scholarly journals Antiviral Activity of Isoquinolone Derivatives against Influenza Viruses and Their Cytotoxicity

2021 ◽  
Vol 14 (7) ◽  
pp. 650
Author(s):  
Yejin Jang ◽  
Jinhe Han ◽  
Xiaoli Li ◽  
Hyunjin Shin ◽  
Won-Jea Cho ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Influenza A ◽  
Viral Infections ◽  
Respiratory Infections ◽  
Polymerase Activity ◽  
Influenza Viruses ◽  
Viral Polymerase ◽  
Chemical Library ◽  
Design And Synthesis ◽  
Chemical Derivatives

Influenza viruses are one of the major causative agents for human respiratory infections. Currently, vaccines and antivirals approved for preventing and treating viral infections are available. However, limited protection efficacy and frequent emergence of drug-resistant viruses stand for a need for the development of antivirals with different chemical skeletons from existing drugs. Screening of a chemical library identified an isoquinolone compound (1) as a hit with 50% effective concentrations (EC50s) between 0.2 and 0.6 µM against the influenza A and B viruses. However, it exhibited severe cytotoxic effects with a 50% cytotoxic concentration (CC50) of 39.0 µM in canine kidney epithelial cells. To address this cytotoxic issue, we synthesized an additional 22 chemical derivatives. Through structure-activity, as well as structure-cytotoxicity relationship studies, we discovered compound 21 that has higher EC50 values ranging from 9.9 to 18.5 µM, but greatly alleviated cytotoxicity with a CC50 value over 300 µM. Mode-of-action and cell type-dependent antiviral experiments indicated that it targets viral polymerase activity and functions also in human cells. Here, we present a new class of viral polymerase inhibitors with a core skeleton of isoquinolone, of which antiviral activity could be better improved through following design and synthesis of its derivatives for drug development.

scholarly journals Identification and Characterization of Novel Compounds with Broad-Spectrum Antiviral Activity against Influenza A and B Viruses

2020 ◽  
Vol 94 (7) ◽  
Author(s):  
Jun-Gyu Park ◽  
Ginés Ávila-Pérez ◽  
Aitor Nogales ◽  
Pilar Blanco-Lobo ◽  
Juan C. de la Torre ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Rna Polymerase Ii ◽  
Broad Spectrum ◽  
Influenza A ◽  
Viral Infections ◽  
Influenza Infection ◽  
Inhibitory Effect ◽  
Influenza Viruses ◽  
Influenza B ◽  
Genome Replication

ABSTRACT Influenza A (IAV) and influenza B (IBV) viruses are highly contagious pathogens that cause fatal respiratory disease every year, with high economic impact. In addition, IAV can cause pandemic infections with great consequences when new viruses are introduced into humans. In this study, we evaluated 10 previously described compounds with antiviral activity against mammarenaviruses for their ability to inhibit IAV infection using our recently described bireporter influenza A/Puerto Rico/8/34 (PR8) H1N1 (BIRFLU). Among the 10 tested compounds, eight (antimycin A [AmA], brequinar [BRQ], 6-azauridine, azaribine, pyrazofurin [PF], AVN-944, mycophenolate mofetil [MMF], and mycophenolic acid [MPA]), but not obatoclax or Osu-03012, showed potent anti-influenza virus activity under posttreatment conditions [median 50% effective concentration (EC50) = 3.80 nM to 1.73 μM; selective index SI for 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay, >28.90 to 13,157.89]. AmA, 6-azauridine, azaribine, and PF also showed potent inhibitory effect in pretreatment (EC50 = 0.14 μM to 0.55 μM; SI-MTT = 70.12 to >357.14) or cotreatment (EC50 = 34.69 nM to 7.52 μM; SI-MTT = 5.24 to > 1,441.33) settings. All of the compounds tested inhibited viral genome replication and gene transcription, and none of them affected host cellular RNA polymerase II activities. The antiviral activity of the eight identified compounds against BIRFLU was further confirmed with seasonal IAVs (A/California/04/2009 H1N1 and A/Wyoming/3/2003 H3N2) and an IBV (B/Brisbane/60/2008, Victoria lineage), demonstrating their broad-spectrum prophylactic and therapeutic activity against currently circulating influenza viruses in humans. Together, our results identified a new set of antiviral compounds for the potential treatment of influenza viral infections. IMPORTANCE Influenza viruses are highly contagious pathogens and are a major threat to human health. Vaccination remains the most effective tool to protect humans against influenza infection. However, vaccination does not always guarantee complete protection against drifted or, more noticeably, shifted influenza viruses. Although U.S. Food and Drug Administration (FDA) drugs are approved for the treatment of influenza infections, influenza viruses resistant to current FDA antivirals have been reported and continue to emerge. Therefore, there is an urgent need to find novel antivirals for the treatment of influenza viral infections in humans, a search that could be expedited by repurposing currently approved drugs. In this study, we assessed the influenza antiviral activity of 10 compounds previously shown to inhibit mammarenavirus infection. Among them, eight drugs showed antiviral activities, providing a new battery of drugs that could be used for the treatment of influenza infections.

