Antiviral activity and mechanism of ESC-1GN from skin secretion of hylarana guentheri against influenza a virus

Abstract Development of new and effective anti-influenza drugs is critical for prophylaxis and treatment of influenza A virus infection. A wide range of amphibian skin secretions have been identified to show antiviral activity. Our previously reported ESC-1GN, a peptide from the skin secretion of Hylarana guentheri, displayed good antimicrobial and anti-inflammatory effects. Here, we found that ESC-1GN possessed significant antiviral effects against influenza A viruses. Moreover, ESC-1GN could inhibit the entry of divergent H5N1 and H1N1 virus strains with the IC50 values from 1.29 to 4.59 μM. Mechanism studies demonstrated that ESC-1GN disrupted membrane fusion activity of influenza A viruses by interaction with HA2 subunit. The results of site-directed mutant assay and molecular docking revealed that E105, N50 and the residues around them on HA2 subunit could form hydrogen bonds with amino acid on ESC-1GN, which were critical for ESC-1GN binding to HA2 and inhibiting the entry of influenza A viruses. Altogether, these not only suggest that ESC-1GN maybe represent a new type of excellent template designing drugs against influenza A viruses, but also it may shed light on the immune mechanism and survival strategy of H. guentheri against viral pathogens.

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Functional Comparison of Mx1 from Two Different Mouse Species Reveals the Involvement of Loop L4 in the Antiviral Activity against Influenza A Viruses

Journal of Virology ◽

10.1128/jvi.01744-15 ◽

2015 ◽

Vol 89 (21) ◽

pp. 10879-10890 ◽

Cited By ~ 14

Author(s):

Judith Verhelst ◽

Jan Spitaels ◽

Cindy Nürnberger ◽

Dorien De Vlieger ◽

Tine Ysenbaert ◽

...

Keyword(s):

Influenza Virus ◽

Antiviral Activity ◽

Influenza A Virus ◽

Mus Musculus ◽

Influenza A ◽

Common Mechanism ◽

Mus Spretus ◽

Influenza A Viruses ◽

Content Type ◽

Mouse Species

ABSTRACTThe interferon-inducedMx1gene is an important part of the mammalian defense against influenza viruses.Mus musculusMx1 inhibits influenza A virus replication and transcription by suppressing the polymerase activity of viral ribonucleoproteins (vRNPs). Here, we compared the anti-influenza virus activity of Mx1 fromMus musculusA2G with that of its ortholog fromMus spretus. We found that the antiviral activity ofM. spretusMx1 was less potent than that ofM. musculusMx1. Comparison of theM. musculusMx1 sequence with theM. spretusMx1 sequence revealed 25 amino acid differences, over half of which were present in the GTPase domain and 2 of which were present in loop L4. However, thein vitroGTPase activity of Mx1 from the two mouse species was similar. Replacement of one of the residues in loop L4 inM. spretusMx1 by the corresponding residue of A2G Mx1 increased its antiviral activity. We also show that deletion of loop L4 prevented the binding of Mx1 to influenza A virus nucleoprotein and, hence, abolished the antiviral activity of mouse Mx1. These results indicate that loop L4 of mouse Mx1 is a determinant of antiviral activity. Our findings suggest that Mx proteins from different mammals use a common mechanism to inhibit influenza A viruses.IMPORTANCEMx proteins are evolutionarily conserved in vertebrates and inhibit a wide range of viruses. Still, the exact details of their antiviral mechanisms remain largely unknown. Functional comparison of theMxgenes from two species that diverged relatively recently in evolution can provide novel insights into these mechanisms. We show that bothMus musculusA2G Mx1 andMus spretusMx1 target the influenza virus nucleoprotein. We also found that loop L4 in mouse Mx1 is crucial for its antiviral activity, as was recently reported for primate MxA. This indicates that human and mouse Mx proteins, which have diverged by 75 million years of evolution, recognize and inhibit influenza A viruses by a common mechanism.

