scholarly journals Spike Glycoprotein-Mediated Entry of SARS Coronaviruses

Viruses ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 1289 ◽  
Author(s):  
Lin Wang ◽  
Ye Xiang
Keyword(s):  
Conformational Changes ◽  
Antiviral Agents ◽  
Host Cells ◽  
Structural Studies ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2 ◽  
Public Health Emergencies ◽  
Positive Sense ◽  
Epidemic Diseases

Severe acute respiratory syndrome coronavirus (SARS-CoV) and SARS-CoV-2 are enveloped, positive-sense, single-stranded RNA viruses and causes of epidemic diseases that have resulted in public health emergencies worldwide. Angiotensin-converting enzyme 2 (ACE2) is the receptor that allows the entry of these two viruses into host cells, a key step in the life cycle of the pathogens. The characterization of the interactions of ACE2 with the viral spike glycoproteins and structural studies of the ACE2-binding-induced conformational changes in the viral spike glycoproteins have furthered our understanding of the entry processes of these two viruses, and these studies provide useful information that will facilitate the development of antiviral agents and vaccines to control the diseases.

scholarly journals Neutralization of SARS-CoV-2 by destruction of the prefusion Spike

2020 ◽  
Author(s):  
Jiandong Huo ◽  
Yuguang Zhao ◽  
Jingshan Ren ◽  
Daming Zhou ◽  
Helen ME Duyvesteyn ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Immune Responses ◽  
Conformational Changes ◽  
Therapeutic Potential ◽  
Host Cells ◽  
List Type ◽  
Receptor Binding Domain ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2 ◽  
Cryptic Epitope

SummaryThere are as yet no licenced therapeutics for the COVID-19 pandemic. The causal coronavirus (SARS-CoV-2) binds host cells via a trimeric Spike whose receptor binding domain (RBD) recognizes angiotensin-converting enzyme 2 (ACE2), initiating conformational changes that drive membrane fusion. We find that monoclonal antibody CR3022 binds the RBD tightly, neutralising SARS-CoV-2 and report the crystal structure at 2.4 Å of the Fab/RBD complex. Some crystals are suitable for screening for entry-blocking inhibitors. The highly conserved, structure-stabilising, CR3022 epitope is inaccessible in the prefusion Spike, suggesting that CR3022 binding would facilitate conversion to the fusion-incompetent post-fusion state. Cryo-EM analysis confirms that incubation of Spike with CR3022 Fab leads to destruction of the prefusion trimer. Presentation of this cryptic epitope in an RBD-based vaccine might advantageously focus immune responses. Binders at this epitope may be useful therapeutically, possibly in synergy with an antibody blocking receptor attachment.HighlightsCR3022 neutralises SARS-CoV-2Neutralisation is by destroying the prefusion SPIKE conformationThis antibody may have therapeutic potential alone or with one blocking receptor attachment

scholarly journals Receptor binding and proteolysis do not induce large conformational changes in the SARS-CoV spike

2018 ◽  
Author(s):  
Robert N. Kirchdoerfer ◽  
Nianshuang Wang ◽  
Jesper Pallesen ◽  
Daniel Wrapp ◽  
Hannah L. Turner ◽  
...  
Keyword(s):  
Conformational Changes ◽  
Viral Entry ◽  
Cleavage Site ◽  
Host Protein ◽  
Host Cells ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2 ◽  
Protein Receptor ◽  
Proteolytic Cleavages ◽  
Secondary Cleavage

AbstractSevere acute respiratory syndrome coronavirus (SARS-CoV) emerged in 2002 as a highly transmissible pathogenic human betacoronavirus. The viral spike glycoprotein (S) utilizes angiotensin-converting enzyme 2 (ACE2) as a host protein receptor and mediates fusion of the viral and host membranes, making S essential to viral entry into host cells and host species tropism. As SARS-CoV enters host cells, the viral S undergoes two proteolytic cleavages at S1/S2 and S2’ sites necessary for efficient membrane fusion. Here, we present a cryo-EM analysis of the trimeric SARS-CoV S interactions with ACE2 and of the trypsin-cleaved S. Surprisingly, neither binding to ACE2 nor cleavage by trypsin at the S1/S2 cleavage site impart large conformational changes within S or expose the secondary cleavage site, S2’. These observations suggest that S2’ cleavage does not occur in the S prefusion conformation and that additional triggers may be required.