scholarly journals Antiviral Activity of Chrysin against Influenza Virus Replication via Inhibition of Autophagy

Viruses ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1350
Author(s):  
Seong-Ryeol Kim ◽  
Myeong-Seon Jeong ◽  
Seo-Hyeon Mun ◽  
Jaewon Cho ◽  
Min-Duk Seo ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Influenza A ◽  
Time Course ◽  
Respiratory Infections ◽  
A549 Cells ◽  
Enterovirus 71 ◽  
Influenza Viruses ◽  
High Morbidity ◽  
Early Stages ◽  
Infected Cells

Influenza viruses cause respiratory infections in humans and animals, which have high morbidity and mortality rates. Although several drugs that inhibit viral neuraminidase are used to treat influenza infections, the emergence of resistant viruses necessitates the urgent development of new antiviral drugs. Chrysin (5,7-dihydroxyflavone) is a natural flavonoid that exhibits antiviral activity against enterovirus 71 (EV71) by inhibiting viral 3C protease activity. In this study, we evaluated the antiviral activity of chrysin against influenza A/Puerto Rico/8/34 (A/PR/8). Chrysin significantly inhibited A/PR/8-mediated cell death and the replication of A/PR/8 at concentrations up to 2 mM. Viral hemagglutinin expression was also markedly decreased by the chrysin treatment in A/PR/8-infected cells. Through the time course experiment and time-of-addition assay, we found that chrysin inhibited viral infection at the early stages of the replication cycle. Additionally, the nucleoprotein expression of A/PR/8 in A549 cells was reduced upon treatment with chrysin. Regarding the mechanism of action, we found that chrysin inhibited autophagy activation by increasing the phosphorylation of mammalian target of rapamycin (mTOR). We also confirmed a decrease in LC3B expression and LC3-positive puncta levels in A/PR/8-infected cells. These results suggest that chrysin exhibits antiviral activity by activating mTOR and inhibiting autophagy to inhibit the replication of A/PR/8 in the early stages of infection.

scholarly journals MICROBIOLOGICAL DIAGNOSIS AND IMPORTANCE OF INFECTIONS CAUSED BY INFLENZAE – А VIRUS

2019 ◽  
Vol 31 (4) ◽  
pp. 1057-1061
Author(s):  
Zivadinka Cvetanovska ◽  
Vaso Taleski
Keyword(s):  
Influenza A ◽  
Viral Infections ◽  
Respiratory Infections ◽  
Great Influence ◽  
Influenza Viruses ◽  
Influenza B ◽  
Number Of Patients ◽  
Viral Respiratory Infections ◽  
Subtype A