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Avian Influenza A Virus Pandemic Preparedness and Vaccine Development

Vaccines ◽

10.3390/vaccines6030046 ◽

2018 ◽

Vol 6 (3) ◽

pp. 46 ◽

Cited By ~ 7

Author(s):

Rory de Vries ◽

Sander Herfst ◽

Mathilde Richard

Keyword(s):

Avian Influenza ◽

Influenza A Virus ◽

Influenza A ◽

Vaccine Development ◽

Influenza Pandemic ◽

Broad Host Range ◽

Influenza A Viruses ◽

Vaccination Strategies ◽

Pandemic Virus ◽

Wide Range

Influenza A viruses can infect a wide range of hosts, creating opportunities for zoonotic transmission, i.e., transmission from animals to humans, and placing the human population at constant risk of potential pandemics. In the last hundred years, four influenza A virus pandemics have had a devastating effect, especially the 1918 influenza pandemic that took the lives of at least 40 million people. There is a constant risk that currently circulating avian influenza A viruses (e.g., H5N1, H7N9) will cause a new pandemic. Vaccines are the cornerstone in preparing for and combating potential pandemics. Despite exceptional advances in the design and development of (pre-)pandemic vaccines, there are still serious challenges to overcome, mainly caused by intrinsic characteristics of influenza A viruses: Rapid evolution and a broad host range combined with maintenance in animal reservoirs, making it near impossible to predict the nature and source of the next pandemic virus. Here, recent advances in the development of vaccination strategies to prepare against a pandemic virus coming from the avian reservoir will be discussed. Furthermore, remaining challenges will be addressed, setting the agenda for future research in the development of new vaccination strategies against potentially pandemic influenza A viruses.

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Zinc-embedded fabrics inactivate SARS-CoV-2 and influenza A virus

10.1101/2020.11.02.365833 ◽

2020 ◽

Author(s):

Vikram Gopal ◽

Benjamin E. Nilsson-Payant ◽

Hollie French ◽

Jurre Y. Siegers ◽

Wai-shing Yung ◽

...

Keyword(s):

Influenza A Virus ◽

Influenza A ◽

Rna Virus ◽

Zinc Content ◽

Respiratory Viruses ◽

Zinc Ions ◽

Liquid Droplets ◽

Influenza A Viruses ◽

Wide Range ◽

Polyamide 6.6

AbstractInfections with respiratory viruses can spread via liquid droplets and aerosols, and cause diseases such as influenza and COVID-19. Face masks and other personal protective equipment (PPE) can act as barriers that prevent the spread of respiratory droplets containing these viruses. However, influenza A viruses and coronaviruses are stable for hours on various materials, which makes frequent and correct disposal of these PPE important. Metal ions embedded into PPE may inactivate respiratory viruses, but confounding factors such as absorption of viruses make measuring and optimizing the inactivation characteristics difficult. Here we used polyamide 6.6 (PA66) fibers that had zinc ions embedded during the polymerisation process and systematically investigated if these fibers can absorb and inactivate pandemic SARS-CoV-2 and influenza A virus H1N1. We find that these viruses are readily absorbed by PA66 fabrics and inactivated by zinc ions embedded into this fabric. The inactivation rate (pfu·gram−1·min−1) exceeds the number of active virus particles expelled by a cough and supports a wide range of viral loads. Moreover, we found that the zinc content and the virus inactivating property of the fabric remain stable over 50 standardized washes. Overall, these results provide new insight into the development of “pathogen-free” PPE and better protection against RNA virus spread.

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Potent sialic acid inhibitors that target influenza A virus hemagglutinin

Scientific Reports ◽

10.1038/s41598-021-87845-0 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Yu-Jen Chang ◽

Cheng-Yun Yeh ◽

Ju-Chien Cheng ◽

Yu-Qi Huang ◽

Kai-Cheng Hsu ◽

...

Keyword(s):

Sialic Acid ◽

Antiviral Activity ◽

Binding Site ◽

Influenza A Virus ◽

Receptor Binding ◽

Influenza A ◽

The United States ◽

Ligand Complex ◽

Receptor Binding Site ◽

Computational Strategy

AbstractEradicating influenza A virus (IAV) is difficult, due to its genetic drift and reassortment ability. As the infectious cycle is initiated by the influenza glycoprotein, hemagglutinin (HA), which mediates the binding of virions to terminal sialic acids moieties, HA is a tempting target of anti-influenza inhibitors. However, the complexity of the HA structure has prevented delineation of the structural characterization of the HA protein–ligand complex. Our computational strategy efficiently analyzed > 200,000 records of compounds held in the United States National Cancer Institute (NCI) database and identified potential HA inhibitors, by modeling the sialic acid (SA) receptor binding site (RBS) for the HA structure. Our modeling revealed that compound NSC85561 showed significant antiviral activity against the IAV H1N1 strain with EC50 values ranging from 2.31 to 2.53 µM and negligible cytotoxicity (CC50 > 700 µM). Using the NSC85561 compound as the template to generate 12 derivatives, robust bioassay results revealed the strongest antiviral efficacies with NSC47715 and NSC7223. Virtual screening clearly identified three SA receptor binding site inhibitors that were successfully validated in experimental data. Thus, our computational strategy has identified SA receptor binding site inhibitors against HA that show IAV-associated antiviral activity.

