scholarly journals Post-Translational Modifications Optimize the Ability of SARS-CoV-2 Spike for Effective Interaction with Host Cell Receptors

2021 ◽  
Author(s):  
Karan Kapoor ◽  
Tianle Chen ◽  
Emad Tajkhorshid
Keyword(s):  
Cell Surface ◽  
Host Cell ◽  
Effective Interaction ◽  
Md Simulations ◽  
Membrane Domain ◽  
Surface Receptors ◽  
Lipid Interactions ◽  
Host Cell Surface ◽  
Membrane Bound ◽  
Prime Target

AbstractSARS-CoV2 spike glycoprotein is prime target for vaccines and for diagnostics and therapeutic antibodies against the virus. While anchored in the viral envelope, for effective virulance, the spike needs to maintain structural flexibility to recognize the host cell surface receptors and bind to them, a property that can heavily hinge upon the dynamics of the unresolved domains, most prominently the stalk. Construction of the complete, membrane-bound spike model and the description of its dynamics remain critical steps in understanding the inner working of this key element in viral infection. Using a hybrid approach, combining homology modeling, protein-protein docking and MD simulations, guided by biochemical and glycomics data, we have developed a full-length, membrane-bound, palmitoylated and fully-glycosylated spike structure in a native membrane. Multi-microsecond MD simulations of this model, the longest known trajectory of the full-spike, reveals conformational dynamics employed by the protein to explore the crowded surface of the host cell. In agreement with cryoEM, three flexiblele hinges in stalk allow for global conformational heterogeneity of spike in the fully-glycosyslated system mediated by glycan-glycan and glycan-lipid interactions. Dynamical range of spike is considerably reduced in its non-glycosylated form, confining the area explored by the spike on the host cell surface. Furthermore, palmitoylation of the membrane domain amplify the local curvature that may prime the fusion. We show that the identified hinge regions are highly conserved in SARS coronaviruses, highlighting their functional importance in enhancing viral infection, and thereby provide novel points for discovery of alternative therapeutics against the virus.SignificanceSARS-CoV2 Spike protein, which forms the basis for high pathogenicity and transmissibility of the virus, is also prime target for the development of both diagnostics and vaccines for the debilitating disease caused by the virus. We present a full model of spike methodically crafted and used to study its atomic-level dynamics by multiple-µs simulations. The results shed new light on the impact of posttranslational modifications in the pathogenicity of the virus. We show how glycan-glycan and glycan-lipid interactions broaden the protein’s dynamical range, and thereby, its effective interaction with the surface receptors on the host cell. Palmitoylation of spike membrane domain, on the other hand, results in a unique deformation pattern that might prime the membrane for fusion.

scholarly journals Interaction of KSHV with Host Cell Surface Receptors and Cell Entry

Viruses ◽  
2014 ◽  
Vol 6 (10) ◽  
pp. 4024-4046 ◽  
Author(s):  
Mohanan Veettil ◽  
Chirosree Bandyopadhyay ◽  
Dipanjan Dutta ◽  
Bala Chandran
Keyword(s):  
Cell Surface ◽  
Host Cell ◽  
Cell Entry ◽  
Cell Surface Receptors ◽  
Surface Receptors ◽  
Host Cell Surface

scholarly journals SARS-CoV-2–host cell surface interactions and potential antiviral therapies

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Aura-Bianca Butnariu ◽  
Alex Look ◽  
Marta Grillo ◽  
Tanveer A. Tabish ◽  
Michael J. McGarvey ◽  
...  
Keyword(s):  
Cell Surface ◽  
Host Cell ◽  
Conformational Changes ◽  
Surface Interactions ◽  
S Protein ◽  
Angiotensin Converting Enzyme 2 ◽  
Surface Receptors ◽  
Antiviral Therapies ◽  
The Us ◽  
Host Cell Surface

In this review, we reveal the latest developments at the interface between SARS-CoV-2 and the host cell surface. In particular, we evaluate the current and potential mechanisms of binding, fusion and the conformational changes of the spike (S) protein to host cell surface receptors, especially the human angiotensin-converting enzyme 2 (ACE2) receptor. For instance, upon the initial attachment, the receptor binding domain of the S protein forms primarily hydrogen bonds with the protease domain of ACE2 resulting in conformational changes within the secondary structure. These surface interactions are of paramount importance and have been therapeutically exploited for antiviral design, such as monoclonal antibodies. Additionally, we provide an insight into novel therapies that target viral non-structural proteins, such as viral RNA polymerase. An example of which is remdesivir which has now been approved for use in COVID-19 patients by the US Food and Drug Administration. Establishing further understanding of the molecular details at the cell surface will undoubtably aid the development of more efficacious and selectively targeted therapies to reduce the burden of COVID-19.

