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The Rac1 inhibitor NSC23766 exerts anti-influenza virus properties by affecting the viral polymerase complex activity.

Dierkes R, Warnking K, Liedmann S, Seyer R, Ludwig S, Ehrhardt C - PLoS ONE (2014)

Bottom Line: The frequent emergence of new influenza viruses in the human population underlines the urgent need for antiviral therapeutics in addition to the preventative vaccination against the seasonal flu.Inhibition of Rac1 by NSC23766 resulted in impaired replication of a wide variety of influenza viruses, including a human virus strain of the pandemic from 2009 as well as highly pathogenic avian virus strains.Furthermore, we identified a crucial role of Rac1 for the activity of the viral polymerase complex.

View Article: PubMed Central - PubMed

Affiliation: Institute of Molecular Virology (IMV), Centre of Molecular Virology (ZMBE), Westfälische Wilhelms-University, Münster, Germany.

ABSTRACT
The frequent emergence of new influenza viruses in the human population underlines the urgent need for antiviral therapeutics in addition to the preventative vaccination against the seasonal flu. To circumvent the development of resistance, recent antiviral approaches target cellular proteins needed by the virus for efficient replication. We investigated the contribution of the small GTPase Rac1 to the replication of influenza viruses. Inhibition of Rac1 by NSC23766 resulted in impaired replication of a wide variety of influenza viruses, including a human virus strain of the pandemic from 2009 as well as highly pathogenic avian virus strains. Furthermore, we identified a crucial role of Rac1 for the activity of the viral polymerase complex. The antiviral potential of NSC23766 was confirmed in mouse experiments, identifying Rac1 as a new cellular target for therapeutic treatment of influenza virus infections.

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NSC23766 has an antiviral potential in mice.BALB/c mice were infected with A/Puerto-Rico/8/34 rec. (200 PFU (A) or 100 PFU (B)). Immediately after infection, treatment with nebulized NSC23766 was started (twice per day for 20 min with indicated concentrations). (A) Viral load in the lungs was determined at day three p.i. (control n = 8, 0.1 mg/ml and 1 mg/ml n = 7). (B–C) Infected mice were treated with NSC23766 (1 mg/ml) until day seven p.i and disease progression was monitored over a period of 16 days (n = 8). Mice were humanly sacrificed when they lost 25% of their body weight. (B) Mean body weight ± SD is depicted. (C) A Kaplan-Meier survival curve was plotted by GraphPad Prism 5 Software. Statistical significance was determined by Student's t-test (* p<0.05; ** p<0.01).
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pone-0088520-g008: NSC23766 has an antiviral potential in mice.BALB/c mice were infected with A/Puerto-Rico/8/34 rec. (200 PFU (A) or 100 PFU (B)). Immediately after infection, treatment with nebulized NSC23766 was started (twice per day for 20 min with indicated concentrations). (A) Viral load in the lungs was determined at day three p.i. (control n = 8, 0.1 mg/ml and 1 mg/ml n = 7). (B–C) Infected mice were treated with NSC23766 (1 mg/ml) until day seven p.i and disease progression was monitored over a period of 16 days (n = 8). Mice were humanly sacrificed when they lost 25% of their body weight. (B) Mean body weight ± SD is depicted. (C) A Kaplan-Meier survival curve was plotted by GraphPad Prism 5 Software. Statistical significance was determined by Student's t-test (* p<0.05; ** p<0.01).

Mentions: Finally, we wanted to know if NSC23766 shows antiviral activity in the mouse model. We infected BALB/c mice with 200 PFU of A/Puerto-Rico/8/34 rec. and treated them twice per day for 20 min with a nebulized NSC23766 solution (0.1 or 1 mg/ml) or water as solvent control. Three days p.i. the mice were sacrificed and the viral loads in the lungs were analyzed (Fig. 8A). In comparison to untreated mice, the replication of IV in NSC23766-treated mice was reduced. While the treatment with 0.1 mg/ml resulted in a moderate drop of viral titers (29%), the concentration of 1 mg/ml was sufficient to significantly reduce viral lung loads by 61%.