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Antiviral Activity of Chicken Cathelicidin B1 Against Influenza A Virus

Frontiers in Microbiology ◽

10.3389/fmicb.2020.00426 ◽

2020 ◽

Vol 11 ◽

Cited By ~ 1

Author(s):

Lianci Peng ◽

Wenjuan Du ◽

Melanie D. Balhuizen ◽

Henk P. Haagsman ◽

Cornelis A. M. de Haan ◽

...

Keyword(s):

Antiviral Activity ◽

Influenza A Virus ◽

Influenza A

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Investigating Influenza A Virus Infection: Tools To Track Infection and Limit Tropism: TABLE 1

Journal of Virology ◽

10.1128/jvi.00462-15 ◽

2015 ◽

Vol 89 (12) ◽

pp. 6167-6170 ◽

Cited By ~ 19

Author(s):

Jessica K. Fiege ◽

Ryan A. Langlois

Keyword(s):

Influenza A Virus ◽

Influenza A ◽

Therapeutic Interventions ◽

Microrna Target ◽

Influenza A Viruses ◽

Host Interactions ◽

Target Sites ◽

Recent Developments ◽

Cellular Tropism ◽

The Relationship

Influenza A viruses display a broad cellular tropism within the respiratory tracts of mammalian hosts. Uncovering the relationship between tropism and virus immunity, pathogenesis, and transmission will be critical for the development of therapeutic interventions. Here we discuss recent developments of several recombinant strains of influenza A virus. These viruses have inserted reporters to track tropism, microRNA target sites to restrict tropism, or barcodes to assess transmission dynamics, expanding our understanding of pathogen-host interactions.

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Unexpected Functional Divergence of Bat Influenza Virus NS1 Proteins

Journal of Virology ◽

10.1128/jvi.02097-17 ◽

2017 ◽

Vol 92 (5) ◽

Cited By ~ 4

Author(s):

Hannah L. Turkington ◽

Mindaugas Juozapaitis ◽

Nikos Tsolakos ◽

Eugenia Corrales-Aguilar ◽

Martin Schwemmle ◽

...

Keyword(s):

Influenza A Virus ◽

Virulence Factor ◽

Influenza A ◽

Nonstructural Protein ◽

Functional Divergence ◽

Protein A ◽

Regulatory Subunit ◽

Ns1 Protein ◽

Influenza A Viruses ◽

Hydrophobic Patch

ABSTRACT Recently, two influenza A virus (FLUAV) genomes were identified in Central and South American bats. These sequences exhibit notable divergence from classical FLUAV counterparts, and functionally, bat FLUAV glycoproteins lack canonical receptor binding and destroying activity. Nevertheless, other features that distinguish these viruses from classical FLUAVs have yet to be explored. Here, we studied the viral nonstructural protein NS1, a virulence factor that modulates host signaling to promote efficient propagation. Like all FLUAV NS1 proteins, bat FLUAV NS1s bind double-stranded RNA and act as interferon antagonists. Unexpectedly, we found that bat FLUAV NS1s are unique in being unable to bind host p85β, a regulatory subunit of the cellular metabolism-regulating enzyme, phosphoinositide 3-kinase (PI3K). Furthermore, neither bat FLUAV NS1 alone nor infection with a chimeric bat FLUAV efficiently activates Akt, a PI3K effector. Structure-guided mutagenesis revealed that the bat FLUAV NS1-p85β interaction can be reengineered (in a strain-specific manner) by changing two to four NS1 residues (96L, 99M, 100I, and 145T), thereby creating a hydrophobic patch. Notably, ameliorated p85β-binding is insufficient for bat FLUAV NS1 to activate PI3K, and a chimeric bat FLUAV expressing NS1 with engineered hydrophobic patch mutations exhibits cell-type-dependent, but species-independent, propagation phenotypes. We hypothesize that bat FLUAV hijacking of PI3K in the natural bat host has been selected against, perhaps because genes in this metabolic pathway were differentially shaped by evolution to suit the unique energy use strategies of this flying mammal. These data expand our understanding of the enigmatic functional divergence between bat FLUAVs and classical mammalian and avian FLUAVs. IMPORTANCE The potential for novel influenza A viruses to establish infections in humans from animals is a source of continuous concern due to possible severe outbreaks or pandemics. The recent discovery of influenza A-like viruses in bats has raised questions over whether these entities could be a threat to humans. Understanding unique properties of the newly described bat influenza A-like viruses, such as their mechanisms to infect cells or how they manipulate host functions, is critical to assess their likelihood of causing disease. Here, we characterized the bat influenza A-like virus NS1 protein, a key virulence factor, and found unexpected functional divergence of this protein from counterparts in other influenza A viruses. Our study dissects the molecular changes required by bat influenza A-like virus NS1 to adopt classical influenza A virus properties and suggests consequences of bat influenza A-like virus infection, potential future evolutionary trajectories, and intriguing virus-host biology in bat species.

