scholarly journals Diversity of ACE2 and its interaction with SARS-CoV-2 receptor binding domain

2021 ◽  
Author(s):  
Jessie L Gan ◽  
Ruiqi Huang ◽  
Abigail Kelley ◽  
Gabrielle Warner ◽  
Duncan McGregor ◽  
...  
Keyword(s):  
Receptor Binding ◽  
Binding Activity ◽  
Clinical Syndrome ◽  
Binding Domain ◽  
Host Cells ◽  
Potential Candidate ◽  
Receptor Binding Domain ◽  
Protein Receptor ◽  
Candidate Species ◽  
Horseshoe Bat

COVID-19, the clinical syndrome caused by the SARS-CoV-2 virus, has rapidly spread globally causing hundreds of millions of infections and over two million deaths.  The potential animal reservoirs for SARS-CoV-2 are currently unknown, however sequence analysis has provided plausible potential candidate species.  SARS-CoV-2 binds to the angiotensin I converting enzyme 2 (ACE2) to enable its entry into host cells and establish infection.  We analyzed the binding surface of ACE2 from several important animal species to begin to understand the parameters for the ACE2 recognition by the SARS-CoV-2 spike protein receptor binding domain (RBD).  We employed Shannon entropy analysis to determine the variability of ACE2 across its sequence and particularly in its RBD interacting region, and assessed differences between various species’ ACE2 and human ACE2.  Recombinant ACE2 from human, hamster, horseshoe bat, cat, ferret, and cow were evaluated for RBD binding.  A gradient of binding affinities were seen where human and hamster ACE2 were similarly in the low nanomolar range, followed by cat and cow. Surprisingly, horseshoe bat (Rhinolophus sinicus) and ferret (Mustela putorius) ACE2s had poor binding activity compared to the other species’ ACE2.  The residue differences and binding properties between the species’ variants provide a framework for understanding ACE2-RBD binding and virus tropism.

scholarly journals Diversity of ACE2 and its interaction with SARS-CoV-2 receptor binding domain

2020 ◽  
Author(s):  
Jessie Low-Gan ◽  
Ruiqi Huang ◽  
Gabrielle Warner ◽  
Abigail Kelley ◽  
Duncan McGregor ◽  
...  
Keyword(s):  
Receptor Binding ◽  
Clinical Syndrome ◽  
Binding Domain ◽  
Host Cells ◽  
Potential Candidate ◽  
Receptor Binding Domain ◽  
Viral Receptor ◽  
Protein Receptor ◽  
Fold Reduction ◽  
Candidate Species

AbstractCOVID-19, the clinical syndrome caused by the SARS-CoV-2 virus, has rapidly spread globally causing tens of millions of infections and over a million deaths. The potential animal reservoirs for SARS-CoV-2 are currently unknown, however sequence analysis has provided plausible potential candidate species. SARS-CoV-2 binds to the angiotensin I converting enzyme 2 (ACE2) to enable its entry into host cells and establish infection. We analyzed the binding surface of ACE2 from several important animal species to begin to understand the parameters for the ACE2 recognition by the SARS-CoV-2 spike protein receptor binding domain (RBD). We employed Shannon entropy analysis to determine the variability of ACE2 across its sequence and particularly in its RBD interacting region, and assessed differences between various species’ ACE2 and human ACE2. As cattle are a known reservoir for coronaviruses with previous human zoonotic transfer, and has a relatively divergent ACE2 sequence, we compared the binding kinetics of bovine and human ACE2 to SARS-CoV-2 RBD. This revealed a nanomolar binding affinity for bovine ACE2 but an approximate ten-fold reduction of binding compared to human ACE2. Since cows have been experimentally infected by SARS-CoV-2, this lower affinity sets a threshold for sequences with lower homology to human ACE2 to be able to serve as a productive viral receptor for SARS-CoV-2.

scholarly journals Withanone from Withania somnifera May Inhibit Novel Coronavirus (COVID-19) Entry by Disrupting Interactions between Viral S-Protein Receptor Binding Domain and Host ACE2 Receptor