scholarly journals Bromodomain and Extraterminal Protein Inhibitor, Apabetalone (RVX-208), Reduces ACE2 Expression and Attenuates SARS-Cov-2 Infection In Vitro

Biomedicines ◽  
2021 ◽  
Vol 9 (4) ◽  
pp. 437
Author(s):  
Dean Gilham ◽  
Audrey L. Smith ◽  
Li Fu ◽  
Dalia Y. Moore ◽  
Abenaya Muralidharan ◽  
...  
Keyword(s):  
Antiviral Agents ◽  
Host Cells ◽  
Protein Inhibitor ◽  
Angiotensin Converting Enzyme 2 ◽  
Dipeptidyl Peptidase 4 ◽  
Surface Receptors ◽  
Bet Inhibitor ◽  
Epigenetic Machinery ◽  
Unexplored Area

Effective therapeutics are urgently needed to counter infection and improve outcomes for patients suffering from COVID-19 and to combat this pandemic. Manipulation of epigenetic machinery to influence viral infectivity of host cells is a relatively unexplored area. The bromodomain and extraterminal (BET) family of epigenetic readers have been reported to modulate SARS-CoV-2 infection. Herein, we demonstrate apabetalone, the most clinical advanced BET inhibitor, downregulates expression of cell surface receptors involved in SARS-CoV-2 entry, including angiotensin-converting enzyme 2 (ACE2) and dipeptidyl-peptidase 4 (DPP4 or CD26) in SARS-CoV-2 permissive cells. Moreover, we show that apabetalone inhibits SARS-CoV-2 infection in vitro to levels comparable to those of antiviral agents. Taken together, our study supports further evaluation of apabetalone to treat COVID-19, either alone or in combination with emerging therapeutics.

Angiotensin Converting Enzyme 2 (ACE2) Expression in the Visual System

2021 ◽  
Author(s):  
James M. Hill ◽  
Christian Clement ◽  
L. Arceneaux ◽  
Walter Lukiw
Keyword(s):  
Signal Processing ◽  
Angiotensin Converting Enzyme ◽  
Occipital Lobe ◽  
Cell Types ◽  
Receptor Expression ◽  
Host Cells ◽  
Visual Signal ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2 ◽  
The Brain

Abstract Background: Multiple lines of evidence currently indicate that the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)gains entry into human host cells via a high-affinity interaction with the angiotensin-converting enzyme 2 (ACE2) transmembrane receptor. Research has further shown the widespread expression of the ACE2 receptor on the surface of many different immune, non-immune and neural host cell types, and that SARS-CoV-2 has there markable capability to attack many different types of human-host cells simultaneously. One principal neuroanatomical region for highACE2 expression patterns occurs in the brainstem, an area of the brain containing regulatory centers for respiration, and this may in part explain the predisposition of many COVID-19 patients to respiratory distress. Early studies also indicated extensive ACE2 expression in the whole eye and the brain’s visual circuitry. In this study we analyzed ACE2 receptor expression at the mRNA and protein level in multiple cell types involved in human vision, including cell types of the external eye and several deep brain regions known to be involved in the processing of visual signals.Methods: ACE2 mRNA and protein analysis; multiple eye and brain cells and tissues; gamma32P-adenosine tri-phosphate ([γ-32P]dATP) radiolabeled probes; Northern analysis; ELISA.Results: The four main findings were: (i)that many different optical and neural cell types of the human visual system provide receptors essential for SARS-CoV-2 invasion; (ii)the remarkable ubiquity of ACE2 presence in cells of the eye and anatomical regions of the brain involved in visual signal processing; (iii)that ACE2 receptor expression in different ocular cell types and visual processing centers of the brain provide multiple compartments for SARS-CoV-2 infiltration; and (iv)a gradient of increasing ACE2 expression from the anterior surface of the eye to the visual signal processing areas of the occipital lobe and the primary visual neocortex.Conclusion: A gradient of ACE2 expression from the eye surface to the occipital lobe provide the SARS-CoV-2 virus a novel pathway from the outer eye into deeper anatomical regions of the brain involved in vision. These findings may explain, in part, the many recently reported neuro-ophthalmic manifestations of SARS-CoV-2infection in COVID-19 affected patients.