The Rac1 inhibitor NSC23766 exerts anti-influenza virus properties by affecting the viral polymerase complex activity.

Dierkes R, Warnking K, Liedmann S, Seyer R, Ludwig S, Ehrhardt C - PLoS ONE (2014)

NSC23766 has an antiviral potential in mice.BALB/c mice were infected with A/Puerto-Rico/8/34 rec. (200 PFU (A) or 100 PFU (B)). Immediately after infection, treatment with nebulized NSC23766 was started (twice per day for 20 min with indicated concentrations). (A) Viral load in the lungs was determined at day three p.i. (control n = 8, 0.1 mg/ml and 1 mg/ml n = 7). (B–C) Infected mice were treated with NSC23766 (1 mg/ml) until day seven p.i and disease progression was monitored over a period of 16 days (n = 8). Mice were humanly sacrificed when they lost 25% of their body weight. (B) Mean body weight ± SD is depicted. (C) A Kaplan-Meier survival curve was plotted by GraphPad Prism 5 Software. Statistical significance was determined by Student's t-test (* p<0.05; ** p<0.01).
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pone-0088520-g008: NSC23766 has an antiviral potential in mice.BALB/c mice were infected with A/Puerto-Rico/8/34 rec. (200 PFU (A) or 100 PFU (B)). Immediately after infection, treatment with nebulized NSC23766 was started (twice per day for 20 min with indicated concentrations). (A) Viral load in the lungs was determined at day three p.i. (control n = 8, 0.1 mg/ml and 1 mg/ml n = 7). (B–C) Infected mice were treated with NSC23766 (1 mg/ml) until day seven p.i and disease progression was monitored over a period of 16 days (n = 8). Mice were humanly sacrificed when they lost 25% of their body weight. (B) Mean body weight ± SD is depicted. (C) A Kaplan-Meier survival curve was plotted by GraphPad Prism 5 Software. Statistical significance was determined by Student's t-test (* p<0.05; ** p<0.01).
Mentions: Finally, we wanted to know if NSC23766 shows antiviral activity in the mouse model. We infected BALB/c mice with 200 PFU of A/Puerto-Rico/8/34 rec. and treated them twice per day for 20 min with a nebulized NSC23766 solution (0.1 or 1 mg/ml) or water as solvent control. Three days p.i. the mice were sacrificed and the viral loads in the lungs were analyzed (Fig. 8A). In comparison to untreated mice, the replication of IV in NSC23766-treated mice was reduced. While the treatment with 0.1 mg/ml resulted in a moderate drop of viral titers (29%), the concentration of 1 mg/ml was sufficient to significantly reduce viral lung loads by 61%.

Bottom Line: The frequent emergence of new influenza viruses in the human population underlines the urgent need for antiviral therapeutics in addition to the preventative vaccination against the seasonal flu.Inhibition of Rac1 by NSC23766 resulted in impaired replication of a wide variety of influenza viruses, including a human virus strain of the pandemic from 2009 as well as highly pathogenic avian virus strains.Furthermore, we identified a crucial role of Rac1 for the activity of the viral polymerase complex.

View Article: PubMed Central - PubMed

Affiliation: Institute of Molecular Virology (IMV), Centre of Molecular Virology (ZMBE), Westfälische Wilhelms-University, Münster, Germany.

ABSTRACT
The frequent emergence of new influenza viruses in the human population underlines the urgent need for antiviral therapeutics in addition to the preventative vaccination against the seasonal flu. To circumvent the development of resistance, recent antiviral approaches target cellular proteins needed by the virus for efficient replication. We investigated the contribution of the small GTPase Rac1 to the replication of influenza viruses. Inhibition of Rac1 by NSC23766 resulted in impaired replication of a wide variety of influenza viruses, including a human virus strain of the pandemic from 2009 as well as highly pathogenic avian virus strains. Furthermore, we identified a crucial role of Rac1 for the activity of the viral polymerase complex. The antiviral potential of NSC23766 was confirmed in mouse experiments, identifying Rac1 as a new cellular target for therapeutic treatment of influenza virus infections.

Show MeSH
Related in: MedlinePlus