Influenza is one of the commonest acute viral respiratory infections with a great potential for spreading as an epidemic or pandemic appearance. Until 2009 relevant data about types and subtypes of influenza viruses circulated in Republic of Macedonia, did not exist. Since pandemic in 2009, molecular method RT-PCR was introduced real time detection of types and subtypes of influenza viruses, which enabled continuously and accurate follow up. Flu differ in types and subtypes presence in each new season, with great influence on number of patients and deaths caused by influenza viral infections. In season 2009/2010 - type Influenza A dominated, subtype A (H1N1) pdm. Total number of 54.343 cases were registered and 30 deaths. In season 2010/2011 – co-circulated types of Influenza A and Influenza B, with small domination of subtype A (H1N1) pdm. Total number of 27.635 cases were registered and 17 deaths. In season 2011/2012 - dominant was type Influenza A, subtype A (H3N2). Total number of 9.732 cases were registered and only one case of death. In season 2012/2013 - co-circulated types of Influenza A and Influenza B, with domination of subtype A (H1N1) pdm. Total number of 24.524 were registered, no deaths. In season 2013/2014 - co-circulated types of Influenza A and Influenza B, with domination of subtype A (H3N2). Total number of 29.074 were registered and 12 deaths. In season 2014/2015 - dominant was type Influenza B, and also Influenza A subtype A(H3N2) circulated. Total number of reported cases was 33.228, no deaths. In season 2015/2016 - Influenza A, subtype A(H1N1) pdm was dominant. During same period, type Influenza B, subtype Victoria was detected as well. Total number of reported cases was 29.094 and 2 deaths. In season 2016/2017 - type Influenza A, subtype A/H3, was dominant. Total number of reported cases was 35.079 and 2 deaths. In season 2017/2018 година – simultaneously circulation of types Influenza А and Influenza B, with domination of lineage B/Yamagata. Total number of 23.954 cases were registered, no deaths. In season 2018/2019 - highest number of cases were caused by type Influenza A subtype A(H1) pdm, in co-circulation with Influenza А(H3). Total number of reported cases was 21.404 and 29 deaths, that present the highest number of deaths in correlation with number of diseased.

Etiology of severe acute respiratory infections in Ekaterinburg in different epidemic seasons

2021 ◽  
Vol 21 (3) ◽  
pp. 123-126
Author(s):  
Evgeniya Viktorovna Lelenkova ◽  
Alexandr Yurievich Markaryan
Keyword(s):  
Influenza A ◽  
Viral Infections ◽  
Respiratory Infections ◽  
Respiratory Viruses ◽  
Influenza Viruses ◽  
Hospital Treatment ◽  
Acute Respiratory Infections ◽  
Severe Acute Respiratory Infection ◽  
Hospital Patients ◽  
Severe Acute Respiratory Infections

BACKGROUND: Acute respiratory viral infections are ubiquitous. Part of the cases are severe and require hospital treatment. AIM: Studying the etiology of severe acute respiratory infections in patients of Ekaterinburg hospitals in different epidemic seasons (from 2017 to 2020). MATERIALS AND METHODS: 1,132 cases of severe acute respiratory infection were assessed. The structure of laboratory-confirmed cases was determined. RESULTS: In the assessed seasons, the proportion of respiratory viruses in the etiological structure of severe acute respiratory infections was 56.0% on average. B/Yamagata lineage of influenza viruses was predominant in the season of 2017/2018 (23.9% from the total number of respiratory viruses), influenza А (H1N1)pdm09 viruses were predominant in the season of 2018/2019 (27.7%), and influenza A and B viruses were identified in 2019/2020 (39.4% and 31.7%, respectively). СONCLUSIONS: The obtained results confirm a key role of influenza viruses in the etiology of severe acute respiratory infections among the hospital patients in different epidemic seasons.

scholarly journals The role of influenza viruses in the development of severe acute respiratory infection in patients admitted to Yekaterinburg hospitals during 2017–2018 epidemic season