scholarly journals Virtual screening as therapeutic strategy of COVID-19 targeting angiotensin-converting enzyme 2

2021 ◽  
Vol 2 (1) ◽  
pp. 16-27
Author(s):  
Zahra Sharifinia ◽  
◽  
Samira Asadi ◽  
Mahyar Irani ◽  
Abdollah Allahverdi ◽  
...  
Keyword(s):  
Virtual Screening ◽  
Angiotensin Converting Enzyme ◽  
Host Cells ◽  
Spike Protein ◽  
Potential Drug ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2 ◽  
Approved Drugs ◽  
Fda Approved Drugs

Objective: The receptor-binding domain (RBD) of the S1 domain of the SARS-CoV- 2 Spike protein performs a key role in the interaction with Angiotensin-converting enzyme 2 (ACE2), leading to both subsequent S2 domain-mediated membrane fusion and incorporation of viral RNA in host cells. Methods: In this study, we investigated the inhibitor’s targeted compounds through existing human ACE2 drugs to use as a future viral invasion. 54 FDA approved drugs were selected to assess their binding affinity to the ACE2 receptor. The structurebased methods via computational ones have been used for virtual screening of the best drugs from the drug database. Key Findings: The ligands “Cinacalcet” and “Levomefolic acid” highaffinity scores can be a potential drug preventing Spike protein of SARS-CoV-2 and human ACE2 interaction. Levomefolic acid from vitamin B family was proved to be a potential drug as a spike protein inhibitor in previous clinical and computational studies. Besides that, in this study, the capability of Levomefolic acid to avoid ACE2 and Spike protein of SARS-CoV-2 interaction is indicated. Therefore, it is worth to consider this drug for more in vitro investigations as ACE2 and Spike protein inhibition candidate. Conclusion: The two Cinacalcet and Levomefolic acid are the two ligands that have highest energy binding for human ACE2 blocking among 54 FDA approved drugs.

Identification of the interaction between Angiotensin-converting Enzyme Residues and Severe Acute Respiratory Syndrome Coronavirus 2.

2021 ◽  
Vol 27 ◽  
Author(s):  
Youness Kadil ◽  
Mohammed Mouhcine ◽  
Imane Rahmoune ◽  
Houda Filali
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Angiotensin Converting Enzyme ◽  
Receptor Binding Domain ◽  
Converting Enzyme ◽  
Methodological Study ◽  
Angiotensin Converting Enzyme 2 ◽  
Enveloped Virus ◽  
Positive Sense ◽  
Contact Residues ◽  
Cell Membrane Protein

Introduction: Coronaviruses are an enveloped virus with a positive-sense single-stranded RNA genome. It has been shown that the viral spike S glycoprotein binds to the cell membrane protein angiotensin-converting enzyme 2 as an invasive process of the virus. The aim of this research is the application of a computational approach in the identification of the interaction residues ACE2 with severe acute respiratory syndrome Coronavirus 2. A methodological study to understand the interactions between SARS CoV2 and ACE2, which is essential for the development of a vaccine and an antiviral. Methods: The S protein is cleaved into two subunits, S1 and S2. S1 contains the receptor-binding domain (RBD) which allows the virus to bind directly to the peptidase domain of ACE2. Results: Our results present the overall differences in contact residues between the different chains, and an alignment between the two SARS Viruses, along with a presentation of similarity between them.Then S2 likely plays a role in membrane fusion. Conclusions : The synthesis of our results appears to provide potentially a rational set of objectives that can help in the development of a SARS-CoV-2 vaccine.

scholarly journals Receptor Recognition by the Novel Coronavirus from Wuhan: an Analysis Based on Decade-Long Structural Studies of SARS Coronavirus

2020 ◽  
Vol 94 (7) ◽  
Author(s):  
Yushun Wan ◽  
Jian Shang ◽  
Rachel Graham ◽  
Ralph S. Baric ◽  
Fang Li
Keyword(s):  
Animal Species ◽  
Atomic Level ◽  
Spike Protein ◽  
Structural Studies ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2 ◽  
Receptor Usage ◽  
Receptor Recognition ◽  
Critical Residues ◽  
Novel Coronavirus

