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Comparison of ACE2 binding by the SARS-CoV RBD, SARS-CoV-2 wild-type RBD and SARS-CoV-2 chimeric RBD a, Buried surface areas at SARS-CoV RBM–ACE2 and SARS-CoV-2 RBM–ACE2 interfaces. In the crystals for both the SARS-CoV RBD–ACE2 complex and chimeric RBD–ACE2 complex, two copies of each complex were present in one asymmetric unit. Numbers for both copies of the complexes are shown. The interaction between Arg439 on the side loop of the RBM and Glu329 of ACE2 was excluded from the calculation of the buried surface area of SARS-CoV-2. b, List of contact residues from RBM and ACE2 that are directly involved in RBM–ACE2 binding. The engineered Arg439 in the chimeric RBD is shown in orange. Contact residues of the SARS-CoV RBM–ACE2 complex are taken from PDB 2AJF. c, Binding affinities between the RBDs and ACE2 measured using SPR.
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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...
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... In the closed conformation, three RBDs of the trimeric S protein can mask themselves to avoid recognition by the immune system. The S protein undergoes conformational changes and only one RBD reveals its binding motif to interact with ACE2 in open conformation, which is then followed by the sequential opening of the other two RBD motifs and thereby forms the trimeric S protein-ACE2 receptor complex [25][26][27] . Many studies have shown that a multivalent display of RBDs induces a stronger immune response and a higher level of neutralizing antibody titer in comparison with monomeric RBD [28][29][30][31] . ...
Effective and safe vaccines are invaluable tools in the arsenal to fight infectious diseases. The rapid spreading of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) responsible for the coronavirus disease 2019 pandemic has highlighted the need to develop methods for rapid and efficient vaccine development. DNA origami nanoparticles (DNA-NPs) presenting multiple antigens in prescribed nanoscale patterns have recently emerged as a safe, efficient, and easily scalable alternative for rational design of vaccines. Here, we are leveraging the unique properties of these DNA-NPs and demonstrate that precisely patterning ten copies of a reconstituted trimer of the receptor binding domain (RBD) of SARS-CoV-2 along with CpG adjuvants on the DNA-NPs is able to elicit a robust protective immunity against SARS-CoV-2 in a mouse model. Our results demonstrate the potential of our DNA-NP-based approach for developing safe and effective nanovaccines against infectious diseases with prolonged antibody response and effective protection in the context of a viral challenge.
... Crystal structures indicate that the S protein trimer could bind to a maximum of 3 human ACE2 receptors simultaneously ( Figure 2). Three binding and mutational hotspots for SARS-CoV-2 RBD were previously defined: hotspot 31, hotspot 353 and hotspot ridge [8]. These three areas are where most interactions take place ( Figure 4). ...
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) belongs to the family of beta coronavirus. The virus led to the outbreak of COVID-19 in early 2020. Characterized by its Spike (S) proteins, SARS-CoV-2 can recognize the human angiotensin-converting enzyme 2 (ACE2) receptor. Viral membrane fusion is initiated by the interaction between the S protein and the human ACE2 receptor. Due to its crucial role in receptor recognition, the S protein attracted great interest in being a drug target. The structure and functions of different domains of the S protein are presented in this article. Current progress in therapeutic compounds which targets the Receptor Binding Domain (RBD), Heptapeptide repeat sequence (HR) and the Fusion Loop (FL) domain are highlighted. Acquiring information on the S protein from a structural perspective and understanding treatment opportunities against SARS-CoV-2 will assist in combatting the disease.
... The formation of helical ribonucleocapsid (RNP) from the viral genome RNA (gRNA) is promoted by N protein [24,25]. S protein is responsible for receptor binding and the fusion of membrane [25,26]. In addition, three structural proteins, E, M, and N proteins, are responsible for improving particle formation and viral assembly [22, 23, and 25]. ...
The Outbreak of coronavirus disease 2019 (COVID-19) has become a global pandemic since December 2019. In order to combat the COVID-19, researchers have carried out many related experiments, including the pathogenesis of virus, to understand the structure and mechanism of the novel coronavirus. In addition, they have conducted in vitro and clinical trials for drug development. In this paper, the possible drug targets are discussed from the perspective of inhibiting virus entry into cells and inhibiting virus replication. In addition, the structure of the virus and its mechanism of entry into host cells are reviewed. Through this review, drug researchers can have a comprehensive understanding of the potential targets being investigated.
... [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.
