Organic synthesis and anti-influenza A virus activity of cyclobakuchiols A, B, C, and D

Novel antiviral agents for influenza, which poses a substantial threat to humans, are required. Cyclobakuchiols A and B have been isolated from Psoralea glandulosa, and cyclobakuchiol C has been isolated from P. corylifolia. The structural differences between cyclobakuchiol A and C arise due to the oxidation state of isopropyl group, and these compounds can be derived from (+)-(S)-bakuchiol, a phenolic isoprenoid compound present in P. corylifolia seeds. We previously reported that bakuchiol induces enantiospecific anti-influenza A virus activity involving nuclear factor erythroid 2-related factor 2 (Nrf2) activation. However, it remains unclear whether cyclobakuchiols A–C induce anti-influenza A virus activity. In this study, cyclobakuchiols A, B, and C along with cyclobakuchiol D, a new artificial compound derived from cyclobakuchiol B, were synthesized and examined for their anti-influenza A virus activities using Madin-Darby canine kidney cells. As a result, cyclobakuchiols A–D were found to inhibit influenza A viral infection, growth, and the reduction of expression of viral mRNAs and proteins in influenza A virus-infected cells. Additionally, these compounds markedly reduced the mRNA expression of the host cell influenza A virus-induced immune response genes, interferon-β and myxovirus-resistant protein 1. In addition, cyclobakuchiols A–D upregulated the mRNA levels of NAD(P)H quinone oxidoreductase 1, an Nrf2-induced gene, in influenza A virus-infected cells. Notably, cyclobakuchiols A, B, and C, but not D, induced the Nrf2 activation pathway. These findings demonstrate that cyclobakuchiols have anti-influenza viral activity involving host cell oxidative stress response. In addition, our results suggest that the suitably spatial configuration between oxidized isopropyl group and phenol moiety in the structure of cyclobakuchiols is required for their effect.

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Bakuchiol Is a Phenolic Isoprenoid with Novel Enantiomer-selective Anti-influenza A Virus Activity Involving Nrf2 Activation

Journal of Biological Chemistry ◽

10.1074/jbc.m115.669465 ◽

2015 ◽

Vol 290 (46) ◽

pp. 28001-28017 ◽

Cited By ~ 22

Author(s):

Masaki Shoji ◽

Yumie Arakaki ◽

Tomoyuki Esumi ◽

Shuntaro Kohnomi ◽

Chihiro Yamamoto ◽

...

Keyword(s):

Influenza A Virus ◽

Influenza A ◽

Virus Activity ◽

Nrf2 Activation

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Discovery of the anti-influenza A virus activity of SB216763 and cyclosporine A by mining infected cells and compound cellular signatures

Chinese Chemical Letters ◽

10.1016/j.cclet.2021.09.017 ◽

2021 ◽

Author(s):

Ke Tang ◽

You Wu ◽

Shubing Chen ◽

Yijing Xin ◽

Ying Guo

Keyword(s):

Influenza A Virus ◽

Cyclosporine A ◽

Influenza A ◽

Virus Activity ◽

Infected Cells

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Dicer is involved in protection against influenza A virus infection

Journal of General Virology ◽

10.1099/vir.0.83103-0 ◽

2007 ◽

Vol 88 (10) ◽

pp. 2627-2635 ◽

Cited By ~ 80

Author(s):

Alexey A. Matskevich ◽

Karin Moelling

Keyword(s):

Virus Infection ◽

Influenza A Virus ◽

Mammalian Cells ◽

Influenza A ◽

Virus Production ◽

Vero Cells ◽

Antiviral Response ◽

Protein Levels ◽

Infected Cells ◽

Influenza A Virus Infection

In mammals the interferon (IFN) system is a central innate antiviral defence mechanism, while the involvement of RNA interference (RNAi) in antiviral response against RNA viruses is uncertain. Here, we tested whether RNAi is involved in the antiviral response in mammalian cells. To investigate the role of RNAi in influenza A virus-infected cells in the absence of IFN, we used Vero cells that lack IFN-α and IFN-β genes. Our results demonstrate that knockdown of a key RNAi component, Dicer, led to a modest increase of virus production and accelerated apoptosis of influenza A virus-infected cells. These effects were much weaker in the presence of IFN. The results also show that in both Vero cells and the IFN-producing alveolar epithelial A549 cell line influenza A virus targets Dicer at mRNA and protein levels. Thus, RNAi is involved in antiviral response, and Dicer is important for protection against influenza A virus infection.