ABSTRACT Recently, a novel coronavirus (2019-nCoV) has emerged from Wuhan, China, causing symptoms in humans similar to those caused by severe acute respiratory syndrome coronavirus (SARS-CoV). Since the SARS-CoV outbreak in 2002, extensive structural analyses have revealed key atomic-level interactions between the SARS-CoV spike protein receptor-binding domain (RBD) and its host receptor angiotensin-converting enzyme 2 (ACE2), which regulate both the cross-species and human-to-human transmissions of SARS-CoV. Here, we analyzed the potential receptor usage by 2019-nCoV, based on the rich knowledge about SARS-CoV and the newly released sequence of 2019-nCoV. First, the sequence of 2019-nCoV RBD, including its receptor-binding motif (RBM) that directly contacts ACE2, is similar to that of SARS-CoV, strongly suggesting that 2019-nCoV uses ACE2 as its receptor. Second, several critical residues in 2019-nCoV RBM (particularly Gln493) provide favorable interactions with human ACE2, consistent with 2019-nCoV’s capacity for human cell infection. Third, several other critical residues in 2019-nCoV RBM (particularly Asn501) are compatible with, but not ideal for, binding human ACE2, suggesting that 2019-nCoV has acquired some capacity for human-to-human transmission. Last, while phylogenetic analysis indicates a bat origin of 2019-nCoV, 2019-nCoV also potentially recognizes ACE2 from a diversity of animal species (except mice and rats), implicating these animal species as possible intermediate hosts or animal models for 2019-nCoV infections. These analyses provide insights into the receptor usage, cell entry, host cell infectivity and animal origin of 2019-nCoV and may help epidemic surveillance and preventive measures against 2019-nCoV. IMPORTANCE The recent emergence of Wuhan coronavirus (2019-nCoV) puts the world on alert. 2019-nCoV is reminiscent of the SARS-CoV outbreak in 2002 to 2003. Our decade-long structural studies on the receptor recognition by SARS-CoV have identified key interactions between SARS-CoV spike protein and its host receptor angiotensin-converting enzyme 2 (ACE2), which regulate both the cross-species and human-to-human transmissions of SARS-CoV. One of the goals of SARS-CoV research was to build an atomic-level iterative framework of virus-receptor interactions to facilitate epidemic surveillance, predict species-specific receptor usage, and identify potential animal hosts and animal models of viruses. Based on the sequence of 2019-nCoV spike protein, we apply this predictive framework to provide novel insights into the receptor usage and likely host range of 2019-nCoV. This study provides a robust test of this reiterative framework, providing the basic, translational, and public health research communities with predictive insights that may help study and battle this novel 2019-nCoV.

scholarly journals Increasing Host Cellular Receptor—Angiotensin-Converting Enzyme 2 (ACE2) Expression by Coronavirus may Facilitate 2019-nCoV Infection

2020 ◽  
Author(s):  
Pei-Hui Wang ◽  
Yun Cheng
Keyword(s):  
Angiotensin Converting Enzyme ◽  
Emerging Infectious Diseases ◽  
Cell Receptor ◽  
Host Cells ◽  
Cellular Receptor ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2 ◽  
Host Cell Receptor ◽  
Coronavirus Infection ◽  
Entry Receptor

AbstractThe ongoing outbreak of a new coronavirus (2019-nCoV) causes an epidemic of acute respiratory syndrome in humans. 2019-nCoV rapidly spread to national regions and multiple other countries, thus, pose a serious threat to public health. Recent studies show that spike (S) proteins of 2019-nCoV and SARS-CoV may use the same host cell receptor called angiotensin-converting enzyme 2 (ACE2) for entering into host cells. The affinity between ACE2 and 2019-nCoV S is much higher than ACE2 binding to SARS-CoV S protein, explaining that why 2019-nCoV seems to be more readily transmitted from the human to human. Here, we reported that ACE2 can be significantly upregulated after infection of various viruses including SARS-CoV and MERS-CoV. Basing on findings here, we propose that coronavirus infection can positively induce its cellular entry receptor to accelerate their replication and spread, thus drugs targeting ACE2 expression may be prepared for the future emerging infectious diseases caused by this cluster of viruses.

