Sabine Eva Dudek

University of Münster

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Stephan Ludwig

University of Münster

Viktor Wixler

Institute of Molecular Biology

Fernando Durán

University of Buenos Aires

Karen Luise Lang

Universidade Federal de Juiz de Fora

Izabella Thaís Silva

Universidade Federal de Santa Catarina

Christina Ehrhardt

Jena University Hospital

Cláudia Maria Oliveira Simões

Universidade Federal de Santa Catarina

Eloir Paulo Schenkel

Universidade Federal de Santa Catarina

Ludmilla Wixler

University of Münster

Oliver Planz

University of Tübingen

Cooperative Institutions

Institute of Molecular Biology

University of Münster

Universidade Federal de Santa Catarina

University Hospital Münster

Friedrich-Alexander-Universität Erlangen-Nürnberg

Heidelberg University

Charité - Universitätsmedizin Berlin

Institute of Virology of the Slovak Academy of Sciences

Friedrich-Loeffler-Institut

University of Tübingen

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The clinically approved MEK inhibitor Trametinib efficiently blocks influenza A virus propagation and cytokine expression

Antiviral Research (2018)

Tobias Schräder Sabine Eva Dudek André Schreiber Christina Ehrhardt Oliver Planz

Influenza A virus (IAV) infections are still a major global threat for humans, especially for the risk groups of young children and the elderly. Annual epidemics and sporadically occurring pandemics highlight the necessity of effective antivirals that can limit viral replication. The currently licensed antiviral drugs target viral factors and are prone to provoke viral resistance. In infected host cells IAV induces various cellular signaling cascades. The Raf/MEK/ERK signaling cascade is indispensable for IAV replication because it triggers the nuclear export of newly assembled viral ribonucleoproteins (vRNPs). Inhibition of this cascade limits viral replication. Thus, next to their potential in anti-tumor therapy, inhibitors targeting the Raf/MEK/ERK signaling cascade came into focus as potential antiviral drugs. The first licensed MEK inhibitor Trametinib (GSK-1120212) is used for treatment of malignant melanoma, being highly selective and having a promising side effect profile. Since Trametinib may be qualified for a repurposing approach that would significantly shorten development time for an anti-flu use, we evaluated its antiviral potency and mode of action. In this study, we describe that Trametinib efficiently blocks replication of different IAV subtypes in vitro and in vivo. The broad antiviral activity against various IAV strains was due to its ability to interfere with export of progeny vRNPs from the nucleus. The compound also limited hyper-expression of several cytokines. Thus, we show for the first time that a clinically approved MEK inhibitor acts as a potent anti-influenza agent.

Trametinib

10.1016/j.antiviral.2018.07.006

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Pharmacodynamics, Pharmacokinetics, and Antiviral Activity of BAY 81-8781, a Novel NF-κB Inhibiting Anti-influenza Drug

Frontiers in Microbiology (2017)

Karoline Droebner Emanuel Haasbach Sabine Eva Dudek G. Scheuch Karlheinz Nocker

Influenza is a respiratory disease that causes annual epidemics. Antiviral treatment options targeting the virus exist, but their efficiency is limited and influenza virus strains easily develop resistance. Thus, new treatment strategies are urgently needed. In the present study we investigated the anti-influenza virus properties of D,L-lysine acetylsalicylate • glycine (BAY 81-8781; LASAG) that is approved as Aspirin i.v. for intravenous application. Instead of targeting the virus directly BAY 81-8781 inhibits the activation of the NF-B pathway, which is required for efficient influenza virus propagation. Using highly pathogenic avian influenza virus strains we could demonstrate that BAY 81-8781 was able to control influenza virus infection in vitro. In the mouse infection model, inhalation of BAY 81-8781 resulted in reduced lung virus titers and protection of mice from lethal infection. Pharmacological studies demonstrated that the oral route of administration was not suitable to reach the sufficient concentrations of BAY 81-8781 for a successful antiviral effect in the lung. BAY 81-8781 treatment of mice infected with influenza virus started as late as 48 h after infection was still effective in protecting 50% of the animals from death. In summary, the data represent a successful proof of the novel innovative antiviral concept of targeting a host cell signaling pathway that is required for viral propagation instead of viral structures.

