scholarly journals Single virus tracking of Ebola virus entry through lipid rafts in living host cells

2020 ◽  
Vol 2 (1) ◽  
pp. 25-31 ◽  
Author(s):  
Cong Jin ◽  
Bin Che ◽  
Zhengyuan Guo ◽  
Chuan Li ◽  
Yang Liu ◽  
...  
Keyword(s):  
Lipid Rafts ◽  
Ebola Virus ◽  
Virus Entry ◽  
Host Cells ◽  
Single Virus Tracking

scholarly journals Identification of Diaryl-Quinoline Compounds as Entry Inhibitors of Ebola Virus

Viruses ◽  
2018 ◽  
Vol 10 (12) ◽  
pp. 678 ◽  
Author(s):  
Qinghua Cui ◽  
Han Cheng ◽  
Rui Xiong ◽  
Gang Zhang ◽  
Ruikun Du ◽  
...  
Keyword(s):  
Drug Development ◽  
Ebola Virus ◽  
Virus Disease ◽  
Virus Entry ◽  
Surface Protein ◽  
Host Cells ◽  
Entry Inhibitor ◽  
Entry Inhibitors ◽  
Promising Target ◽  
Virus Entry Inhibitors

Ebola virus is the causative agent of Ebola virus disease in humans. The lethality of Ebola virus infection is about 50%, supporting the urgent need to develop anti-Ebola drugs. Glycoprotein (GP) is the only surface protein of the Ebola virus, which is functionally critical for the virus to attach and enter the host cells, and is a promising target for anti-Ebola virus drug development. In this study, using the recombinant HIV-1/Ebola pseudovirus platform we previously established, we evaluated a small molecule library containing various quinoline compounds for anti-Ebola virus entry inhibitors. Some of the quinoline compounds specifically inhibited the entry of the Ebola virus. Among them, compound SYL1712 was the most potent Ebola virus entry inhibitor with an IC50 of ~1 μM. The binding of SYL1712 to the vial glycoprotein was computationally modeled and was predicted to interact with specific residues of GP. We used the time of the addition assay to show that compound SYL1712 blocks Ebola GP-mediated entry. Finally, consistent with being an Ebola virus entry inhibitor, compound SYL1712 inhibited infectious Ebola virus replication in tissue culture under biosafety level 4 containment, with an IC50 of 2 μM. In conclusion, we identified several related molecules with a diaryl-quinoline scaffold as potential anti-EBOV entry inhibitors, which can be further optimized for anti-Ebola drug development.

scholarly journals Specific Association of Glycoprotein B with Lipid Rafts during Herpes Simplex Virus Entry

2003 ◽  
Vol 77 (17) ◽  
pp. 9542-9552 ◽  
Author(s):  
Florent C. Bender ◽  
J. Charles Whitbeck ◽  
Manuel Ponce de Leon ◽  
Huan Lou ◽  
Roselyn J. Eisenberg ◽  
...  
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Lipid Rafts ◽  
Ebola Virus ◽  
Virus Entry ◽  
Vero Cells ◽  
Inhibitory Effect ◽  
Membrane Lipid ◽  
Dependent Manner ◽  
Simplex Virus

ABSTRACT Herpes simplex virus (HSV) entry requires the interaction of glycoprotein D (gD) with a cellular receptor such as herpesvirus entry mediator (HVEM or HveA) or nectin-1 (HveC). However, the fusion mechanism is still not understood. Since cholesterol-enriched cell membrane lipid rafts are involved in the entry of other enveloped viruses such as human immunodeficiency virus and Ebola virus, we tested whether HSV entry proceeds similarly. Vero cells and cells expressing either HVEM or nectin-1 were treated with cholesterol-sequestering drugs such as methyl-β-cyclodextrin or nystatin and then exposed to virus. In all cases, virus entry was inhibited in a dose-dependent manner, and the inhibitory effect was fully reversible by replenishment of cholesterol. To examine the association of HVEM and nectin-1 with lipid rafts, we analyzed whether they partitioned into nonionic detergent-insoluble glycolipid-enriched membranes (DIG). There was no constitutive association of either receptor with DIG. Binding of soluble gD or virus to cells did not result in association of nectin-1 with the raft-containing fractions. However, during infection, a fraction of gB but not gC, gD, or gH associated with DIG. Similarly, when cells were incubated with truncated soluble glycoproteins, soluble gB but not gC was found associated with DIG. Together, these data favor a model in which HSV uses gB to rapidly mobilize lipid rafts that may serve as a platform for entry and cell signaling. It also suggests that gB may interact with a cellular molecule associated with lipid rafts.