2020 ◽  
Author(s):  
Acharya Balkrishna ◽  
SUBARNA POKHREL ◽  
Jagdeep Singh ◽  
Anurag Varshney
Keyword(s):  
Receptor Binding ◽  
Withania Somnifera ◽  
Binding Domain ◽  
Host Cells ◽  
Receptor Binding Domain ◽  
Salt Bridges ◽  
Binding Interface ◽  
Electrostatic Component ◽  
Protein Receptor ◽  
First Choice

Abstract Background Newly emerged COVID-19 has been shown to engage the host cell ACE2 through its spike protein receptor binding domain (RBD). Here we show that natural phytochemical from a medicinal herb, Withania somnifera, have distinct effects on viral RBD and host ACE2 receptor complex. Methods We employed molecular docking to screen thousands of phytochemicals against the ACE2-RBD complex, performed molecular dynamics (MD) simulation, and estimated the electrostatic component of binding free energy, along with the computation of salt bridge electrostatics. Results We report that W. somnifera compound, Withanone, docked very well in the binding interface of AEC2-RBD complex, and was found to move slightly towards the interface centre on simulation. Withanone significantly decreased electrostatic component of binding free energies of ACE2-RBD complex. Two salt bridges were also identified at the interface; incorporation of Withanone destabilized these salt bridges and decreased their occupancies. We postulate, such an interruption of electrostatic interactions between the RBD and ACE2 would block or weaken COVID-19 entry and its subsequent infectivity. Conclusion Our data, for the first time, show that natural phytochemicals could well be the viable options for controlling COVID-19 entry into host cells, and W. somnifera may be the first choice of herbs in these directions to curb the COVID-19 infectivity.

Tinocordiside from Tinospora cordifolia (Giloy) May Curb SARS-CoV-2 Contagion by Disrupting the Electrostatic Interactions between Host ACE2 and Viral S-Protein Receptor Binding Domain

2020 ◽  
Vol 23 ◽  
Author(s):  
Acharya Balkrishna ◽  
Subarna Pokhrel ◽  
Anurag Varshney
Keyword(s):  
Conformational Change ◽  
Receptor Binding ◽  
Electrostatic Interactions ◽  
Md Simulation ◽  
Binding Domain ◽  
Host Cells ◽  
Tinospora Cordifolia ◽  
Receptor Binding Domain ◽  
Electrostatic Component ◽  
Protein Receptor

Background: SARS-CoV-2 has been shown to bind the host cell ACE2 receptor through its spike protein receptor binding domain (RBD), required for its entry into the host cells. Objective: We have screened phytocompounds from a medicinal herb, Tinospora cordifolia, for their capacities to interrupt the viral RBD and host ACE2 interactions. Method: We employed molecular docking to screen phytocompounds in T. cordifolia against the ACE2-RBD complex, performed molecular dynamics (MD) simulation, and estimated the electrostatic component of binding free energy. Results: ‘Tinocordiside’ docked very well at the center of the interface of ACE2-RBD complex, and was found to be well stabilized during MD simulation. Tinocordiside incorporation significantly decreased electrostatic component of binding free energies of ACE2-RBD complex (23.5 and 17.10 kcal/mol in the trajectories without or with the ligand, respectively). As the basal rate constant of protein association is in the order of 5, (105 to 106 M-1 S-1 ), there might be no big conformational change or loop reorganization, but involves only local conformational change typically observed in diffusion-controlled association. Taken together, the increase in global flexibility of the complex, clearly indicates the start of unbinding process of the complex. Conclusion: It indicates that such an interruption of electrostatic interactions between the RBD and ACE2, and the increase in global flexibility of the complex, would weaken or block SARS-CoV-2 entry and its subsequent infectivity. We postulate that natural phytochemicals like Tinocordiside could be the viable options for controlling SARS-CoV-2 contagion and its entry into host cells.

scholarly journals A Fungal Defensin Targets the SARS−CoV−2 Spike Receptor−Binding Domain

