pd-184352 and Orthomyxoviridae-Infections

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