Discovery of New Ginsenol-like Compounds with High Antiviral Activity

A number of framework amides with a ginsenol backbone have been synthesized using the Ritter reaction. We named the acetamide as Ginsamide. A method was developed for the synthesis of the corresponding amine and thioacetamide. The new compounds revealed a high activity against H1N1 influenza, which was confirmed using an animal model. Biological experiments were performed to determine the mechanism of action of the new agents, a ginsamide-resistant strain of influenza virus was obtained, and the pathogenicity of the resistant strain and the control strain was studied. It was shown that the emergence of resistance to Ginsamide was accompanied by a reduction in the pathogenicity of the influenza virus.

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The mechanism of resistance to favipiravir in influenza

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1811345115 ◽

2018 ◽

Vol 115 (45) ◽

pp. 11613-11618 ◽

Cited By ~ 87

Author(s):

Daniel H. Goldhill ◽

Aartjan J. W. te Velthuis ◽

Robert A. Fletcher ◽

Pinky Langat ◽

Maria Zambon ◽

...

Keyword(s):

Influenza Virus ◽

Influenza A Virus ◽

Influenza A ◽

H1n1 Influenza ◽

Viral Fitness ◽

Virus Infections ◽

Virus Rna ◽

Evolution Of Resistance ◽

Emergence Of Resistance

Favipiravir is a broad-spectrum antiviral that has shown promise in treatment of influenza virus infections. While emergence of resistance has been observed for many antiinfluenza drugs, to date, clinical trials and laboratory studies of favipiravir have not yielded resistant viruses. Here we show evolution of resistance to favipiravir in the pandemic H1N1 influenza A virus in a laboratory setting. We found that two mutations were required for robust resistance to favipiravir. We demonstrate that a K229R mutation in motif F of the PB1 subunit of the influenza virus RNA-dependent RNA polymerase (RdRP) confers resistance to favipiravir in vitro and in cell culture. This mutation has a cost to viral fitness, but fitness can be restored by a P653L mutation in the PA subunit of the polymerase. K229R also conferred favipiravir resistance to RNA polymerases of other influenza A virus strains, and its location within a highly conserved structural feature of the RdRP suggests that other RNA viruses might also acquire resistance through mutations in motif F. The mutations identified here could be used to screen influenza virus-infected patients treated with favipiravir for the emergence of resistance.

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Swine Influenza H1N1 Virus Induces Acute Inflammatory Immune Responses in Pig Lungs: a Potential Animal Model for Human H1N1 Influenza Virus

Journal of Virology ◽

10.1128/jvi.01211-10 ◽

2010 ◽

Vol 84 (21) ◽

pp. 11210-11218 ◽

Cited By ~ 92

Author(s):

Mahesh Khatri ◽

Varun Dwivedi ◽

Steven Krakowka ◽

Cordelia Manickam ◽

Ahmed Ali ◽

...

Keyword(s):

Animal Model ◽

T Cells ◽

Influenza Virus ◽

Immune Responses ◽

Swine Influenza ◽

H1n1 Influenza ◽

Influenza Viruses ◽

Nasal Discharge ◽

Pandemic H1n1 ◽

H1n1 Influenza Virus

ABSTRACT Pigs are capable of generating reassortant influenza viruses of pandemic potential, as both the avian and mammalian influenza viruses can infect pig epithelial cells in the respiratory tract. The source of the current influenza pandemic is H1N1 influenza A virus, possibly of swine origin. This study was conducted to understand better the pathogenesis of H1N1 influenza virus and associated host mucosal immune responses during acute infection in humans. Therefore, we chose a H1N1 swine influenza virus, Sw/OH/24366/07 (SwIV), which has a history of transmission to humans. Clinically, inoculated pigs had nasal discharge and fever and shed virus through nasal secretions. Like pandemic H1N1, SwIV also replicated extensively in both the upper and lower respiratory tracts, and lung lesions were typical of H1N1 infection. We detected innate, proinflammatory, Th1, Th2, and Th3 cytokines, as well as SwIV-specific IgA antibody in lungs of the virus-inoculated pigs. Production of IFN-γ by lymphocytes of the tracheobronchial lymph nodes was also detected. Higher frequencies of cytotoxic T lymphocytes, γδ T cells, dendritic cells, activated T cells, and CD4+ and CD8+ T cells were detected in SwIV-infected pig lungs. Concomitantly, higher frequencies of the immunosuppressive T regulatory cells were also detected in the virus-infected pig lungs. The findings of this study have relevance to pathogenesis of the pandemic H1N1 influenza virus in humans; thus, pigs may serve as a useful animal model to design and test effective mucosal vaccines and therapeutics against influenza virus.

