u-0126 and Influenza--Human

Influenza virus exploits a number of cellular signaling pathways during the course of its replication, rendering them potential targets for new therapeutic interventions. Several preclinical approaches are now focusing on cellular factors or pathways as a means of treating influenza. By targeting host factors, rather than viral mechanisms, these novel therapies may be effective against multiple virus strains and subtypes, and are less likely to elicit viral drug resistance. The most promising candidates are inhibitors of intracellular signaling cascades that are essential for virus replication. This article reviews novel approaches and compounds that target the Raf/MEK/ERK signaling pathway, NF-κB signaling, the PI3K/Akt pathway and the PKC signaling cascade. Although these new antiviral strategies are still in an early phase of preclinical development, results to date suggest they offer a new approach to the treatment of influenza, supplementing direct-acting antiviral drugs.

Topics: Animals; Antiviral Agents; Benzamides; Butadienes; Enzyme Activation; Humans; Influenza, Human; Leupeptins; MAP Kinase Signaling System; NF-kappa B; Nitriles; Orthomyxoviridae; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Protein Kinase Inhibitors; Virus Replication

Influenza A virus vRNP nuclear export is CRM1-dependent. Ran-binding protein 3 (RanBP3) is a Ran-interacting protein that is best known for its role as a cofactor of CRM1-mediated cargo nuclear export. In this study, we investigated the role of RanBP3 during the influenza A virus life cycle. We found that RanBP3 was phosphorylated at Ser58 in the early and late phases of infection. Knockdown of RanBP3 expression led to vRNP nuclear retention, suggesting that RanBP3 is involved in vRNP nuclear export. Moreover, we demonstrated that the function of RanBP3 during vRNP nuclear export is regulated by phosphorylation at Ser58, and that RanBP3 phosphorylation is modulated by both PI3K/Akt and Ras/ERK/RSK pathways in the late phase of viral infection.

Topics: Active Transport, Cell Nucleus; Animals; Butadienes; Cell Line; Cell Nucleus; Chick Embryo; Chromones; Dogs; Enzyme Inhibitors; Exportin 1 Protein; Gene Expression Regulation, Viral; Gene Knockdown Techniques; Humans; Influenza A virus; Influenza, Human; Karyopherins; Morpholines; Nitriles; Nuclear Proteins; Nucleocytoplasmic Transport Proteins; Phosphoinositide-3 Kinase Inhibitors; Phosphorylation; ras Proteins; Receptors, Cytoplasmic and Nuclear; Serine; Viral Proteins; Virus Replication