Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Antigens, Differentiation
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Apoptosis / drug effects*
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Cell Cycle Proteins
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Cell Line
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Cinnamates / pharmacology*
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Cinnamates / toxicity
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Cytoprotection*
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Dose-Response Relationship, Drug
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Endoplasmic Reticulum / metabolism*
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Enzyme Inhibitors / pharmacology
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Eukaryotic Initiation Factor-2 / metabolism*
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Genes, Reporter
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Herpesvirus 1, Human / drug effects
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Herpesvirus 1, Human / physiology
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Keratitis, Herpetic / drug therapy
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Keratitis, Herpetic / virology
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Male
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Marine Toxins
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Mice
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Oxazoles / pharmacology
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Oxazoles / toxicity
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PC12 Cells
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Phosphoprotein Phosphatases / metabolism
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Phosphorylation
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Protein Folding
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Protein Kinases / metabolism
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Protein Phosphatase 1
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Proteins / metabolism
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Rats
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Thiourea / analogs & derivatives*
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Thiourea / pharmacology*
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Thiourea / toxicity
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Tunicamycin / pharmacology
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Viral Proteins / metabolism
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Virus Replication / drug effects
Substances
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Antigens, Differentiation
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Cell Cycle Proteins
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Cinnamates
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Enzyme Inhibitors
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Eukaryotic Initiation Factor-2
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Marine Toxins
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Oxazoles
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Proteins
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Viral Proteins
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gamma 34.5 protein, Human herpesvirus 1
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salubrinal
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Tunicamycin
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calyculin A
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Protein Kinases
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Phosphoprotein Phosphatases
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Ppp1r15a protein, mouse
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Ppp1r15b protein, mouse
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Protein Phosphatase 1
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Thiourea