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Faculty Opinions recommendation of Pregnancy-Related Immune Adaptation Promotes the Emergence of Highly Virulent H1N1 Influenza Virus Strains in Allogenically Pregnant Mice.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.727388657.793541863 ◽

2018 ◽

Author(s):

Shabir Madhi

Keyword(s):

Influenza Virus ◽

H1n1 Influenza ◽

H1n1 Influenza Virus ◽

Pregnant Mice ◽

Virus Strains ◽

Highly Virulent

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Therapeutic p28 peptide targets essential H1N1 influenza virus proteins: insights from docking and molecular dynamics simulations

Molecular Diversity ◽

10.1007/s11030-021-10193-8 ◽

2021 ◽

Author(s):

Santanu Sasidharan ◽

Vijayakumar Gosu ◽

Donghyun Shin ◽

Subhradip Nath ◽

Timir Tripathi ◽

...

Keyword(s):

Molecular Dynamics ◽

Influenza Virus ◽

Molecular Dynamics Simulations ◽

H1n1 Influenza ◽

H1n1 Influenza Virus ◽

Dynamics Simulations ◽

Virus Proteins

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Sequential Seasonal H1N1 Influenza Virus Infections Protect Ferrets against Novel 2009 H1N1 Influenza Virus

Journal of Virology ◽

10.1128/jvi.02257-12 ◽

2012 ◽

Vol 87 (3) ◽

pp. 1400-1410 ◽

Cited By ~ 45

Author(s):

Donald M. Carter ◽

Chalise E. Bloom ◽

Eduardo J. M. Nascimento ◽

Ernesto T. A. Marques ◽

Jodi K. Craigo ◽

...

Keyword(s):

Influenza Virus ◽

H1n1 Influenza ◽

Cross Reactivity ◽

Influenza Viruses ◽

The Novel ◽

Virus Infections ◽

H1n1 Influenza Virus ◽

Virus Shedding ◽

2009 H1n1 ◽

Novel H1n1 Influenza

ABSTRACTIndividuals <60 years of age had the lowest incidence of infection, with ∼25% of these people having preexisting, cross-reactive antibodies to novel 2009 H1N1 influenza. Many people >60 years old also had preexisting antibodies to novel H1N1. These observations are puzzling because the seasonal H1N1 viruses circulating during the last 60 years were not antigenically similar to novel H1N1. We therefore hypothesized that a sequence of exposures to antigenically different seasonal H1N1 viruses can elicit an antibody response that protects against novel 2009 H1N1. Ferrets were preinfected with seasonal H1N1 viruses and assessed for cross-reactive antibodies to novel H1N1. Serum from infected ferrets was assayed for cross-reactivity to both seasonal and novel 2009 H1N1 strains. These results were compared to those of ferrets that were sequentially infected with H1N1 viruses isolated prior to 1957 or more-recently isolated viruses. Following seroconversion, ferrets were challenged with novel H1N1 influenza virus and assessed for viral titers in the nasal wash, morbidity, and mortality. There was no hemagglutination inhibition (HAI) cross-reactivity in ferrets infected with any single seasonal H1N1 influenza viruses, with limited protection to challenge. However, sequential H1N1 influenza infections reduced the incidence of disease and elicited cross-reactive antibodies to novel H1N1 isolates. The amount and duration of virus shedding and the frequency of transmission following novel H1N1 challenge were reduced. Exposure to multiple seasonal H1N1 influenza viruses, and not to any single H1N1 influenza virus, elicits a breadth of antibodies that neutralize novel H1N1 even though the host was never exposed to the novel H1N1 influenza viruses.