scholarly journals Interaction of Human Tumor Viruses with Host Cell Surface Receptors and Cell Entry

Viruses ◽  
2015 ◽  
Vol 7 (5) ◽  
pp. 2592-2617 ◽  
Author(s):  
Georgia Schäfer ◽  
Melissa Blumenthal ◽  
Arieh Katz
Keyword(s):  
Cell Surface ◽  
Host Cell ◽  
Human Tumor ◽  
Cell Entry ◽  
Cell Surface Receptors ◽  
Surface Receptors ◽  
Tumor Viruses ◽  
Host Cell Surface

scholarly journals A Single-Pass Type I Membrane Protein from the Apicomplexan Parasite Cryptosporidium parvum with Nanomolar Binding Affinity to Host Cell Surface

2021 ◽  
Vol 9 (5) ◽  
pp. 1015
Author(s):  
Tianyu Zhang ◽  
Xin Gao ◽  
Dongqiang Wang ◽  
Jixue Zhao ◽  
Nan Zhang ◽  
...  
Keyword(s):  
Membrane Protein ◽  
Cell Surface ◽  
Host Cell ◽  
Binding Affinity ◽  
Cryptosporidium Parvum ◽  
Host Cells ◽  
Watery Diarrhea ◽  
Type I ◽  
Single Pass ◽  
Host Cell Surface

Cryptosporidium parvum is a globally recognized zoonotic parasite of medical and veterinary importance. This parasite mainly infects intestinal epithelial cells and causes mild to severe watery diarrhea that could be deadly in patients with weakened or defect immunity. However, its molecular interactions with hosts and pathogenesis, an important part in adaptation of parasitic lifestyle, remain poorly understood. Here we report the identification and characterization of a C. parvum T-cell immunomodulatory protein homolog (CpTIPH). CpTIPH is a 901-aa single-pass type I membrane protein encoded by cgd5_830 gene that also contains a short Vibrio, Colwellia, Bradyrhizobium and Shewanella (VCBS) repeat and relatively long integrin alpha (ITGA) N-terminus domain. Immunofluorescence assay confirmed the location of CpTIPH on the cell surface of C. parvum sporozoites. In congruence with the presence of VCBS repeat and ITGA domain, CpTIPH displayed high, nanomolar binding affinity to host cell surface (i.e., Kd(App) at 16.2 to 44.7 nM on fixed HCT-8 and CHO-K1 cells, respectively). The involvement of CpTIPH in the parasite invasion is partly supported by experiments showing that an anti-CpTIPH antibody could partially block the invasion of C. parvum sporozoites into host cells. These observations provide a strong basis for further investigation of the roles of CpTIPH in parasite-host cell interactions.

scholarly journals Extracellular Bacterial Pathogen Induces Host Cell Surface Reorganization to Resist Shear Stress

2009 ◽  
Vol 5 (2) ◽  
pp. e1000314 ◽  
Author(s):  
Guillain Mikaty ◽  
Magali Soyer ◽  
Emilie Mairey ◽  
Nelly Henry ◽  
Dave Dyer ◽  
...  
Keyword(s):  
Shear Stress ◽  
Cell Surface ◽  
Host Cell ◽  
Bacterial Pathogen ◽  
Host Cell Surface

scholarly journals Heparan Sulfate Facilitates Spike Protein-Mediated SARS-CoV-2 Host Cell Invasion and Contributes to Increased Infection of SARS-CoV-2 G614 Mutant and in Lung Cancer

2021 ◽  
Vol 8 ◽  
Author(s):  
Jingwen Yue ◽  
Weihua Jin ◽  
Hua Yang ◽  
John Faulkner ◽  
Xuehong Song ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Surface ◽  
Heparan Sulfate ◽  
Host Cell ◽  
Host Cells ◽  
Cell Surface Receptor ◽  
Spike Protein ◽  
Effective Prevention ◽  
Heparin Derivatives ◽  
Host Cell Surface

