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

A small circular DNA was found extrachromosomally in a clone of F9 embryonal carcinoma (EC) cells at high copy numbers per cell. The DNA was cloned in plasmid pUC19. Restriction endonuclease analyses of the DNA indicated that the DNA (fPyF9) was a mutant of polyomavirus (Py) DNA and had a mutation in a noncoding regulatory region. There have been many reports on the isolation of Py mutants capable of replication in undifferentiated cells. However, fPyF9 was different from other Py mutants in the following aspects: it was harbored stably as a free copy at 1 X 10(4) to 5 X 10(4) copies per cell in EC cells; it replicated in undifferentiated cells better than in differentiated cells; it was extremely rearranged in the sequences of the enhancer B domain; and it carried in the enhancer B domain three copies of an exogenous sequence which does not exist in Py strain A2. From these observations, we propose a new class of Py EC mutant which has an autonomous state similar to that of plasmid and small circular DNA in host cells.

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Structural Basis for the Understanding of Entry Inhibitors Against SARS Viruses

Current Medicinal Chemistry ◽

10.2174/0929867328666210514122418 ◽

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.

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TIM-1 Promotes Japanese Encephalitis Virus Entry and Infection

Viruses ◽

10.3390/v10110630 ◽

2018 ◽

Vol 10 (11) ◽

pp. 630 ◽

Cited By ~ 9

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.

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

Viruses ◽

10.3390/v10120678 ◽

2018 ◽

Vol 10 (12) ◽

pp. 678 ◽

Cited By ~ 6

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.

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Molecular Signaling and Cellular Pathways for Virus Entry

ISRN Virology ◽

10.5402/2013/306595 ◽

2013 ◽

Vol 2013 ◽

pp. 1-8 ◽

Cited By ~ 1

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.

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Metainflammation in COVID-19

Endocrine Metabolic & Immune Disorders - Drug Targets ◽

10.2174/1871530322666220104103325 ◽

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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CD147-spike protein is a novel route for SARS-CoV-2 infection to host cells

Signal Transduction and Targeted Therapy ◽

10.1038/s41392-020-00426-x ◽

2020 ◽

Vol 5 (1) ◽

Cited By ~ 3

Author(s):

Ke Wang ◽

Wei Chen ◽

Zheng Zhang ◽

Yongqiang Deng ◽

Jian-Qi Lian ◽

...

Keyword(s):

Virus Entry ◽

Rapid Evolution ◽

Cell Receptor ◽

Host Cells ◽

Spike Protein ◽

Dependent Manner ◽

Viral Loads ◽

Host Cell Receptor ◽

Human T Cells ◽

Effective Drugs

AbstractIn face of the everlasting battle toward COVID-19 and the rapid evolution of SARS-CoV-2, no specific and effective drugs for treating this disease have been reported until today. Angiotensin-converting enzyme 2 (ACE2), a receptor of SARS-CoV-2, mediates the virus infection by binding to spike protein. Although ACE2 is expressed in the lung, kidney, and intestine, its expressing levels are rather low, especially in the lung. Considering the great infectivity of COVID-19, we speculate that SARS-CoV-2 may depend on other routes to facilitate its infection. Here, we first discover an interaction between host cell receptor CD147 and SARS-CoV-2 spike protein. The loss of CD147 or blocking CD147 in Vero E6 and BEAS-2B cell lines by anti-CD147 antibody, Meplazumab, inhibits SARS-CoV-2 amplification. Expression of human CD147 allows virus entry into non-susceptible BHK-21 cells, which can be neutralized by CD147 extracellular fragment. Viral loads are detectable in the lungs of human CD147 (hCD147) mice infected with SARS-CoV-2, but not in those of virus-infected wild type mice. Interestingly, virions are observed in lymphocytes of lung tissue from a COVID-19 patient. Human T cells with a property of ACE2 natural deficiency can be infected with SARS-CoV-2 pseudovirus in a dose-dependent manner, which is specifically inhibited by Meplazumab. Furthermore, CD147 mediates virus entering host cells by endocytosis. Together, our study reveals a novel virus entry route, CD147-spike protein, which provides an important target for developing specific and effective drug against COVID-19.

