngeal aspirates. However, this method lacks sensitivity and cannot assess disease severity. A CT scan of the thorax provides a CT severity score (CT-SS), which depicts lung involvement and disease severity. This study aims to investigate the diagnostic value of chest CT compared with RT-PCR cycle threshold (Ct) values in COVID-19 and relate it clinically with the disease severity of patients.
Methods: This retrospective observational study was conducted in a tertiary center from April 2021 to March 2022. We included 511 patients who had tested RT-PCR positive for COVID-19, were hospitalized, and had undergone high-resolution CT (HRCT) thorax. Data was collected from patient records regarding name, age, sex, admission data, baseline investigations including Ct value, management, and outcome. HRCT was reviewed to assess lung involvement and calculate CT-SS. Data was analyzed using SPSS Statistics version 25 (IBM Corp. Released 2017. IBM SPSS Statistics for Windows, Version 25.0. Armonk, NY: IBM Corp.).
Result: The mean age of patients was 50.4 ± 13.7 years, and the majority (67.5%) were male. Gender-wise, there was no difference in RT-PCR cycle threshold (Ct) values; however, CT-SS was significantly higher in males (17.5 ± 4.8 vs.10.5 ± 6.6, t=-13.6, p<0.0001). ICU admission was needed for 34.8% of patients, and they had a significantly lower Ct value (21.7 ± 3.3 vs. 22.8 ± 3.7, t=21.10, p<0.0001) and higher CT-SS (16.3 ± 4.5 vs. 6.7 ± 5.1, t=-3.32, p=0.001).
Conclusion: Ct values could not differentiate between moderate and severe patients. CT-SS was not related to the viral load at admission. Patients who succumbed had significantly lower Ct values and higher CT-SS.
... and representing a prime target for antiviral interventions (3,4). The receptor-binding domain (RBD) located at the tip of the spike protein is responsible for binding the host receptor ACE2 and is heavily targeted by the host's immune defenses (5)(6)(7). ...
Nanobodies are single-domain antibodies derived from camelid animals. Here, we discovered three anti-SARS-CoV-2 nanobodies, namely, Nanosota-2, -3, and -4, from an alpaca immunized with SARS-CoV spike protein. We further characterized the antiviral activities of these Fc-tag-fused nanobodies. Notably, Nanosota-2 inhibits the prototypic SARS-CoV-2 strain in vitro (with an IC 50 of 2 pM) and in mice (at a dosage of 4 mg/kg or administered 18 hours post-challenge). These potency metrics are the best among known SARS-CoV-2 entry inhibitors. Moreover, Nanosota-3 effectively inhibits the omicron variant, both in vitro and in mice, regardless of the administration route (intraperitoneal or intranasal). Furthermore, Nanosota-3 has been biochemically engineered to inhibit both early and currently circulating subvariants of omicron. Additionally, Nanosota-4 uniquely inhibits both SARS-CoV-1 and SARS-CoV-2. Cryo-EM data revealed that the three nanobodies bind to functionally critical and non-overlapping regions in the spike protein. Given their cost-effectiveness, ease of adaptation to new viral strains, and potential use as inhalers, the Nanosota series are powerful therapeutic tools against coronavirus pandemics.
IMPORTANCE
The COVID-19 pandemic exposed limitations of conventional antibodies as therapeutics, including high cost, limited potency, ineffectiveness against new viral variants, and primary reliance on injection-only delivery. Nanobodies are single-domain antibodies with therapeutic potentials. We discovered three anti-SARS-CoV-2 nanobodies, named Nanosota-2, -3, and -4, from an immunized alpaca. Nanosota-2 is super potent against prototypic SARS-CoV-2, Nanosota-3 is highly potent against the omicron variant, and Nanosota-4 is effective against both SARS-CoV-1 and SARS-CoV-2. In addition to their super potency and combined broad antiviral spectrum, these nanobodies are cost-effective, can be easily adapted to new viral variants through phage display, and can potentially be administered as inhalers. The Nanosota series are powerful therapeutic candidates to combat circulating SARS-CoV-2 and prepare for possible future coronavirus pandemics.
... The S-protein RBD is the domain that precisely combines with ACE 2 to induce viral ingress into the host cell [38][39][40][41][42]. An assessment of the polypeptides of the S-protein of five SARS-CoV-2 variants discovered polymorphisms in India, the UK, South Africa, and Brazil except for Pakistan at numerous nucleotide and amino acid positions ( Table 1). ...