2021 ◽  
Vol 7 (7) ◽  
pp. 553
Author(s):  
Bin Gao ◽  
Shunyi Zhu
Keyword(s):  
Receptor Binding ◽  
Viral Entry ◽  
Single Point ◽  
Binding Domain ◽  
Host Cells ◽  
Single Point Mutation ◽  
Binding Motif ◽  
Microsporum Canis ◽  
Receptor Binding Domain ◽  
Fungal Defensin

Coronavirus Disease 2019 (COVID−19) elicited by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS−CoV−2) is calling for novel targeted drugs. Since the viral entry into host cells depends on specific interactions between the receptor−binding domain (RBD) of the viral Spike protein and the membrane−bound monocarboxypeptidase angiotensin converting enzyme 2 (ACE2), the development of high affinity RBD binders to compete with human ACE2 represents a promising strategy for the design of therapeutics to prevent viral entry. Here, we report the discovery of such a binder and its improvement via a combination of computational and experimental approaches. The binder micasin, a known fungal defensin from the dermatophytic fungus Microsporum canis with antibacterial activity, can dock to the crevice formed by the receptor−binding motif (RBM) of RBD via an extensive shape complementarity interface (855.9 Å2 in area) with numerous hydrophobic and hydrogen−bonding interactions. Using microscale thermophoresis (MST) technique, we confirmed that micasin and its C−terminal γ−core derivative with multiple predicted interacting residues exhibited a low micromolar affinity to RBD. Expanding the interface area of micasin through a single point mutation to 970.5 Å2 accompanying an enhanced hydrogen bond network significantly improved its binding affinity by six−fold. Our work highlights the naturally occurring fungal defensins as an emerging resource that may be suitable for the development into antiviral agents for COVID−19.

scholarly journals Stereotypic neutralizing VH antibodies against SARS-CoV-2 spike protein receptor binding domain in COVID-19 patients and healthy individuals

2021 ◽  
pp. eabd6990
Author(s):  
Sang Il Kim ◽  
Jinsung Noh ◽  
Sujeong Kim ◽  
Younggeun Choi ◽  
Duck Kyun Yoo ◽  
...  
Keyword(s):  
B Cells ◽  
Receptor Binding ◽  
Neutralizing Antibodies ◽  
De Novo ◽  
Binding Domain ◽  
Host Cells ◽  
Spike Protein ◽  
Receptor Binding Domain ◽  
Healthy Individuals

Stereotypic antibody clonotypes exist in healthy individuals and may provide protective immunity against viral infections by neutralization. We observed that 13 out of 17 patients with COVID-19 had stereotypic variable heavy chain (VH) antibody clonotypes directed against the receptor-binding domain (RBD) of SARS-CoV-2 spike protein. These antibody clonotypes were comprised of immunoglobulin heavy variable (IGHV)3-53 or IGHV3-66 and immunoglobulin heavy joining (IGHJ)6 genes. These clonotypes included IgM, IgG3, IgG1, IgA1, IgG2, and IgA2 subtypes and had minimal somatic mutations, which suggested swift class switching after SARS-CoV-2 infection. The different immunoglobulin heavy variable chains were paired with diverse light chains resulting in binding to the RBD of SARS-CoV-2 spike protein. Human antibodies specific for the RBD can neutralize SARS-CoV-2 by inhibiting entry into host cells. We observed that one of these stereotypic neutralizing antibodies could inhibit viral replication in vitro using a clinical isolate of SARS-CoV-2. We also found that these VH clonotypes existed in six out of 10 healthy individuals, with IgM isotypes predominating. These findings suggest that stereotypic clonotypes can develop de novo from naïve B cells and not from memory B cells established from prior exposure to similar viruses. The expeditious and stereotypic expansion of these clonotypes may have occurred in patients infected with SARS-CoV-2 because they were already present.

scholarly journals A COVID-19 vaccine candidate using SpyCatcher multimerization of the SARS-CoV-2 spike protein receptor-binding domain induces potent neutralising antibody responses