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LY6E Restricts Entry of Human Coronaviruses, Including Currently Pandemic SARS-CoV-2

Journal of Virology ◽

10.1128/jvi.00562-20 ◽

2020 ◽

Vol 94 (18) ◽

Cited By ~ 7

Author(s):

Xuesen Zhao ◽

Shuangli Zheng ◽

Danying Chen ◽

Mei Zheng ◽

Xinglin Li ◽

...

Keyword(s):

Influenza A ◽

Yellow Fever Virus ◽

Virus Entry ◽

Ectopic Expression ◽

A549 Cells ◽

Cellular Protein ◽

Host Cells ◽

Cellular Proteins ◽

Human Coronavirus ◽

Human Coronaviruses

ABSTRACT C3A is a subclone of the human hepatoblastoma HepG2 cell line with strong contact inhibition of growth. We fortuitously found that C3A was more susceptible to human coronavirus HCoV-OC43 infection than HepG2, which was attributed to the increased efficiency of virus entry into C3A cells. In an effort to search for the host cellular protein(s) mediating the differential susceptibility of the two cell lines to HCoV-OC43 infection, we found that ArfGAP with dual pleckstrin homology (PH) domains 2 (ADAP2), gamma-interferon-inducible lysosome/endosome-localized thiolreductase (GILT), and lymphocyte antigen 6 family member E (LY6E), the three cellular proteins identified to function in interference with virus entry, were expressed at significantly higher levels in HepG2 cells. Functional analyses revealed that ectopic expression of LY6E, but not GILT or ADAP2, in HEK 293 cells inhibited the entry of HCoV-O43. While overexpression of LY6E in C3A and A549 cells efficiently inhibited the infection of HCoV-OC43, knockdown of LY6E expression in HepG2 significantly increased its susceptibility to HCoV-OC43 infection. Moreover, we found that LY6E also efficiently restricted the entry mediated by the envelope spike proteins of other human coronaviruses, including the currently pandemic SARS-CoV-2. Interestingly, overexpression of serine protease TMPRSS2 or amphotericin treatment significantly neutralized the IFN-inducible transmembrane 3 (IFITM3) restriction of human coronavirus (CoV) entry, but did not compromise the effect of LY6E on the entry of human coronaviruses. The work reported herein thus demonstrates that LY6E is a critical antiviral immune effector that controls CoV infection and pathogenesis via a mechanism distinct from other factors that modulate CoV entry. IMPORTANCE Virus entry into host cells is one of the key determinants of host range and cell tropism and is subjected to the control of host innate and adaptive immune responses. In the last decade, several interferon-inducible cellular proteins, including IFITMs, GILT, ADAP2, 25CH, and LY6E, had been identified to modulate the infectious entry of a variety of viruses. Particularly, LY6E was recently identified as a host factor that facilitates the entry of several human-pathogenic viruses, including human immunodeficiency virus, influenza A virus, and yellow fever virus. Identification of LY6E as a potent restriction factor of coronaviruses expands the biological function of LY6E and sheds new light on the immunopathogenesis of human coronavirus infection.

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The veterinary perspective of COVID-19

Sokoto Journal of Veterinary Sciences ◽

10.4314/sokjvs.v18i2.1 ◽

2020 ◽

Vol 18 (2) ◽

pp. 53-66

Author(s):

N. Lawal ◽

A.B. Onoja

Keyword(s):

Animal Species ◽

Control Strategies ◽

Virus Entry ◽

Respiratory Illness ◽

Host Cells ◽

Epidemiological Trend ◽

The Family ◽

Epidemiological Trends ◽

And Control ◽

Severe Respiratory Illness

Coronaviridae is a family of RNA viruses responsible for two previous epidemics of viral pneumonia and related illnesses: Severe Acute Respiratory Syndrome in 2002 and Middle East Respiratory Syndrome in 2012. The current COVID-19 pandemic is caused by a new member of the family Coronaviridae, named SARS-CoV-2 which emerged in December, 2019 in Wuhan, China. Infected persons present with severe respiratory illness including pneumonia. There have been reports of confirmed cases in different animal species that became infected with SARS-CoV-2, suggesting possible reverse zoonosis. In this review, we discussed the origin, biology, genome organization, replication and virus entry into host cells, immune mechanisms, epidemiological trends, prevention and control strategies employed in combating the threat posed by the COVID-19 pandemic. Keywords: COVID-19, Epidemiological trend, Pandemic, SARS-CoV-2

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