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Characterization of a Human H5N1 Influenza A Virus Isolated in 2003

Journal of Virology ◽

10.1128/jvi.79.15.9926-9932.2005 ◽

2005 ◽

Vol 79 (15) ◽

pp. 9926-9932 ◽

Cited By ~ 70

Author(s):

Kyoko Shinya ◽

Masato Hatta ◽

Shinya Yamada ◽

Ayato Takada ◽

Shinji Watanabe ◽

...

Keyword(s):

Hong Kong ◽

Avian Influenza ◽

Influenza A Virus ◽

Influenza A ◽

Mainland China ◽

Virus Infections ◽

Influenza A Viruses ◽

H5n1 Avian Influenza Virus ◽

H5n1 Influenza ◽

Avian Influenza A Virus

ABSTRACT In 2003, H5N1 avian influenza virus infections were diagnosed in two Hong Kong residents who had visited the Fujian province in mainland China, affording us the opportunity to characterize one of the viral isolates, A/Hong Kong/213/03 (HK213; H5N1). In contrast to H5N1 viruses isolated from humans during the 1997 outbreak in Hong Kong, HK213 retained several features of aquatic bird viruses, including the lack of a deletion in the neuraminidase stalk and the absence of additional oligosaccharide chains at the globular head of the hemagglutinin molecule. It demonstrated weak pathogenicity in mice and ferrets but caused lethal infection in chickens. The original isolate failed to produce disease in ducks but became more pathogenic after five passages. Taken together, these findings portray the HK213 isolate as an aquatic avian influenza A virus without the molecular changes associated with the replication of H5N1 avian viruses in land-based poultry such as chickens. This case challenges the view that adaptation to land-based poultry is a prerequisite for the replication of aquatic avian influenza A viruses in humans.

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Influenza type A virus M protein expression on infected cells is responsible for cross-reactive recognition by cytotoxic thymus-derived lymphocytes

Infection and Immunity ◽

10.1128/iai.29.2.719-723.1980 ◽

1980 ◽

Vol 29 (2) ◽

pp. 719-723 ◽

Cited By ~ 1

Author(s):

C S Reiss ◽

J L Schulman

Keyword(s):

T Cell ◽

Influenza A Virus ◽

Influenza A ◽

Rabbit Antiserum ◽

Type A ◽

M Protein ◽

Cytotoxic T Cell ◽

Influenza A Viruses ◽

Infected Cells ◽

Cytotoxic T Cell Responses

M protein of influenza A virus was detected with rabbit antiserum by both indirect immunofluorescence and by antibody plus complement-mediated cytolysis on the cell surfaces of both productively and nonproductively infected cells. In contrast, antiserum to nucleoprotein failed to react with unfixed infected cells, but did bind to fixed infected cells, especially in the perinuclear area. Incorporation of antiserum to M protein in a T-cell-mediated cytotoxicity assay produced almost complete abrogation of lysis of H-2-compatible cells infected with an influenza A virus of a subtype which differed from that used to elicit the cytotoxic T cells. However, the antibody did not significantly block 51Cr release from cells infected with the homotypic type A influenza virus. These observations are in accord with the hypothesis that the cross-reactive cytotoxic T-cell responses seen with cells infected by heterotypic influenza A viruses are due to recognition of a common M protein.

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