Obatoclax, Saliphenylhalamide, and Gemcitabine Inhibit Influenza A Virus Infection

Denisova, Oxana V.; Kakkola, Laura; Lin, Feng Yen; Stenman, Jakob; Nagaraj, Ashwini S.; Lampe, Johanna W.; Yadav, Bhagwan; Aittokallio, Tero; Kaukinen, Pasi; Ahola, Tero; Kuivanen, Suvi; Vapalahti, Olli; Kantele, Anu; Tynell, Janne; Julkunen, Ilkka; Kallio‐Kokko, Hannimari; Paavilainen, Henrik; Hukkanen, Veijo; Elliott, Richard M.; Brabander, Jef K. De; Saelens, Xavier; Kainov, Denis E.

doi:10.1074/jbc.m112.392142

Cited by 90 publications

(137 citation statements)

References 28 publications

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“…Strikingly, the accumulation of MK2206 in the vesicles was abrogated by inhibitors of cellular v-ATPase and Mcl-1 (Fig. 1D) (6,8,20). These results suggest that endosome acidification and Mcl-1 function are required for MK2206 accumulation in the vesicles in cytoplasm.…”

Section: Agentsupporting

confidence: 48%

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Akt Inhibitor MK2206 Prevents Influenza pH1N1 Virus Infection In Vitro

Denisova

Söderholm

Virtanen

et al. 2014

Antimicrob Agents Chemother

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The influenza pH1N1 virus caused a global flu pandemic in 2009 and continues manifestation as a seasonal virus. Better understanding of the virus-host cell interaction could result in development of better prevention and treatment options. Here we show that the Akt inhibitor MK2206 blocks influenza pH1N1 virus infection in vitro. In particular, at noncytotoxic concentrations, MK2206 alters Akt signaling and inhibits endocytic uptake of the virus. Interestingly, MK2206 is unable to inhibit H3N2, H7N9, and H5N1 viruses, indicating that pH1N1 evolved specific requirements for efficient infection. Thus, Akt signaling could be exploited further for development of better therapeutics against pH1N1 virus.

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Section: Agentsupporting

confidence: 48%

“…It was proposed that temporal inhibition of proviral cellular functions with small molecules is less likely to elicit viral drug resistance (6)(7)(8). There are dozens of commercially available small molecules that inhibit cellular functions.…”

mentioning

confidence: 99%

Akt Inhibitor MK2206 Prevents Influenza pH1N1 Virus Infection In Vitro

Denisova

Söderholm

Virtanen

et al. 2014

Antimicrob Agents Chemother

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“…We infected MDCK cells with WSN-202, WSN-220 or WSN-230 viruses at an m.o.i. of 0.01 following the procedure described by Denisova et al (2012). We found that WSN-202, WSN-220 and WSN-230 viruses replicated efficiently in MDCK cells (Fig.…”

mentioning

confidence: 85%

“…Human monocyte-derived macrophages serve as an excellent cellular model for studying antiviral responses, because alveolar macrophages represent primary targets for influenza virus infection (Denisova et al, 2012 To monitor the effect of NS1 C-terminal truncations on antiviral responses, we infected macrophages with WSN-202, WSN-220 or WSN-230 virus at an m.o.i. of 2.…”

mentioning

confidence: 99%

The C terminus of NS1 protein of influenza A/WSN/1933(H1N1) virus modulates antiviral responses in infected human macrophages and mice

Anastasina

Schepens

Söderholm

et al. 2015

Journal of General Virology

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Non-structural protein NS1 of influenza A viruses interacts with cellular factors through its Nterminal RNA-binding, middle effector and C-terminal non-structured domains. NS1 attenuates antiviral responses in infected cells and thereby secures efficient virus replication. Some influenza strains express C-terminally truncated NS1 proteins due to nonsense mutations in the NS1 gene. To understand the role of the NS1 C-terminal region in regulation of antiviral responses, we engineered influenza viruses expressing C-terminally truncated NS1 proteins using A/WSN/33(H1N1) reverse genetics and tested them in human macrophages and in mice. We showed that a WSN virus expressing NS1 with a 28 aa deletion from its C terminus is a more powerful inducer of antiviral responses than the virus expressing full-length NS1, or one with a 10 aa truncation of NS1 in vitro. Thus, our findings suggest that the C-terminal region of NS1 is essential for regulation of antiviral responses. Moreover, viruses expressing truncated NS1 proteins could be good vaccine candidates.

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“…The most significant canonical pathways specifically associated with virus infections, according to gene set enrichment analysis (GSEA; www.broadinstitute.org/gsea, [16]), were interferon-α, -β, and -γ signaling, cytokine signaling, [10][11][12][13]. These molecules should be first evaluated in vitro using antiviral efficacy assays, and then in animal models as described in our previous studies [14]. The immuno-modulatory effects of these drugs should also be studied, followed by drug resistant tests as in ref.…”

Section: Combination Of Various Omics Techniques Identifies Potentialmentioning

confidence: 99%

Multi-Omics Studies towards Novel Modulators of Influenza A Virus-Host Interaction

Söderholm¹,

Fu²,

Gaelings³

et al. 2016

Preprint

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Human influenza A viruses (IAVs) cause global pandemics and epidemics. These viruses evolve rapidly, making current treatment options ineffective. To identify novel modulators of IAV-host interactions, we re-analyzed our recent transcriptomics, metabolomics, proteomics, phosphoproteomics, and genomics/virtual ligand screening data. We identified 713 potential modulators targeting 199 cellular and two viral proteins. Anti-influenza activity for 48 of them has been reported previously, whereas the antiviral efficacy of the 665 remains unknown. Studying anti-influenza efficacy and immuno/neuro-modulating properties of these compounds and their combinations as well as potential viral and host resistance to them may lead to the discovery of novel modulators of IAV-host interactions, which might be more effective than the currently available anti-influenza therapeutics.

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Obatoclax, Saliphenylhalamide, and Gemcitabine Inhibit Influenza A Virus Infection

Cited by 90 publications

References 28 publications

Akt Inhibitor MK2206 Prevents Influenza pH1N1 Virus Infection In Vitro

Akt Inhibitor MK2206 Prevents Influenza pH1N1 Virus Infection In Vitro

The C terminus of NS1 protein of influenza A/WSN/1933(H1N1) virus modulates antiviral responses in infected human macrophages and mice

Multi-Omics Studies towards Novel Modulators of Influenza A Virus-Host Interaction

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