Antiviral drug

10.3389/fmicb.2017.02130

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Phosphorylation of the influenza A virus protein PB1-F2 by PKC is crucial for apoptosis promoting functions in monocytes

Cellular Microbiology (2009)

David Mitzner Sabine Eva Dudek Nicole Studtrucker Darisuren Anhlan Igor Mazur

The 11th influenza A virus (IAV) protein PB1-F2 is encoded by an alternative reading frame of the PB1 polymerase gene and found in the nucleus, cytosol and at the mitochondria of infected cells, the latter is consistent with experimental evidence for its pro-apoptotic function. Here, the function of PB1-F2 as a phosphoprotein was characterized. PB1-F2 derived from isolate IAVPR8 and synthetic fragments thereof were phosphorylated in vitro by purified protein kinase C (PKC) and cellular extract. Constitutively active PKCα interacts with PB1-F2 in yeast two-hybrid assays. 32P radiolabelling of transfected 293T cells revealed that phosphorylation of PB1-F2 is sensitive to inhibitors of PKC and could be increased by the PKC activator PMA. ESI-MS analysis and cellular expression of PB1-F2 mutants identified the positions Ser-35 as the major and the Thr-27 as an alternative PKC phosphorylation site. Infection of MDCK cells with recombinant IAVPR8 lacking these PKC sites abrogated phosphorylation of PB1-F2 in vivo. Furthermore, infection of primary human monocytes with mutant viruses lacking these PB1-F2 phosphorylation sites resulted in impaired caspase 3 activation and reduced progeny virus titres, indicating that the integrity of the identified phosphorylation sites is crucial for a cell-specific function of PB1-F2 during virus replication.

Monocyte

10.1111/j.1462-5822.2009.01343.x

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A Plant Extract of Ribes nigrum folium Possesses Anti-Influenza Virus Activity In Vitro and In Vivo by Preventing Virus Entry to Host Cells

PLoS ONE (2013)

Christina Ehrhardt Sabine Eva Dudek Magdalena Holzberg Urban Sabine Eike R. Hrincius

Infections with influenza A viruses (IAV) are still amongst the major causes of highly contagious severe respiratory diseases not only bearing a devastating effect to human health, but also significantly impact the economy. Besides vaccination that represents the best option to protect from IAV infections, only two classes of anti-influenza drugs, inhibitors of the M2 ion channel and the neuraminidase, often causing resistant IAV variants have been approved. That is why the need for effective and amply available antivirals against IAV is of high priority. Here we introduce LADANIA067 from the leaves of the wild black currant (Ribes nigrum folium) as a potent compound against IAV infections in vitro and in vivo. LADANIA067 treatment resulted in a reduction of progeny virus titers in cell cultures infected with prototype avian and human influenza virus strains of different subtypes. At the effective dose of 100 µg/ml the extract did not exhibit apparent harming effects on cell viability, metabolism or proliferation. Further, viruses showed no tendency to develop resistance to LADANIA067 when compared to amantadine that resulted in the generation of resistant variants after only a few passages. On a molecular basis the protective effect of LADANIA067 appears to be mainly due to interference with virus internalisation. In the mouse infection model LADANIA067 treatment reduces progeny virus titers in the lung upon intranasal application. In conclusion, an extract from the leaves of the wild black currant might be a promising source for the development of new antiviral compounds to fight IAV infections.

Ribes

Neuraminidase inhibitor

10.1371/journal.pone.0063657

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Cytotoxic effects of natural and semisynthetic cucurbitacins on lung cancer cell line A549

Investigational New Drugs (2016)

Izabella Thaís Silva Fabiana Cristina Geller Lara Persich Sabine Eva Dudek Karen Luise Lang

10.1007/s10637-015-0317-4

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Influenza A viruses suppress cyclooxygenase-2 expression by affecting its mRNA stability

Scientific Reports (2016)

Sabine Eva Dudek Katja Nitzsche Stephan Ludwig Christina Ehrhardt

Infection with influenza A viruses (IAV) provokes activation of cellular defence mechanisms contributing to the innate immune and inflammatory response. In this process the cyclooxygenase-2 (COX-2) plays an important role in the induction of prostaglandin-dependent inflammation. While it has been reported that COX-2 is induced upon IAV infection, in the present study we observed a down-regulation at later stages of infection suggesting a tight regulation of COX-2 by IAV. Our data indicate the pattern-recognition receptor RIG-I as mediator of the initial IAV-induced COX-2 synthesis. Nonetheless, during on-going IAV replication substantial suppression of COX-2 mRNA and protein synthesis could be detected, accompanied by a decrease in mRNA half-life. Interestingly, COX-2 mRNA stability was not only imbalanced by IAV replication but also by stimulation of cells with viral RNA. Our results reveal tristetraprolin (TTP), which is known to bind COX-2 mRNA and promote its rapid degradation, as regulator of COX-2 expression in IAV infection. During IAV replication and viral RNA accumulation TTP mRNA synthesis was induced, resulting in reduced COX-2 levels. Accordingly, the down-regulation of TTP resulted in increased COX-2 protein expression after IAV infection. These findings indicate a novel IAV-regulated cellular mechanism, contributing to the repression of host defence and therefore facilitating viral replication.