Background: Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) upsurge sprang up in Wuhan, China, in late December 2019. Objectives: Due to the exceptionally high mutation frequency, comparative genomics of viruses isolated throughout time and in various geographical locations are crucial. To better understand how SARS-CoV-2 heterogeneity has changed around the globe, this research was conducted. Methods: Nucleotide and protein sequences of SARS-CoV-2, SARS-CoV, and bat SARS-like CoV were extracted from the NCBI Virus database. The Wuhan SARS-CoV-2 variant was used as a reference. Molecular Evolutionary Genetics Study performed the phylogenetic analysis, while the Genome Detective Coronavirus Typing Tool performed the mutational analysis. Results: The evolutionary research has revealed that bats are the primary host for coronavirus evolution and the origin of the formation of SARS-CoV and SARS-CoV-2. Numerous mutations have been discovered in the spike, envelope, and nucleocapsid protein. Conclusions: The current research findings may have an implication that facilitates the development of prospective immunization candidates/small pharmacological compounds targeting COVID-19. Keywords: SARS-CoV-2; COVID-19; pandemic; comparative genomics; spike protein; envelope protein; nucleocapsid protein.
... This reasoning is especially relevant in the healthrelated context, where understanding how to address the root causes of a disease is paramount to effectively countering its harmfulness for humans (Foulkes & Sharpless, 2021). For instance, the broader scientific knowledge that allows us to comprehend the life cycle and pathogenesis of a virus may be helpful in developing an invention that will spur the production of vaccines and therapeutics against the virus itself but also for other viruses that rely on the same biological mechanisms (Du et al., 2009). Consequently, the invention resulting from intense scientific search may be used to discover multiple drugs. ...
The present study seeks to shed further light on what favors the conversion of inventions into innovations in for-profit firms and to advance our understanding of how to tackle cancer grand challenges (CGCs). Specifically, following the literature on knowledge search and recombination, we analyze whether and how cancer-related inventions developed through an intense adoption of scientific knowledge (scientific search intensity) result in (i) a higher number of approved drugs and (ii) a shorter approval time for new drugs. Notably, while the role of science with regard to technological development has been widely studied, the extent to which science-based solutions relate to new product introduction, especially in terms of coping with grand challenges such as approved cancer drugs, is less known. Furthermore, considering the digitiza-tion of (health) R&D and the role of information and communication technologies (i.e., digital technologies) to address grand challenges, we examine whether and how cancer-related inventions developed through an intense adoption of digital knowledge (digital search intensity) directly affect the extent and speed of cancer drug approval, as well as whether interaction effects between scientific and digital search intensity exist. We develop hypotheses that we test on a sample of 65,861 cancer-related patents owned by 139 for-profit firms, collected from the USPTO Cancer Moonshot Patent Data. These have a priority date between 1990 and 2010, and have led to 1035 approved drugs. Results reveal that scientific search intensity is not associated with the number of different drugs developed from a single cancer-related invention but is associated with the speed at which the invention leads to a newly approved drug. Digital search intensity appears not to directly affect cancer drug approval, but it lessens the effects of scientific search intensity, thus pointing to a limit of digitization in cancer R&D and innovation processes.
... During membrane fusion, the interactions between the HR1 and HR2 domains within the S protein trimer result in the formation of a six-helix bundle structure. This structural module brings the viral and host cell membranes into close proximity, facilitating membrane fusion and the subsequent injection of the viral genome into the host cell (Du et al., 2009;Xia et al., 2020). A synthetic HR2 derived peptide can interact with the HR1 to form a stable six-helix bundle (Liu et al., 2004) and inhibit SARS-CoV and SARS-CV-2 infection. ...
Cryogenic electron microscopy (cryo-EM) and electron tomography (cryo-ET) have become a critical tool for studying viral particles. Cryo-EM has enhanced our understanding of viral assembly and replication processes at a molecular resolution. Meanwhile, in situ cryo-ET has been used to investigate how viruses attach to and invade host cells. These advances have significantly contributed to our knowledge of viral biology. Particularly, prompt elucidations of structures of the SARS-CoV-2 spike protein and its variants have directly impacted the development of vaccines and therapeutic measures. This review discusses the progress made by cryo-EM based technologies in comprehending the severe acute respiratory syndrome coronavirus-2 (SARS-Cov-2), the virus responsible for the devastating global COVID-19 pandemic in 2020 with focus on the SARS-CoV-2 spike protein and the mechanisms of the virus entry and replication.
... The S protein is key in inducing neutralizing antibody and T-cell responses and protective immunity upon SARS-CoV infection. [23][24][25][26] The SARS-CoV spike is processed by lysosomal proteases such as cathepsin B and cathepsin L by an endocytosis mechanism. Hence, the virus enters the host cell via endocytosis. ...
... Thus, protein convertases are not responsible for splitting the SARS-CoV spike during virus packaging, and it remains intact during mature virions. [26][27][28] Despite this well-established research data, the results of the second cluster of keywords in this bibliometric analysis showed that virus transition and mutation continue to be a subject of ongoing research for developing new strategies for the prevention and treatment of other emerging infections caused by enveloped viruses. ...
Aim Nanomedicine can play an important role in the various stages of prevention, diagnosis, treatment, vaccination, and research related to coronavirus disease 2019 (COVID-19). While nanomedicine is a powerful interdisciplinary means that offers various approaches in patient treatment, a number of factors should be critically studied to find approaches and mechanisms in the prevention, diagnosis, and treatment of this disease. This bibliometric analysis was designed to explore studies on the current knowledge of the structure, its mechanism of cell binding, and the therapeutic effect of nanomedicine on COVID-19.