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Influenza A Virus Replication Induces Cell Cycle Arrest in G0/G1 Phase

Journal of Virology ◽

10.1128/jvi.01216-10 ◽

2010 ◽

Vol 84 (24) ◽

pp. 12832-12840 ◽

Cited By ~ 85

Author(s):

Yuan He ◽

Ke Xu ◽

Bjoern Keiner ◽

Jianfang Zhou ◽

Volker Czudai ◽

...

Keyword(s):

Cell Cycle ◽

Cell Cycle Arrest ◽

Influenza A Virus ◽

Influenza A ◽

Cell Cycle Progression ◽

Virus Production ◽

Phase Cell ◽

Cycle Progression ◽

Cycle Arrest ◽

Infected Cells

ABSTRACT Many viruses interact with the host cell division cycle to favor their own growth. In this study, we examined the ability of influenza A virus to manipulate cell cycle progression. Our results show that influenza A virus A/WSN/33 (H1N1) replication results in G0/G1-phase accumulation of infected cells and that this accumulation is caused by the prevention of cell cycle entry from G0/G1 phase into S phase. Consistent with the G0/G1-phase accumulation, the amount of hyperphosphorylated retinoblastoma protein, a necessary active form for cell cycle progression through late G1 into S phase, decreased after infection with A/WSN/33 (H1N1) virus. In addition, other key molecules in the regulation of the cell cycle, such as p21, cyclin E, and cyclin D1, were also changed and showed a pattern of G0/G1-phase cell cycle arrest. It is interesting that increased viral protein expression and progeny virus production in cells synchronized in the G0/G1 phase were observed compared to those in either unsynchronized cells or cells synchronized in the G2/M phase. G0/G1-phase cell cycle arrest is likely a common strategy, since the effect was also observed in other strains, such as H3N2, H9N2, PR8 H1N1, and pandemic swine H1N1 viruses. These findings, in all, suggest that influenza A virus may provide favorable conditions for viral protein accumulation and virus production by inducing a G0/G1-phase cell cycle arrest in infected cells.

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Type I IFN Triggers RIG-I/TLR3/NLRP3-dependent Inflammasome Activation in Influenza A Virus Infected Cells

PLoS Pathogens ◽

10.1371/journal.ppat.1003256 ◽

2013 ◽

Vol 9 (4) ◽

pp. e1003256 ◽

Cited By ~ 124

Author(s):

Julien Pothlichet ◽

Isabelle Meunier ◽

Beckley K. Davis ◽

Jenny P-Y. Ting ◽

Emil Skamene ◽

...

Keyword(s):

Influenza A Virus ◽

Influenza A ◽

Inflammasome Activation ◽

Type I ◽

Type I Ifn ◽

Infected Cells

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Amphotericin b effect on the sensitivity to influenza infection of WI-38 VA-13 cells with IFITM3 gene knockout

Medical academic journal ◽

10.17816/maj76106 ◽

2021 ◽

Vol 21 (3) ◽

pp. 109-112

Author(s):

Kira S. Koryabina ◽

Mariya V. Sergeeva ◽

Andrey B. Komissarov ◽

Nataliya V. Eshchenko ◽

Grigoriy A. Stepanov

Keyword(s):

