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A novel SARS-like coronavirus (SARS-CoV-2) recently emerged and is rapidly spreading in humans1,2. A key to tackling this epidemic is to understand the virus’s receptor recognition mechanism, which regulates its infectivity, pathogenesis and host range. SARS-CoV-2 and SARS-CoV recognize the same receptor - human ACE2 (hACE2)3,4. Here we determined...
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SARS- CoV-2 is a recently emerged coronavirus that binds angiotensin- converting enzyme 2 (ACE2) for cell entry via its receptor- binding domain (RBD) on a surface- expressed spike glycoprotein. Studies show that despite its similarities to severe acute respiratory syndrome (SARS) coronavirus, there are critical differences in key RBD residues when...
SARS-CoV-2 is threatening people worldwide, and there are no drugs or vaccines available to mitigate its spread. The origin of the virus is still unclear, and whether pets and livestock can be infected and transmit SARS-CoV-2 are important and unknown scientific questions. Effective binding to the host receptor ACE2 is the first prerequisite for in...
An outbreak of the coronavirus disease 2019 (COVID-19)1–3, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)4 spread globally. Countermeasures are needed to treat and prevent further dissemination of the virus. In this study, we report the isolation of 2 specific human monoclonal antibodies (MAbs) from a convalescent COVID-...
The outbreak of COVID-19 poses unprecedent challenges to global health1. The new coronavirus, SARS-CoV-2, shares high sequence identity to SARS-CoV and a bat coronavirus RaTG132. While bats may be the reservoir host for various coronaviruses3,4, whether SARS-CoV-2 has other hosts remains ambiguous. In this study, one coronavirus isolated from a Mal...
Citations
... [17] Moreover, SARS-CoV-2 RBD shows a significantly higher binding affinity to hACE2 than SARS-CoV RBD does. [18] The preclinical study has identified that the recombinant RBD of the SARS-CoV-2 can be used as an effective and safe vaccine candidate against viral infection. [19] Due to the ongoing pandemic caused by SARS-CoV-2, there is a constant demand of recombinant RBD for a wide range of diagnosis and drug development purposes. ...
... [17] Moreover, SARS-CoV-2 RBD shows a significantly higher binding affinity to hACE2 than SARS-CoV RBD does. [18] The preclinical study has identified that the recombinant RBD of the SARS-CoV-2 can be used as an effective and safe vaccine candidate against viral infection. [19] Due to the ongoing pandemic caused by SARS-CoV-2, there is a constant demand of recombinant RBD for a wide range of diagnosis and drug development purposes. ...
... The evidence and knowledge gaps regarding these hypotheses are described below and summarized in Table 1. [75][76][77] • Trial to test this hypothesis ongoing [78] Vaccines 2023, 11, 693 6 of 25 (i) ACE-2 receptor expression: The SARS-CoV-2 attaches to the ACE-2 receptor in the epithelium via the S-protein, similar to SARS-CoV-1 [79]. ACE-2 is found in multiple sites, including epithelial cells of the oral, nasopharyngeal, and oropharyngeal mucosal epithelium; alveolar epithelium; endothelium of blood vessels and the heart; renal tubules; and small intestinal enterocytes [80]. ...
Since the coronavirus disease (COVID-19) pandemic hit the globe in early 2020, we have steadily gained insight into its pathogenesis; thereby improving surveillance and preventive measures. In contrast to other respiratory viruses, neonates and young children infected with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) have a milder clinical presentation, with only a small proportion needing hospitalization and intensive care support. With the emergence of novel variants and improved testing services, there has been a higher incidence of COVID-19 disease reported among children and neonates. Despite this, the proportion of young children with severe disease has not increased. Key mechanisms that protect young children from severe COVID-19 disease include the placental barrier, differential expression of angiotensin-converting enzyme 2 (ACE-2) receptors, immature immune response, and passive transfer of antibodies via placenta and human milk. Implementing mass vaccination programs has been a major milestone in reducing the global disease burden. However, considering the lower risk of severe COVID-19 illness in young children and the limited evidence about long-term vaccine safety, the risk-benefit balance in children under five years of age is more complex. In this review, we do not support or undermine vaccination of young children but outline current evidence and guidelines, and highlight controversies, knowledge gaps, and ethical issues related to COVID-19 vaccination in young children. Regulatory bodies should consider the individual and community benefits of vaccinating younger children in their local epidemiological setting while planning regional immunization policies.
... SARS-CoV-2's receptor-binding domains (RBDs) have a higher hACE2 binding affinity than SARS-CoV RBD, supporting efficient cell entry. However, the hACE2 binding affinity of the entire SARS-CoV-2 spike is comparable to or lower than that of the SARS-CoV spike [36,38]. Effective immune response against viral infection relies heavily on the interferon (IFN) type I responses. ...
... It has already been proven that the means of entry of SARS-CoV-2 entry to, and spread through, the placenta is via the main receptors: the angiotensin-converting enzyme 2 (ACE2) receptor [23] and the serine protease TMPRSS2 [24]. Other authors considered that the low expression of both receptors at the same time and the lack of evidence for those receptors in the chorio-amniotic membranes in the third trimester (unlike other viruses such as CMV, Zika, etc.) can explain why the virus does not affect the foetus and why the placenta acts as a gatekeeper [25]. ...