scholarly journals Identification of Ellagic Acid from Plant Rhodiola rosea L. as an Anti-Ebola Virus Entry Inhibitor

Viruses ◽  
2018 ◽  
Vol 10 (4) ◽  
pp. 152 ◽  
Author(s):  
Qinghua Cui ◽  
Ruikun Du ◽  
Manu Anantpadma ◽  
Adam Schafer ◽  
Lin Hou ◽  
...  
Keyword(s):  
Ellagic Acid ◽  
Ebola Virus ◽  
Virus Entry ◽  
Rhodiola Rosea ◽  
Entry Inhibitor

Structural Basis for the Understanding of Entry Inhibitors Against SARS Viruses

2021 ◽  
Vol 28 ◽  
Author(s):  
Prem Kumar Kushwaha ◽  
Neha Kumari ◽  
Sneha Nayak ◽  
Keshav Kishor ◽  
Ashoke Sharon
Keyword(s):  
Viral Entry ◽  
Molecular Level ◽  
Virus Entry ◽  
Holistic Approach ◽  
Symptomatic Treatment ◽  
Host Cells ◽  
Structural Basis ◽  
Viral Fusion ◽  
Structural Studies ◽  
Entry Inhibitors

: Outbreaks due to Severe Acute Respiratory Syndrome-Corona virus 2 (SARS-CoV-2) initiated in Wuhan city, China, in December 2019 which continued to spread internationally, posing a pandemic threat as declared by WHO and as of March 10, 2021, confirmed cases reached 118 million along with 2.6 million deaths worldwide. In the absence of specific antiviral medication, symptomatic treatment and physical isolation remain the options to control the contagion. The recent clinical trials on antiviral drugs highlighted some promising compounds such as umifenovir (haemagglutinin-mediated fusion inhibitor), remdesivir (RdRp nucleoside inhibitor), and favipiravir (RdRp Inhibitor). WHO launched a multinational clinical trial on several promising analogs as a potential treatment to combat SARS infection. This situation urges a holistic approach to invent safe and specific drugs as a prophylactic and therapeutic cure for SARS-related-viral diseases, including COVID-19. : It is significant to note that researchers worldwide have been doing their best to handle the crisis and have produced an extensive and promising literature body. It opens a scope and allows understanding the viral entry at the molecular level. A structure-based approach can reveal the molecular-level understanding of viral entry interaction. The ligand profiling and non-covalent interactions among participating amino-acid residues are critical information to delineate a structural interpretation. The structural investigation of SARS virus entry into host cells will reveal the possible strategy for designing drugs like entry inhibitors. : The structure-based approach demonstrates details at the 3D molecular level. It shows specificity about SARS-CoV-2 spike interaction, which uses human angiotensin-converting enzyme 2 (ACE2) as a receptor for entry, and the human protease completes the process of viral fusion and infection. : The 3D structural studies reveal the existence of two units, namely S1 and S2. S1 is called a receptor-binding domain (RBD) and responsible for interacting with the host (ACE2), and the S2 unit participates in the fusion of viral and cellular membranes. TMPRSS2 mediates the cleavage at S1/S2 subunit interface in S-protein of SARS CoV-2, leading to viral fusion. Conformational difference associated with S1 binding alters ACE2 interaction and inhibits viral fusion. Overall, the detailed 3D structural studies help understand the 3D structural basis of interaction between viruses with host factors and available scope for the new drug discovery process targeting SARS-related virus entry into the host cell.

scholarly journals TIM-1 Promotes Japanese Encephalitis Virus Entry and Infection

Viruses ◽  
2018 ◽  
Vol 10 (11) ◽  
pp. 630 ◽  
Author(s):  
Jichen Niu ◽  
Ya Jiang ◽  
Hao Xu ◽  
Changjing Zhao ◽  
Guodong Zhou ◽  
...  
Keyword(s):  
Japanese Encephalitis Virus ◽  
Point Mutation ◽  
Japanese Encephalitis ◽  
Virus Entry ◽  
A549 Cells ◽  
Binding Pocket ◽  
Cytoplasmic Domain ◽  
Encephalitis Virus ◽  
Host Cells ◽  
Attachment Factor