scholarly journals Structural Dissection of Viral Spike-Protein Binding of SARS-CoV-2 and SARS-CoV-1 to the Human Angiotensin-Converting Enzyme 2 (ACE2) as Cellular Receptor

Biomedicines ◽  
2021 ◽  
Vol 9 (8) ◽  
pp. 1038
Author(s):  
Deborah Giordano ◽  
Luigi De Masi ◽  
Maria Antonia Argenio ◽  
Angelo Facchiano
Keyword(s):  
Angiotensin Converting Enzyme ◽  
In Silico Analysis ◽  
Host Cells ◽  
Spike Protein ◽  
Cellular Receptor ◽  
Receptor Binding Domain ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2 ◽  
The World ◽  
Silico Analysis

An outbreak by a new severe acute respiratory syndrome betacoronavirus (SARS-CoV-2) has spread CoronaVirus Disease 2019 (COVID-19) all over the world. Immediately, following studies have confirmed the human Angiotensin-Converting Enzyme 2 (ACE2) as a cellular receptor of viral Spike-Protein (Sp) that mediates the CoV-2 invasion into the pulmonary host cells. Here, we compared the molecular interactions of the viral Sp from previous SARS-CoV-1 of 2002 and SARS-CoV-2 with the host ACE2 protein by in silico analysis of the available experimental structures of Sp-ACE2 complexes. The K417 amino acid residue, located in the region of Sp Receptor-Binding Domain (RBD) of the new coronavirus SARS-CoV-2, showed to have a key role for the binding to the ACE2 N-terminal region. The R426 residue of SARS-CoV-1 Sp-RBD also plays a key role, although by interacting with the central region of the ACE2 sequence. Therefore, our study evidenced peculiarities in the interactions of the two Sp-ACE2 complexes. Our outcomes were consistent with previously reported mutagenesis studies on SARS-CoV-1 and support the idea that a new and different RBD was acquired by SARS-CoV-2. These results have interesting implications and suggest further investigations.

scholarly journals Stapled peptides based on Human Angiotensin-Converting Enzyme 2 (ACE2) potently inhibit SARS-CoV-2 infection in vitro

2020 ◽  
Author(s):  
Francesca Curreli ◽  
Sofia M B Victor ◽  
Shahad Ahmed ◽  
Aleksandra Drelich ◽  
Xiaohe Tong ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Angiotensin Converting Enzyme ◽  
Host Cells ◽  
Converting Enzyme ◽  
Stapled Peptides ◽  
Angiotensin Converting Enzyme 2 ◽  
Stapled Peptide ◽  
Human Lung Cells ◽  
Critical Binding

AbstractSARS-CoV-2 uses human angiotensin-converting enzyme 2 (ACE2) as the primary receptor to enter host cells and initiate the infection. The critical binding region of ACE2 is a ∼30 aa long helix. Here we report the design of four stapled peptides based on the ACE2 helix, which is expected to bind to SARS-CoV-2 and prevent the binding of the virus to the ACE2 receptor and disrupt the infection. All stapled peptides showed high helical contents (50-94% helicity). On the contrary, the linear control peptide NYBSP-C showed no helicity (19%). We have evaluated the peptides in a pseudovirus based single-cycle assay in HT1080/ACE2 and human lung cells A549/ACE2, overexpressing ACE2. Three of the four stapled peptides showed potent antiviral activity in HT1080/ACE2 (IC50: 1.9 – 4.1 µM) and A549/ACE2 cells (IC50: 2.2 – 2.8 µM). The linear peptides NYBSP-C and the double-stapled peptide StRIP16, used as controls, showed no antiviral activity. Most significantly, none of the stapled peptides show any cytotoxicity at the highest dose tested. We also evaluated the antiviral activity of the peptides by infecting Vero E6 cells with the replication-competent authentic SARS-CoV-2 (US_WA-1/2020). NYBSP-1 was the most efficient preventing the complete formation of cytopathic effects (CPEs) at an IC100 17.2 µM. NYBSP-2 and NYBSP-4 also prevented the formation of the virus-induced CPE with an IC100 of about 33 µM. We determined the proteolytic stability of one of the most active stapled peptides, NYBSP-4, in human plasma, which showed a half-life (T1/2) of >289 min.

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