The impact of the SARS-CoV-2 infection on pregnancy has been studied and many reports have been published, mainly focussing on complications and in utero transmission with neonatal consequences. Although the effects of other viruses on foetuses are well known, the impact of maternal COVID-19 during pregnancy is not completely understood. We report a case of acute foetal intrapartum hypoxia without other risk factors than maternal COVID-19 disease 2 weeks previous to birth at term. Placental histological changes suggested that the viral infection could have been the culprit for the unfavourable outcome during labour. The neonate was promptly delivered by Caesarean section. Neonatal intensive care was started, including therapeutic hypothermia. The procedure was successful, the evolution of the neonate was favourable, and she was discharged after 10 days. Follow-up at 2 months of life indicated a normal neurological development but a drop in head growth. The case raises the idea that pregnancies with even mild COVID-19 symptoms may represent the cause of neonate compromise in a low-risk pregnancy. An important follow-up in the neonatal period and infancy is required to identify and treat any subsequent conditions. Further long-term studies are necessary to identify a cause–effect relationship between COVID-19 pregnancies and the whole spectrum of neonatal and infant consequences.
... A comprehensive studies have identified 380 amino acid variations between these coronaviruses, which may have resulted in functional and pathogenic divergence of new one [13] that briefly includes important mutations in the receptor-binding domains, 27 amino acid substitutions in the spike protein with a length of 1273 amino acids, and four substitutions in the C-terminal of the receptor-binding subunit S1 domain of SARS-CoV-2, compared with SARS-CoV [14,15]. Furthermore, it was shown that SARS-CoV-2 ACE2 protein has a stronger binding affinity than SARS-CoV receptor [16,17]. ...
The respiratory system was primarily considered the only organ affected by Coronavirus disease 2019 (COVID-19). As the pandemic continues, there is an increasing concern from the scientific community about the future effects of the virus on male and female reproductive organs, infertility, and, most significantly, its impact on the future generation. The general presumption is that if the primary clinical symptoms of COVID-19 are not controlled, we will face several challenges, including compromised infertility, infection-exposed cryopreserved germ cells or embryos, and health complications in future generations, likely connected to the COVID-19 infections of parents and ancestors. In this review article, we dedicatedly studied severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) virology, its receptors, and the effect of the virus to induce the activation of inflammasome as the main arm of the innate immune response. Among inflammasomes, nucleotide oligomerization domain-like receptor protein, pyrin domain containing 3 (NLRP3) inflammasome pathway activation is partly responsible for the inflicted damages in both COVID-19 infection and some reproductive disorders, so the main focus of the discussion is on NLRP3 inflammasome in the pathogenesis of COVID-19 infection alongside in the reproductive biology. In addition, the potential effects of the virus on male and female gonad functions were discussed, and we further explored the potential natural and pharmacological therapeutic approaches for comorbidity via NLRP3 inflammasome neutralization to develop a hypothesis for averting the long-term repercussions of COVID-19. Since activation of the NLRP3 inflammasome pathway contributes to the damage caused by COVID-19 infection and some reproductive disorders, NLRP3 inflammasome inhibitors have a great potential to be considered candidates for alleviating the pathological effects of the COVID-19 infection on the germ cells and reproductive tissues. This would impede the subsequent massive wave of infertility that may threaten the patients.
... Binding of ACE2 with Spike S1 (AA: 15-685) proteins allows the virus to adhere to the lung epithelial cells. A small, independently folded subdomain of S1, described as the receptor-binding domain (RBD), directly binds ACE2 (AA: 320-540) when the virus engages the target cells (5). It is predicted that the virus is zoonotic in origin, and mutations in the surface glycoprotein structure enable the transmission to human hosts (6). ...
Background: Mutations in the SARS-CoV-2 genome might influence pathogenicity, transmission rate, and evasion of the host immune system. Therefore, the purpose of this study was to assess the genetic alteration in the receptor binding domain (RBD) of the spike and putative RNA binding site of the RdRp genes of SARS-CoV-2.
Materials and Method: In this cross-sectional study, 45 confirmed COVID-19 patients using qRT-PCR were included and divided into mild, severe, and critical groups based on the severity of the disease. RNA was extracted from nasopharyngeal swab samples using a commercial kit. RT-PCR was performed to amplify the target sequences of the spike and RdRp genes and sequenced them by the Sanger method. Clustal OMEGA, MEGA 11 software, I-mutant tools, and SWISS-MODEL and HDOCK web servers were used for bioinformatics analyses.
Results: The mean age of the patients was 50.68±2.73. The results showed that four of six mutations (L452R, T478K, N501Y, and D614G) in RBD and three of eight in the putative RNA binding site (P214L, E1084D, V1883T) were missense. In the putative RNA binding site, another deletion was discovered. Among missense mutations, N501Y and V1883T were responsible for increasing structural stability, and the others were responsible for decreasing it. The various homology models designed showed that these homologies were like the Wuhan model. The molecular docking analysis revealed that the T478K mutation in RBD had the highest binding affinity. In addition, 35 RBD samples (89.7%) and 33 putative RNA binding site samples (84.6%) were similar to the Delta variant.