2020 ◽  
Vol 97 (2) ◽  
pp. 140-149
Author(s):  
Aleksandr V. Alimov ◽  
Svetlana S. Smirnova ◽  
Evgenia V. Lelenkova ◽  
Aleksandr Yu. Markaryan ◽  
Ivan V. Vyalykh ◽  
...  
Keyword(s):  
Influenza A ◽  
Viral Infections ◽  
Respiratory Infections ◽  
Influenza Viruses ◽  
Clinical Samples ◽  
Influenza B ◽  
Amino Acid Substitutions ◽  
Epidemic Season ◽  
Respiratory Viral Infections

Objective. To study the role of influenza viruses in the development of severe acute respiratory infections (SARI) in patients admitted to Yekaterinburg hospitals during 2017-2018 epidemic season.Materials and Methods. A retrospective epidemiological analysis of influenza incidence in Yekaterinburg was conducted, 403 influenza and acute respiratory viral infections case sheets were studied, and PCR analysis of clinical samples from the patients for respiratory viral infections was performed.Results. During the epidemic period a total 27.0% of the Yekaterinburg population were reported with influenza and other SARI, with 1.8% patients hospitalized. 5.6% of the total number of patients admitted with influenza and SARI in Yekaterinburg hospitals were included in the study. The rate of the detection of influenza A and B viruses RNA in the clinical samples from the patients with SARI was 28.3%. The rates of the detection in PCR of influenza B/Yamagata, A(H1N1)pdm09 and A(H3N2) were 46.5, 20.2 and 10.5%, respectively.Conclusion. The study results indicated that influenza viruses remain significant pathogens of respiratory infections that required hospitalization. Among patients with SARI the highest incidence was observed in children of a younger age group and was mainly associated with influenza B virus of Yamagata lineage and influenza A virus (H1N1)pdm09. According to the results of a molecular genetic study, influenza A (H1N1) pdm09 viruses belonged to clade 6B.1, carried characteristic amino acid substitutions in hemagglutinin S84N, S162N (with the acquisition of a potential glycosylation site) and I216T and were similar to the A/Michigan/45/2015 vaccine strain. The influenza B viruses studied belonged to the Yamagata lineage, clade 3. The influenza B/Ekaterinburg /RII-4723S/2018 virus differed from the reference strain B/Phuket/3073/2013 by two amino acid substitutions in the hemagglutinin gene M251V and L172Q.

scholarly journals Evolution and Adaptation of the Avian H7N9 Virus into the Human Host

2020 ◽  
Vol 8 (5) ◽  
pp. 778
Author(s):  
Andrew T. Bisset ◽  
Gerard F. Hoyne
Keyword(s):  
Amino Acid ◽  
Avian Influenza ◽  
Influenza A ◽  
Amino Acid Sequences ◽  
Influenza Viruses ◽  
Amino Acid Substitutions ◽  
Upper Respiratory Tract ◽  
Viral Polymerase ◽  
Evolutionary Changes ◽  
Avian Origin

Influenza viruses arise from animal reservoirs, and have the potential to cause pandemics. In 2013, low pathogenic novel avian influenza A(H7N9) viruses emerged in China, resulting from the reassortment of avian-origin viruses. Following evolutionary changes, highly pathogenic strains of avian influenza A(H7N9) viruses emerged in late 2016. Changes in pathogenicity and virulence of H7N9 viruses have been linked to potential mutations in the viral glycoproteins hemagglutinin (HA) and neuraminidase (NA), as well as the viral polymerase basic protein 2 (PB2). Recognizing that effective viral transmission of the influenza A virus (IAV) between humans requires efficient attachment to the upper respiratory tract and replication through the viral polymerase complex, experimental evidence demonstrates the potential H7N9 has for increased binding affinity and replication, following specific amino acid substitutions in HA and PB2. Additionally, the deletion of extended amino acid sequences in the NA stalk length was shown to produce a significant increase in pathogenicity in mice. Research shows that significant changes in transmissibility, pathogenicity and virulence are possible after one or a few amino acid substitutions. This review aims to summarise key findings from that research. To date, all strains of H7N9 viruses remain restricted to avian reservoirs, with no evidence of sustained human-to-human transmission, although mutations in specific viral proteins reveal the efficacy with which these viruses could evolve into a highly virulent and infectious, human-to-human transmitted virus.