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Potential impact of biocide adaptation on selection of antibiotic resistance in bacterial isolates

Future Journal of Pharmaceutical Sciences ◽

10.1186/s43094-020-00119-w ◽

2020 ◽

Vol 6 (1) ◽

Author(s):

Engy Elekhnawy ◽

Fatma Sonbol ◽

Ahmed Abdelaziz ◽

Tarek Elbanna

Keyword(s):

Antibiotic Resistance ◽

Cross Resistance ◽

Main Body ◽

Bacterial Isolates ◽

New Agents ◽

Biocidal Products ◽

Potential Impact ◽

Emergence Of Resistance ◽

Vital Factor ◽

Selection Of

Abstract Background Antibiotic resistance in pathogenic bacterial isolates has increased worldwide leading to treatment failures. Main body Many concerns are being raised about the usage of biocidal products (including disinfectants, antiseptics, and preservatives) as a vital factor that contributes to the risk of development of antimicrobial resistance which has many environmental and economic impacts. Conclusion Consequently, it is important to recognize the different types of currently used biocides, their mechanisms of action, and their potential impact to develop cross-resistance and co-resistance to various antibiotics. The use of biocides in medical or industrial purposes should be monitored and regulated. In addition, new agents with biocidal activity should be investigated from new sources like phytochemicals in order to decrease the emergence of resistance among bacterial isolates.

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Next Generation of Computationally Optimized Broadly Reactive HA Vaccines Elicited Cross-Reactive Immune Responses and Provided Protection against H1N1 Virus Infection

Vaccines ◽

10.3390/vaccines9070793 ◽

2021 ◽

Vol 9 (7) ◽

pp. 793

Author(s):

Ying Huang ◽

Monique S. França ◽

James D. Allen ◽

Hua Shi ◽

Ted M. Ross

Keyword(s):

Influenza Virus ◽

Virus Infection ◽

Immune Responses ◽

H1n1 Virus ◽

Influenza Virus Infection ◽

H1n1 Influenza ◽

Influenza Viruses ◽

Next Generation ◽

Wild Type ◽

Influenza A H1n1

Vaccination is the best way to prevent influenza virus infections, but the diversity of antigenically distinct isolates is a persistent challenge for vaccine development. In order to conquer the antigenic variability and improve influenza virus vaccine efficacy, our research group has developed computationally optimized broadly reactive antigens (COBRAs) in the form of recombinant hemagglutinins (rHAs) to elicit broader immune responses. However, previous COBRA H1N1 vaccines do not elicit immune responses that neutralize H1N1 virus strains in circulation during the recent years. In order to update our COBRA vaccine, two new candidate COBRA HA vaccines, Y2 and Y4, were generated using a new seasonal-based COBRA methodology derived from H1N1 isolates that circulated during 2013–2019. In this study, the effectiveness of COBRA Y2 and Y4 vaccines were evaluated in mice, and the elicited immune responses were compared to those generated by historical H1 COBRA HA and wild-type H1N1 HA vaccines. Mice vaccinated with the next generation COBRA HA vaccines effectively protected against morbidity and mortality after infection with H1N1 influenza viruses. The antibodies elicited by the COBRA HA vaccines were highly cross-reactive with influenza A (H1N1) pdm09-like viruses isolated from 2009 to 2021, especially with the most recent circulating viruses from 2019 to 2021. Furthermore, viral loads in lungs of mice vaccinated with Y2 and Y4 were dramatically reduced to low or undetectable levels, resulting in minimal lung injury compared to wild-type HA vaccines following H1N1 influenza virus infection.

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