Japanese encephalitis virus (JEV) is a mosquito-borne Flavivirus, the leading cause of viral-induced encephalitis. Several host molecules have been identified as the JEV attachment factor; however, the molecules involved in JEV entry remain poorly understood. In the present study, we demonstrate that TIM-1 is important for efficient infection by JEV. Firstly, three TIM-1 variants (V1, V2, and V3) were cloned from A549 cells, and we revealed that only ectopically TIM-1 V2 expression in 293T cells significantly promotes JEV attachment, entry and infection. Point mutation of phosphatidylserine (Ptdser) binding pocket in the TIM-1 IgV domain dampened JEV entry, indicating that TIM-1-mediated JEV infection is Ptdser-dependent. Furthermore, we found the cytoplasmic domain of TIM-1 is also required for enhancing JEV entry. Additionally, knock down of TIM-1 expression in A549 cells impaired JEV entry and infection, but not attachment, suggesting that additional factors exist in A549 cells that allow the virus to bind. In conclusion, our findings demonstrate that TIM-1 promotes JEV infection as an entry cofactor, and the polymorphism of TIM-1 is associated with JEV susceptibility to host cells.

scholarly journals Secreted phospholipases A2, a new class of HIV inhibitors that block virus entry into host cells

1999 ◽  
Vol 104 (5) ◽  
pp. 611-618 ◽  
Author(s):  
David Fenard ◽  
Gérard Lambeau ◽  
Emmanuel Valentin ◽  
Jean-Claude Lefebvre ◽  
Michel Lazdunski ◽  
...  
Keyword(s):  
Virus Entry ◽  
Host Cells ◽  
Phospholipases A2 ◽  
New Class ◽  
Hiv Inhibitors

scholarly journals Direct intracellular visualization of Ebola virus-receptor interaction by in situ proximity ligation

2020 ◽  
Author(s):  
Eva Mittler ◽  
Tanwee P Alkutkar ◽  
Rohit K Jangra ◽  
Kartik Chandran
Keyword(s):  
Receptor Binding ◽  
Ebola Virus ◽  
Host Cells ◽  
Proximity Ligation Assay ◽  
Viral Glycoprotein ◽  
Virus Receptor ◽  
Proximity Ligation ◽  
Infected Cells ◽  
Viral Surface

ABSTRACTEbola virus (EBOV) entry into host cells comprises stepwise and extensive interactions of the sole viral surface glycoprotein GP with multiple host factors. During the intricate process, following virus uptake and trafficking to late endosomal/lysosomal compartments, GP is proteolytically processed to GPCL by the endosomal proteases cathepsin B and L unmasking GP’s receptor-binding site. Engagement of GPCL with the universal filoviral intracellular receptor Niemann-Pick C1 (NPC1) eventually culminates in fusion between viral and cellular membranes, cytoplasmic escape of the viral nucleocapsid and subsequent infection. Mechanistic delineation of the indispensable GPCL:NPC1 binding step has been severely hampered by the unavailability of a robust cell-based assay assessing interaction of GPCL with full-length endosomal NPC1.Here, we describe a novel in situ assay to monitor GPCL:NPC1 engagement in intact, infected cells. Visualization of the subcellular localization of binding complexes is based on the principle of DNA-assisted, antibody-mediated proximity ligation. Virus-receptor binding monitored by proximity ligation was contingent on GP’s proteolytic cleavage, and was sensitive to perturbations in the GPCL:NPC1 interface. Our assay also specifically decoupled detection of virus-receptor binding from steps post-receptor binding, such as membrane fusion and infection. Testing of multiple FDA-approved small molecule inhibitors revealed that drug treatments inhibited virus entry and GPCL:NPC1 recognition by distinctive mechanisms. Together, here we present a newly established proximity ligation assay, which will allow us to dissect cellular and viral requirements for filovirus-receptor binding, and to delineate the mechanisms of action of inhibitors on filovirus entry in a cell-based system.IMPORTANCEEbola virus causes episodic but increasingly frequent outbreaks of severe disease in Middle Africa, as shown by a currently ongoing outbreak in the Democratic Republic of Congo. Despite considerable effort, FDA-approved anti-filoviral therapeutics or targeted interventions are not available yet. Virus host-cell invasion represents an attractive target for antivirals; however our understanding of the inhibitory mechanisms of novel therapeutics is often hampered by fragmented knowledge of the filovirus-host molecular interactions required for viral infection. To help close this critical knowledge gap, here, we report an in situ assay to monitor binding of the EBOV glycoprotein to its receptor NPC1 in intact, infected cells. We demonstrate that our in situ assay based on proximity ligation represents a powerful tool to delineate receptor-viral glycoprotein interactions. Similar assays can be utilized to examine receptor interactions of diverse viral surface proteins whose studies have been hampered until now by the lack of robust in situ assays.