10.1038/srep27275

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Proliferative Inhibition and Apoptotic Mechanism on Human Non-small-cell Lung Cancer (A549 Cells) of a Novel Cucurbitacin from Wilbrandia ebracteata Cogn

International Journal of Cancer Research (2013)

Izabella Thaís Silva Marina R. Teixeir Karen Luise Lang Tatiana da R. Guimara Sabine Eva Dudek

Human lung

10.3923/ijcr.2013.54.68

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The influenza virus PB1-F2 protein has interferon antagonistic activity

Biological Chemistry (2011)

Sabine Eva Dudek Ludmilla Wixler Carolin Nordhoff Alexandra Nordmann Darisuren Anhlan

Abstract PB1-F2 is a nonstructural protein of influenza viruses encoded by the PB1 gene segment from a +1 open reading frame. It has been shown that PB1-F2 contributes to viral pathogenicity, although the underlying mechanisms are still unclear. Induction of type I interferon (IFN) and the innate immune response are the first line of defense against viral infection. Here we show that influenza A viruses (IAVs) lacking the PB1-F2 protein induce an enhanced expression of IFN-β and IFN-stimulated genes in infected epithelial cells. Studying molecular mechanisms underlying the PB1-F2-mediated IFN antagonistic activity showed that PB1-F2 interferes with the RIG-I/MAVS protein complex thereby inhibiting the activation of the downstream transcription factor IFN regulatory factor 3. These findings were also reflected in in vivo studies demonstrating that infection with PR8 wild-type (wt) virus resulted in higher lung titers and a more severe onset of disease compared with infection with its PB1-F2-deficient counterpart. Accordingly, a much more pronounced infiltration of lungs with immune cells was detected in mice infected with the PB1-F2 wt virus. In summary, we demonstrate that the PB1-F2 protein of IAVs exhibits a type I IFN-antagonistic function by interfering with the RIG-I/MAVS complex, which contributes to an enhanced pathogenicity in vivo .

10.1515/bc.2011.174

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Scheme for preparation of a novel semisynthetic derivative of cucurbitacin B (DACE).

Izabella Thaís Silva Annelise De Carvalho Karen Luise Lang Sabine Eva Dudek Dörthe Masemann

Derivative (finance)

10.6084/m9.figshare.1308069

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The Clinically Approved Proteasome Inhibitor PS-341 Efficiently Blocks Influenza A Virus and Vesicular Stomatitis Virus Propagation by Establishing an Antiviral State

Journal of Virology (2010)

Sabine Eva Dudek Christina Luig Eva-Katharina Pauli Ulrich S. Schubert Stephan Ludwig

Recently it has been shown that the proinflammatory NF-kappaB pathway promotes efficient influenza virus propagation. Based on these findings, it was suggested that NF-kappaB blockade may be a promising approach for antiviral intervention. The classical virus-induced activation of the NF-kappaB pathway requires proteasomal degradation of the inhibitor of NF-kappaB, IkappaB. Therefore, we hypothesized that inhibition of proteasomal IkappaB degradation should impair influenza A virus (IAV) replication. We chose the specific proteasome inhibitor PS-341, which is a clinically approved anticancer drug also known as Bortezomib or Velcade. As expected, PS-341 treatment of infected A549 cells in a concentration range that was not toxic resulted in a significant reduction of progeny virus titers. However, we could not observe the proposed suppression of NF-kappaB-signaling in vitro. Rather, PS-341 treatment resulted in an induction of IkappaB degradation and activation of NF-kappaB as well as the JNK/AP-1 pathway. This coincides with enhanced expression of antiviral genes, such as interleukin-6 and, most importantly, MxA, which is a strong interferon (IFN)-induced suppressor of influenza virus replication. This suggests that PS-341 may act as an antiviral agent via induction of the type I IFN response. Accordingly, PS-341 did not affect virus titers in Vero cells, which lack type I IFN genes, but strongly inhibited replication of vesicular stomatitis virus (VSV), a highly IFN-sensitive pathogen. Thus, we conclude that PS-341 blocks IAV and VSV replication by inducing an antiviral state mediated by the NF-kappaB-dependent expression of antivirus-acting gene products.

Proinflammatory cytokine

Vero cell

10.1128/jvi.00533-10

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Citations (47)