salubrinal and Keratitis--Herpetic

Most protein phosphatases have little intrinsic substrate specificity, making selective pharmacological inhibition of specific dephosphorylation reactions a challenging problem. In a screen for small molecules that protect cells from endoplasmic reticulum (ER) stress, we identified salubrinal, a selective inhibitor of cellular complexes that dephosphorylate eukaryotic translation initiation factor 2 subunit alpha (eIF2alpha). Salubrinal also blocks eIF2alpha dephosphorylation mediated by a herpes simplex virus protein and inhibits viral replication. These results suggest that selective chemical inhibitors of eIF2alpha dephosphorylation may be useful in diseases involving ER stress or viral infection. More broadly, salubrinal demonstrates the feasibility of selective pharmacological targeting of cellular dephosphorylation events.

Topics: Animals; Antigens, Differentiation; Apoptosis; Cell Cycle Proteins; Cell Line; Cinnamates; Cytoprotection; Dose-Response Relationship, Drug; Endoplasmic Reticulum; Enzyme Inhibitors; Eukaryotic Initiation Factor-2; Genes, Reporter; Herpesvirus 1, Human; Keratitis, Herpetic; Male; Marine Toxins; Mice; Oxazoles; PC12 Cells; Phosphoprotein Phosphatases; Phosphorylation; Protein Folding; Protein Kinases; Protein Phosphatase 1; Proteins; Rats; Thiourea; Tunicamycin; Viral Proteins; Virus Replication