scholarly journals Mutations in the PA Protein of Avian H5N1 Influenza Viruses Affect Polymerase Activity and Mouse Virulence

2017 ◽  
pp. JVI.01557-17 ◽  
Author(s):  
Gongxun Zhong ◽  
Mai Quynh Le ◽  
Tiago J.S. Lopes ◽  
Peter Halfmann ◽  
Masato Hatta ◽  
...  
Keyword(s):  
Amino Acid ◽  
Case Fatality ◽  
Polymerase Activity ◽  
Influenza Viruses ◽  
Viral Polymerase ◽  
Highly Pathogenic ◽  
H5n1 Influenza ◽  
Increased Risk ◽  
Severe Infections ◽  
Viral Determinants

To study the influenza viral determinants of pathogenicity, we characterized two highly pathogenic avian H5N1 influenza viruses isolated in Vietnam in 2012 (A/duck/Vietnam/QT1480/2012; QT1480) and 2013 (A/duck/Vietnam/QT1728/2013; QT1728) and found that the activity of their polymerase complexes differed significantly, even though both viruses were highly pathogenic in mice. Further studies revealed that the PA-S343A/E347D mutations reduced viral polymerase activity and mouse virulence when tested in the genetic background of QT1728 virus. In contrast, the PA-343S/347E mutations increased the polymerase activity of QT1480 and the virulence of a low pathogenic H5N1 influenza virus. The PA-343S residue (which alone increased viral polymerase activity and mouse virulence significantly relative to viral replication complexes encoding PA-343A) is frequently found in H5N1 influenza viruses of several subclades; infection with a virus possessing this amino acid may pose an increased risk to humans.IMPORTANCEH5N1 influenza viruses cause severe infections in humans with a case fatality rate that exceeds 50%. The factors that determine the high virulence of these viruses in humans are not fully understood. Here, we identified two amino acid changes in the viral polymerase PA protein that affect the activity of the viral polymerase complex and virulence in mice. Infection with viruses possessing these amino acid changes may pose an increased risk to humans.

scholarly journals Influenza A and B viruses in the population of Vojvodina, Serbia

2014 ◽  
Vol 66 (1) ◽  
pp. 43-50 ◽  
Author(s):  
J. Radovanov ◽  
V. Milosevic ◽  
I. Hrnjakovic ◽  
V. Petrovic ◽  
M. Ristic ◽  
...  
Keyword(s):  
Influenza A ◽  
Respiratory Infections ◽  
Influenza Viruses ◽  
Influenza B Virus ◽  
Nasopharyngeal Swab ◽  
Influenza B ◽  
Influenza A Viruses ◽  
B Virus ◽  
Life Threatening ◽  
Seasonal Epidemic

At present, two influenza A viruses, H1N1pdm09 and H3N2, along with influenza B virus co-circulate in the human population, causing endemic and seasonal epidemic acute febrile respiratory infections, sometimes with life-threatening complications. Detection of influenza viruses in nasopharyngeal swab samples was done by real-time RT-PCR. There were 60.2% (53/88) positive samples in 2010/11, 63.4% (52/82) in 2011/12, and 49.9% (184/369) in 2012/13. Among the positive patients, influenza A viruses were predominant during the first two seasons, while influenza B type was more active during 2012/13. Subtyping of influenza A positive samples revealed the presence of A (H1N1)pdm09 in 2010/11, A (H3N2) in 2011/12, while in 2012/13, both subtypes were detected. The highest seroprevalence against influenza A was in the age-group 30-64, and against influenza B in adults aged 30-64 and >65.

scholarly journals Epidemiology of Respiratory Pathogens among Elderly Nursing Home Residents with Acute Respiratory Infections in Corsica, France, 2013–2017