Conclusion: Our results indicated that double mutations (T478K and N501Y) in the S protein might increase the binding affinity of SARS-CoV-2 to human ACE2 compared to the wild type (WT) strain. Moreover, variations in the spike and RdRp genes might influence the stability of encoded proteins.
... Computer simulation and crystallography studies revealed the RAB interface. [3][4][5][6][7] Compared with the SARS-CoV RBD, several residue changes in the SARS-CoV-2 RBD stabilized two virus-cell binding hotspots to get 10 times higher affinity, 7 possibly explaining why SARS-CoV-2 is more harmful. The way the SARS-CoV-2 Wuhan isolate enters cells has been suggested to be diverse, including cell surface fusion or endocytosis, 8 and the current widespread Omicron strains have altered its preference to a cathepsin-dependent endosomal route of entry. ...
... The binding of RBD to ACE2 was reported to be strong, dynamic, and heterogeneous, with variable dissociation constants spanning three orders of magnitude from 4.7 to 133.3 nM. [3][4][5] The RAB was also highly environment sensitive. For example, it has been reported that the binding free energy of RAB residues was significantly different at different temperatures. ...
It is urgent to understand the infection mechanism of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) for the prevention and treatment of COVID-19. The infection of SARS-CoV-2 starts when the receptor-binding domain (RBD) of viral spike protein binds to angiotensin-converting enzyme 2 (ACE2) of the host cell, but the endocytosis details after this binding are not clear. Here, RBD and ACE2 were genetically coded and labeled with organic dyes to track RBD endocytosis in living cells. The photostable dyes enable long-term structured illumination microscopy (SIM) imaging and to quantify RBD-ACE2 binding (RAB) by the intensity ratio of RBD/ACE2 fluorescence. We resolved RAB endocytosis in living cells, including RBD-ACE2 recognition, cofactor-regulated membrane internalization, RAB-bearing vesicle formation and transport, RAB degradation, and downregulation of ACE2. The RAB was found to activate the RBD internalization. After vesicles were transported and matured within cells, RAB was finally degraded after being taken up by lysosomes. This strategy is a promising tool to understand the infection mechanism of SARS-CoV-2.
... In addition, our approach is not directly deal with the classification problem and does not require prior knowledge of positive and negative interaction. Further, several experiments show that Gordon et al. do not detect all the significant human-nCoV interactions [133,134]. For example, the essential protein for entry into the human host, ACE2 and TMPRSS2, are surprisingly not found in Gordon et al. ...
SARS-CoV-2 is a novel coronavirus that replicates itself via interacting with the host proteins. As a result, identifying virus and host protein-protein interactions could help researchers better understand the virus disease transmission behavior and identify possible COVID-19 drugs. The International Committee on Virus Taxonomy has determined that nCoV is genetically 89% compared to the SARS-CoV epidemic in 2003. This paper focuses on assessing the host-pathogen protein interaction affinity of the coronavirus family, having 44 different variants. In light of these considerations, a GO-semantic scoring function is provided based on Gene Ontology (GO) graphs for determining the binding affinity of any two proteins at the organism level. Based on the availability of the GO annotation of the proteins, 11 viral variants, viz., SARS-CoV-2, SARS, MERS, Bat coronavirus HKU3, Bat coronavirus Rp3/2004, Bat coronavirus HKU5, Murine coronavirus, Bovine coronavirus, Rat coronavirus, Bat coronavirus HKU4, Bat coronavirus 133/2005, are considered from 44 viral variants. The fuzzy scoring function of the entire host-pathogen network has been processed with~180 million potential interactions generated from 19,281 host proteins and around 242 viral proteins.~4.5 million potential level one host-pathogen interactions are computed based on the estimated interaction affinity threshold. The resulting host-pathogen interactome is also validated with state-of-the-art experimental networks. The study has also been extended further toward the drug-repurposing study by analyzing the FDA-listed COVID drugs.
... Entry into human cell is initiated by interaction between the RBD and the cell surface receptor ACE2 [62][63][64][65][66] making RBD an immunodominant target for neutralizing antibodies [67]. Two clusters (3 and 4) include matches with antibodies interacting with other epitopes than RBD (non-RBD and S2 domain, which contain the fusion peptide). ...
Adaptive immunity's success relies on the extraordinary diversity of protein receptors on B and T cell membranes. Despite this diversity, the existence of public receptors shared by many individuals gives hope for developing population wide vaccines and therapeutics. Using probabilistic modeling, we show many of these public receptors are shared by chance in healthy individuals. This predictable overlap is driven not only by biases in the random generation process of receptors, as previously reported, but also by their common functional selection. However, the model underestimates sharing between repertoires of individuals infected with SARS-CoV-2, suggesting strong specific antigen-driven convergent selection. We exploit this discrepancy to identify COVID-associated receptors, which we validate against datasets of receptors with known viral specificity. We study their properties in terms of sequence features and network organization, and use them to design an accurate diagnosis tool for predicting SARS-CoV-2 status from repertoire data.