Methods The study data was searched from Web of Science Core Collection(WoSCC) between 2017 and 2021. Biblioshiny and VOSviewer were used to analyze and visualize patterns in scientific literature derived from WoS.
Results The three clusters of keywords resulted relating to aim. Cluster 1 looking into epidemiological and public health studies on COVID-19. Cluster 2 included terms associated with virus transition, such as receptor binding, membrane glycoprotein, membrane fusion, and viral envelope proteins. Cluster 3 involved high-frequency keywords associated with nanomedicine, such as metal nanoparticles, drug delivery system doxorubicin, immunology, immune response, inflammation, and unclassified drug. Keywords such as “nanotechnology” and “gold nanoparticles” were at the center of COVID-19 related clusters, indicating the importance of these areas during the outbreak.
Conclusions Understanding the advanced virology of coronaviruses and interfering with their spread through nanomedicine could significantly impact global health and economic stability. Continuous research is needed to accelerate the transfer of nanomedicine results into practice of treatment without risk of side effects.
... The cumulative global impact of SARS-CoV-2 infections has caused over 600 million cases (https://COVID19.who.int/, accessed on 15 March 2023), posing a severe threat to public health [1]. The surface of SARS-CoV-2 features a trimeric spike (S) protein, comprising an S1 subunit bound to the host cell [2]. ...
Continued mutation of the SARS-CoV-2 genome has led to multiple waves of COVID-19 infections, and new variants have continued to emerge and dominate. The emergence of Omicron and its subvariants has substantially increased the infectivity of SARS-CoV-2. RBD genes of the wild-type SARS-CoV-2 strain and the Delta, Omicron BA.1 and Omicron BA.2 variants were used to construct plasmids and express the proteins in glycoengineered Pichia pastoris. A stable 4 L-scale yeast fermentation and purification process was established to obtain high-purity RBD proteins with a complex glycoform N-glycosyl structure that was fucose-free. The RBD glycoproteins were combined with two adjuvants, Al(OH)3 and CpG, which mitigated the typical disadvantage of low immunogenicity associated with recombinant subunit vaccines. To improve the broad-spectrum antiviral activity of the candidate vaccine, Delta RBD proteins were mixed with BA.2 RBD proteins at a ratio of 1:1 and then combined with two adjuvants—Al(OH)3 and CpG—to prepare a bivalent vaccine. The bivalent vaccine effectively induced mice to produce pseudovirus-neutralizing antibodies against SARS-CoV-2 variants, Delta, Beta, and Omicron sublineages BA.1, BA.2, BA.5. The bivalent vaccine could neutralize the authentic wild-type SARS-CoV-2 strain, Delta, BA.1.1, BA.2.2, BA2.3, and BA.2.12.1 viruses, providing a new approach for improving population immunity and delivering broad-spectrum protection under the current epidemic conditions.
... Противовирусный иммунный ответ на коронавирусную инфекцию стал изучаться многими исследовательскими группами после вспышки SARS-CoV в 2002 году [10,11,12]. Нейтрализующие антитела и Т-клеточный ответ, главным образом, были направлены против S-белка, который участвует в распознавании рецептора и проникновении вируса в клетку-мишень и играет важную роль в адаптивной эволюции вируса [4]. ...
The pandemic of coronavirus infection (COVID-19) has stimulated the development, testing and widespread use of preventive vaccines based on various platforms. Our aim was to perform a direct comparison of immunogenicity of various vaccines within a single study in small groups within six months of SARS-CoV-2 vaccination and revaccination. The stdy group included subjects vaccinated with Sputnik V adenovirus vaccine, mRNA vaccines, and CoviVac whole-virion vaccine. Their immune status was assessed by enzyme immunoassay as specific antibody levels. Moreover, the neutralizing ability of detected antibodies was assessed using a cell test system based on pseudoviral technology. All of the mentioned vaccines were shown to elicit an immune response against SARS-CoV-2 RBD antigen, however, appropriate antibody titers and neutralizing capacities differed depending on the type of vaccine. The mRNA vaccines proved to be the most immunogenic, the effectiveness of the immune response to the Sputnik V adenovirus-based vaccine was lower. However, 6 months after vaccination, the effectiveness of virus neutralizing antibodies induced by these vaccines did not differ. The whole-virion CoviVac vaccine with proven efficiency by independent epidemiological studies, induced an antibody response against the RBD protein to a lesser extent. The seropositive participants of the study, both previously exposed to COVID-19 disease or vaccinated, exhibited high-titer production of antibodies already after the first dose of the Sputnik V vaccine, and a significantly higher antibody titer 6 months after the booster immunization as compared with initial level of antibodies, along with direct correlation between the antibody titers and their neutralizing activity.