scholarly journals Molecular Signaling and Cellular Pathways for Virus Entry

ISRN Virology ◽  
2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
Pei-I Chi ◽  
Hung-Jen Liu
Keyword(s):  
Signaling Pathways ◽  
Viral Entry ◽  
Virus Entry ◽  
Host Cells ◽  
Target Cells ◽  
Molecular Signaling ◽  
Cellular Processes ◽  
Cellular Pathways ◽  
Host Life ◽  
Endocytic Vesicles

The cell signaling plays a pivotal role in regulating cellular processes and is often manipulated by viruses as they rely on the functions offered by cells for their propagation. The first stage of their host life is to pass the genetic materials into the cell. Although some viruses can directly penetrate into cytosol, in fact, most virus entry into their host cells is through endocytosis. This machinery initiates with cell type specific cellular signaling pathways, and the signaling compounds can be proteins, lipids, and carbohydrates. The activation can be triggered in a very short time after virus binds on target cells, such as receptors. The signaling pathways involved in regulation of viral entry are wide diversity that often cross-talk between different endocytosis results. Furthermore, some viruses have the ability to use the multiple internalization pathways which leads to the regulation being even more complex. In this paper, we discuss some recent advances in our understanding of cellular pathways for virus entry, molecular signaling during virus entry, formation of endocytic vesicles, and the traffic.

Metainflammation in COVID-19

2022 ◽  
Vol 22 ◽  
Author(s):  
Mojtaba Bakhtiari ◽  
Kamyar Asadipooya
Keyword(s):  
Cell Membrane ◽  
Viral Entry ◽  
Virus Entry ◽  
Host Cells ◽  
Elderly Men ◽  
Virus Binding ◽  
Angiotensin Converting Enzyme 2 ◽  
Dipeptidyl Peptidase 4 ◽  
Beneficial Effects ◽  
Binding Capability

Abstract: A new coronavirus pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2], has been on the rise. This virus is fatal for broad groups of populations, including elderly, men, and patients with comorbidities among which obesity is a possible risk factor. The pathophysiologic connections between obesity/metainflammation and COVID-19 may be directly related to increasing soluble ACE2 (angiotensin-converting enzyme 2] levels which potentiates the viral entrance into the host cells, or indirectly related to dysregulation of immune system, microvascular injury and hypercoagulability. The SARS-CoV-2 S-glycoprotein interacts mainly with ACE2 or possibly DDP4 receptors to enter into the host cells. The host proteases, especially TMPRSS2 (transmembrane protease serine 2], support the fusion process and virus entry. While membranous ACE2 is considered a port of entry to the cell for SARS-CoV-2, it seems that soluble ACE2 retains its virus binding capability and enhances its entry into the cells. Interestingly, ACE2 on cell membrane may have protective roles by diminishing cytokine storm-related injuries to the organs. Applying medications that can reduce soluble ACE2 levels, antagonizing TMPRSS2 or blocking DDP4 can improve the outcomes of COVID-19. Metformin and statins through immunomodulatory activities, Orlistat by reducing viral replication, and thiazolidinediones by upregulating ACE2 expression have potential beneficial effects against COVID-19. However, the combination of dipeptidyl peptidase-4 (DDP4] inhibitors and spironolactone/eplerenone seems to be more effective by reducing soluble ACE2 level, antagonizing TMPRSS2, maintaining ACE2 on cell membrane and reducing risk of viral entry into the cells.

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