Amphotericin B ◽

Influenza A Virus ◽

Influenza A ◽

Gene Knockout ◽

Influenza Infection ◽

Restriction Factors ◽

Host Restriction ◽

Host Restriction Factors ◽

Infected Cells ◽

The Difference

BACKGROUND: The application of CRISPR/Cas9 is one of the most rapidly developing areas in biotechnology. This method was used to obtain clones of а human origin cell line with knockout of one or more genes of the IFITM family, representing host restriction factors for influenza infection. Amphotericin B has previously been shown to promote influenza infection by blocking IFITM3 function. AIM: The aim of this study was to evaluate the effect of amphotericin B on the sensitivity of IFITM knockout cells to influenza A virus infection. MATERIALS AND METHODS: WI-38 VA-13 cells and mutant clones with IFITM3 knockout (F3 clone) or IFITM1, IFITM3 knockout (clone E12) were infected with influenza virus A/PR/8/34 (H1N1) in the presence or absence of amphotericin B. Forty-four hours after infection, the culture medium was taken to determine the infectious activity of the virus by titration in the MDCK cell culture, as well as the hemagglutinating activity of the virus. The infected cells were stained with fluorescently labeled antibodies against the viral NP protein, and the number of NP-positive cells was determined by flow cytometry. RESULTS: The addition of amphotericin B increased the hemagglutinating and infectious activity of the virus in WI-38 VA-13cells, while the difference was insignificant for clones with IFITM gene knockout. A similar dependency was obtained for the percent of infected cells. CONCLUSIONS: Mutant cells with a knockout of one or several genes of the IFITM family were equally susceptible to influenza infection regardless of the addition of amphotericin B, which confirms the crucial importance of a defect in the IFITM3 protein in increasing the permissiveness of cells to influenza A virus.

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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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Suppression of influenza A virus replication in human lung epithelial cells by noncytotoxic concentrations bafilomycin A1

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00011.2014 ◽

2015 ◽

Vol 308 (3) ◽

pp. L270-L286 ◽

Cited By ~ 46

Author(s):

Behzad Yeganeh ◽

Saeid Ghavami ◽

Andrea L. Kroeker ◽

Thomas H. Mahood ◽

Gerald L. Stelmack ◽

...

Keyword(s):

Epithelial Cells ◽

Host Cell ◽

Influenza A Virus ◽

Influenza A ◽

Life Cycles ◽

Host Cells ◽

Nuclear Accumulation ◽

Low Concentration ◽

High Concentrations ◽

The Impact

Subcellular trafficking within host cells plays a critical role in viral life cycles, including influenza A virus (IAV). Thus targeting relevant subcellular compartments holds promise for effective intervention to control the impact of influenza infection. Bafilomycin A1(Baf-A1), when used at relative high concentrations (≥10 nM), inhibits vacuolar ATPase (V-ATPase) and reduces endosome acidification and lysosome number, thus inhibiting IAV replication but promoting host cell cytotoxicity. We tested the hypothesis that much lower doses of Baf-A1also have anti-IAV activity, but without toxic effects. Thus we assessed the antiviral activity of Baf-A1at different concentrations (0.1–100 nM) in human alveolar epithelial cells (A549) infected with IAV strain A/PR/8/34 virus (H1N1). Infected and mock-infected cells pre- and cotreated with Baf-A1were harvested 0–24 h postinfection and analyzed by immunoblotting, immunofluorescence, and confocal and electron microscopy. We found that Baf-A1had disparate concentration-dependent effects on subcellular organelles and suppressed affected IAV replication. At concentrations ≥10 nM Baf-A1inhibited acid lysosome formation, which resulted in greatly reduced IAV replication and release. Notably, at a very low concentration of 0.1 nM that is insufficient to reduce lysosome number, Baf-A1retained the capacity to significantly impair IAV nuclear accumulation as well as IAV replication and release. In contrast to the effects of high concentrations of Baf-A1, very low concentrations did not exhibit cytotoxic effects or induce apoptotic cell death, based on morphological and FACS analyses. In conclusion, our results reveal that low-concentration Baf-A1is an effective inhibitor of IAV replication, without impacting host cell viability.

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