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.
Highlights
Influenza viruses (IVs) are family members of Orthomyxoviridae and are grouped into three different subtypes (A, B and C)
We elucidated whether the specific inhibitor NSC23766, which prevents the interaction of Rac1 with its guanine nucleotide exchange factors (GEFs) Tiam1 and Trio, exerts an antiviral effect against IV infection in cultured cells
We examined the localization of the viral proteins protein basic 1 (PB1), matrix protein 1 (M1), and nonstructural protein 1 (NS1) in presence and absence of NSC23766 (Fig. 5C, lanes 3–4 and 7–8)
Summary
Influenza viruses (IVs) are family members of Orthomyxoviridae and are grouped into three different subtypes (A, B and C). The commonly available drugs target either the viral ion channel M2 (amantadine, rimantadine) or the viral neuraminidase (NA; oseltamivir, zanamivir). Usage of these drugs results in the frequent development of resistant virus variants. Novel antiviral approaches have been directed against cellular factors, which are essential for viral replication [2,3]. Such alternative strategies seem to offer a higher barrier for the development of drug resistance
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