2017 ◽  
Vol 2017 ◽  
pp. 1-7 ◽  
Author(s):  
Shirley Masse ◽  
Lisandru Capai ◽  
Alessandra Falchi
Keyword(s):  
Nursing Home ◽  
Influenza A ◽  
Respiratory Infections ◽  
Nursing Home Residents ◽  
Respiratory Viruses ◽  
Sudden Onset ◽  
Influenza Viruses ◽  
Influenza B ◽  
Acute Respiratory Infections ◽  
Respiratory Pathogens

Background. The current study aims to describe the demographical and clinical characteristics of elderly nursing home (NH) residents with acute respiratory infections (ARIs) during four winter seasons (2013/2014–2016/2017), as well as the microbiological etiology of these infections. Methods. Seventeen NHs with at least one ARI resident in Corsica, France, were included. An ARI resident was defined as a resident developing a sudden onset of any constitutional symptoms in addition to any respiratory signs. Nasopharyngeal swabs from ARI residents were screened for the presence of 21 respiratory agents, including seasonal influenza viruses. Results. Of the 107 ARI residents enrolled from NHs, 61 (57%) were positive for at least one of the 21 respiratory pathogens. Forty-one (38.3%) of the 107 ARI residents had influenza: 38 (92%) were positive for influenza A (100% A(H3N2)) and three (8%) for influenza B/Victoria. Axillary fever (≥38°C) was significantly more common among patients infected with influenza A(H3N2). Conclusion. The circulation of seasonal respiratory viruses other than influenza A(H3N2) seems to be sporadic among elderly NH residents. Investigating the circulation of respiratory viruses in nonwinter seasons seems to be important in order to understand better the dynamic of their year-round circulation in NHs.

scholarly journals PB2 Residue 271 Plays a Key Role in Enhanced Polymerase Activity of Influenza A Viruses in Mammalian Host Cells

2010 ◽  
Vol 84 (9) ◽  
pp. 4395-4406 ◽  
Author(s):  
Kendra A. Bussey ◽  
Tatiana L. Bousse ◽  
Emily A. Desmet ◽  
Baek Kim ◽  
Toru Takimoto
Keyword(s):  
Mammalian Cells ◽  
Influenza A ◽  
Virus Titer ◽  
Polymerase Activity ◽  
Influenza Viruses ◽  
Host Cells ◽  
Mammalian Host ◽  
Influenza A Viruses ◽  
H5n1 Influenza ◽  
Avian Viruses

ABSTRACT The direct infection of humans with highly pathogenic avian H5N1 influenza viruses has suggested viral mutation as one mechanism for the emergence of novel human influenza A viruses. Although the polymerase complex is known to be a key component in host adaptation, mutations that enhance the polymerase activity of avian viruses in mammalian hosts are not fully characterized. The genomic comparison of influenza A virus isolates has identified highly conserved residues in influenza proteins that are specific to either human or avian viruses, including 10 residues in PB2. We characterized the activity of avian polymerase complexes containing avian-to-human mutations at these conserved PB2 residues and found that, in addition to the E627K mutation, the PB2 mutation T271A enhances polymerase activity in human cells. We confirmed the effects of the T271A mutation using recombinant WSN viruses containing avian NP and polymerase genes with wild-type (WT) or mutant PB2. The 271A virus showed enhanced growth compared to that of the WT in mammalian cells in vitro. The 271A mutant did not increase viral pathogenicity significantly in mice compared to that of the 627K mutant, but it did enhance the lung virus titer. Also, cell infiltration was more evident in lungs of 271A-infected mice than in those of the WT. Interestingly, the avian-derived PB2 of the 2009 pandemic H1N1 influenza virus has 271A. The characterization of the polymerase activity of A/California/04/2009 (H1N1) and corresponding PB2 mutants indicates that the high polymerase activity of the pandemic strain in mammalian cells is, in part, dependent on 271A. Our results clearly indicate the contribution of PB2 amino acid 271 to enhanced polymerase activity and viral growth in mammalian hosts.

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