The severe acute respiratory syndrome (SARS)-like coronavirus disease (COVID-19) is caused by SARS-CoV-2 and has been a serious threat to global public health with limited treatment. Cellular heparan sulfate (HS) has been found to bind SARS-CoV-2 spike protein (SV2-S) and co-operate with cell surface receptor angiotensin-converting enzyme 2 (ACE2) to mediate SARS-CoV-2 infection of host cells. In this study, we determined that host cell surface SV2-S binding depends on and correlates with host cell surface HS expression. This binding is required for SARS-Cov-2 virus to infect host cells and can be blocked by heparin lyase, HS antagonist surfen, heparin, and heparin derivatives. The binding of heparin/HS to SV2-S is mainly determined by its overall sulfation with potential, minor contribution of specific SV2-S binding motifs. The higher binding affinity of SV2-S G614 mutant to heparin and upregulated HS expression may be one of the mechanisms underlying the higher infectivity of the SARS-CoV-2 G614 variant and the high vulnerability of lung cancer patients to SARS-CoV-2 infection, respectively. The higher host cell infection by SARS-CoV-2 G614 variant pseudovirus and the increased infection caused by upregulated HS expression both can be effectively blocked by heparin lyase and heparin, and possibly surfen and heparin derivatives too. Our findings support blocking HS-SV2-S interaction may provide one addition to achieve effective prevention and/treatment of COVID-19.

scholarly journals Significance of thiol-disulfide balance in SARS-CoV-2 infection

2021 ◽  
Vol 72 (3) ◽  
pp. 30-36
Author(s):  
Tatjana Simić
Keyword(s):  
Cell Surface ◽  
Host Cell ◽  
Protein Interactions ◽  
Viral Entry ◽  
Molecular Mechanisms ◽  
Alkylating Agents ◽  
Protein S ◽  
Protein Protein Interactions ◽  
Virus Surface ◽  
Host Cell Surface

Studies of the molecular mechanisms regarding interaction of different viruses with receptors on the host cell surface have shown that the viral entry depends on the specific relationship between free thiol (SH) groups and disulfides on the virus surface, as well as the thiol disulfide balance on the host cell surface. The presence of oxidizing compounds or alkylating agents, which disturb the thiol-disulfide balance on the surface of the virus, can also affect its infectious potential. Disturbed thiol-disulfide balance may also influence protein-protein interactions between SARS-CoV-2 protein S and ACE2 receptors of the host cell. This review presents the basic mechanisms of maintaining intracellular and extracellular thiol disulfide balance and previous experimental and clinical evidence in favor of impaired balance in SARS-CoV-2 infection. Besides, the results of the clinical application or experimental analysis of compounds that induce changes in the thiol disulfide balance towards reduction of disulfide bridges in proteins of interest in COVID-19 infection are presented.

Brilacidin, a COVID-19 Drug Candidate, demonstrates broad-spectrum antiviral activity against human coronaviruses OC43, 229E and NL63 through targeting both the virus and the host cell

2021 ◽  
Author(s):  
Yanmei Hu ◽  
Hyunil Jo ◽  
William DeGrado ◽  
Jun Wang
Keyword(s):  
Antiviral Activity ◽  
Cell Surface ◽  
Host Cell ◽  
Mechanism Of Action ◽  
Broad Spectrum ◽  
Drug Candidate ◽  
Host Defense Peptides ◽  
Antibiotic Drug ◽  
Host Cell Surface ◽  
Human Coronaviruses

Brilacidin, a mimetic of host defense peptides (HDPs), is currently in phase 2 clinical trial as an antibiotic drug candidate. A recent study reported that brilacidin has antiviral activity against SARS-CoV-2 by inactivating the virus. In this work, we discovered an additional mechanism of action of brilacidin by targeting heparan sulfate proteoglycans (HSPGs) on host cell surface. Brilacidin, but not acetyl brilacidin, inhibits the entry of SARS-CoV-2 pseudovirus into multiple cell lines, and heparin, a HSPG mimetic, abolishes the inhibitory activity of brilacidin on SARS-CoV-2 pseudovirus cell entry. In addition, we found that brilacidin has broad-spectrum antiviral activity against multiple human coronaviruses (HCoVs) including HCoV-229E, HCoV-OC43, and HCoV-NL63. Mechanistic studies revealed that brilacidin has a dual antiviral mechanism of action including virucidal activity and binding to coronavirus attachment factor HSPGs on host cell surface. Brilacidin partially loses its antiviral activity when heparin was included in the cell cultures, supporting the host-targeting mechanism. Drug combination therapy showed that brilacidin has a strong synergistic effect with remdesivir against HCoV-OC43 in cell culture. Taken together, this study provides appealing findings for the translational potential of brilacidin as a broad-spectrum antiviral for coronaviruses including SARS-CoV-2.

scholarly journals Probability of Immobilization on Host Cell Surface Regulates Viral Infectivity

2020 ◽  
Vol 125 (12) ◽  
Author(s):  
Michael C. DeSantis ◽  
Chunjuan Tian ◽  
Jin H. Kim ◽  
Jamie L. Austin ◽  
Wei Cheng
Keyword(s):  
Cell Surface ◽  
Host Cell ◽  
Viral Infectivity ◽  
Host Cell Surface
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