pd-184352 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

Antiviral therapies against influenza are required, especially for high-risk patients, severe influenza and in case of highly pathogenic influenza virus (IV) strains. However, currently, licensed drugs that target the virus directly are not very effective and often lead to the development of resistant IV variants. This may be overcome by targeting host cell factors that are required for IV propagation. IV induces a variety of host cell signaling cascades, such as the Raf/MEK/ERK kinase pathway. The activation of this pathway is necessary for IV propagation. MEK-inhibitors block the activation of the pathway on the bottleneck of the signaling cascade leading to impaired virus propagation. In the present study, we aimed to compare the antiviral potency and bioavailability of the MEK-inhibitor CI-1040 versus its major active metabolite ATR-002, in vitro as well as in the mouse model. In cell culture assays, an approximately 10-fold higher concentration of ATR-002 is required to generate the same antiviral activity as for CI-1040. Interestingly, we observed that considerably lower concentrations of ATR-002 were required to achieve a reduction of the viral load in vivo. Pharmacokinetic studies with ATR-002 and CI-1040 in mice have found the C

Topics: Animals; Antiviral Agents; Benzamides; Cell Line; Disease Models, Animal; Extracellular Signal-Regulated MAP Kinases; Fenamates; Humans; Influenza A Virus, H1N1 Subtype; Influenza A Virus, H3N2 Subtype; Influenza, Human; Leukocytes, Mononuclear; Lung; Male; MAP Kinase Signaling System; Mice; Mitogen-Activated Protein Kinase Kinases; Orthomyxoviridae Infections; Phosphorylation; Protein Kinase Inhibitors