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Tiong Kit Tan ◽  
Pramila Rijal ◽  
Rolle Rahikainen ◽  
Anthony H. Keeble ◽  
Lisa Schimanski ◽  
...  
Keyword(s):  
Antibody Response ◽  
Receptor Binding ◽  
Binding Domain ◽  
Cold Chain ◽  
Receptor Binding Domain ◽  
Cell Infection ◽  
Protein Receptor ◽  
Virus Like Particle ◽  
Human Sera ◽  
Escape Mutants

AbstractThere is need for effective and affordable vaccines against SARS-CoV-2 to tackle the ongoing pandemic. In this study, we describe a protein nanoparticle vaccine against SARS-CoV-2. The vaccine is based on the display of coronavirus spike glycoprotein receptor-binding domain (RBD) on a synthetic virus-like particle (VLP) platform, SpyCatcher003-mi3, using SpyTag/SpyCatcher technology. Low doses of RBD-SpyVLP in a prime-boost regimen induce a strong neutralising antibody response in mice and pigs that is superior to convalescent human sera. We evaluate antibody quality using ACE2 blocking and neutralisation of cell infection by pseudovirus or wild-type SARS-CoV-2. Using competition assays with a monoclonal antibody panel, we show that RBD-SpyVLP induces a polyclonal antibody response that recognises key epitopes on the RBD, reducing the likelihood of selecting neutralisation-escape mutants. Moreover, RBD-SpyVLP is thermostable and can be lyophilised without losing immunogenicity, to facilitate global distribution and reduce cold-chain dependence. The data suggests that RBD-SpyVLP provides strong potential to address clinical and logistic challenges of the COVID-19 pandemic.

scholarly journals Conjugation of Human β-Defensin 2 to Spike Protein Receptor-Binding Domain Induces Antigen-Specific Protective Immunity against Middle East Respiratory Syndrome Coronavirus Infection in Human Dipeptidyl Peptidase 4 Transgenic Mice

Vaccines ◽  
2020 ◽  
Vol 8 (4) ◽  
pp. 635
Author(s):  
Ju Kim ◽  
Ye Lin Yang ◽  
Yongsu Jeong ◽  
Yong-Suk Jang
Keyword(s):  
Middle East ◽  
Immune Responses ◽  
Receptor Binding ◽  
Dipeptidyl Peptidase ◽  
Binding Domain ◽  
Middle East Respiratory Syndrome ◽  
Spike Protein ◽  
Receptor Binding Domain ◽  
Dipeptidyl Peptidase 4 ◽  
Protein Receptor

Middle East respiratory syndrome coronavirus (MERS-CoV) causes severe acute respiratory symptoms. Due to the lack of medical countermeasures, effective and safe vaccines against MERS-CoV infection are urgently required. Although different types of candidate vaccines have been developed, their immunogenicity is limited, and the dose and administration route need optimization to achieve optimal protection. We here investigated the potential use of human β-defensin 2 (HBD 2) as an adjuvant to enhance the protection provided by MERS-CoV vaccination. We found that immunization of human dipeptidyl peptidase 4 (hDPP4)-transgenic (hDPP4-Tg) mice with spike protein receptor-binding domain (S RBD) conjugated with HBD 2 (S RBD-HBD 2) induced potent antigen (Ag)-specific adaptive immune responses and protected against MERS-CoV infection. In addition, immunization with S RBD-HBD 2 alleviated progressive pulmonary fibrosis in the lungs of MERS-CoV-infected hDPP4-Tg mice and suppressed endoplasmic reticulum stress signaling activation upon viral infection. Compared to intramuscular administration, intranasal administration of S RBD-HBD 2 induced more potent mucosal IgA responses and was more effective for protecting against intranasal MERS-CoV infection. In conclusion, our findings suggest that HBD 2 potentiates Ag-specific immune responses against viral Ag and can be used as an adjuvant enhancing the immunogenicity of subunit vaccine candidates against MERS-CoV.

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