Inhibition of viral protein translation by indomethacin in vesicular stomatitis virus infection: role of eIF2alpha kinase PKR.

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Amici C, La Frazia S, Brunelli C, Balsamo M, Angelini M, Santoro MG

Inhibition of viral protein translation by indomethacin in vesicular stomatitis virus infection: role of eIF2alpha kinase PKR.

Cell Microbiol. 2015 Sep;17(9):1391-404. doi: 10.1111/cmi.12446. Epub 2015 May 13.

PubMed ID

25856684 [ View in PubMed

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Abstract

Indomethacin, a cyclooxygenase-1 and -2 inhibitor widely used in the clinic for its potent anti-inflammatory/analgesic properties, possesses antiviral activity against several viral pathogens; however, the mechanism of antiviral action remains elusive. We have recently shown that indomethacin activates the double-stranded RNA (dsRNA)-dependent protein kinase R (PKR) in human colon cancer cells. Because of the important role of PKR in the cellular defence response against viral infection, herein we investigated the effect of indomethacin on PKR activity during infection with the prototype rhabdovirus vesicular stomatitis virus. Indomethacin was found to activate PKR in an interferon- and dsRNA-independent manner, causing rapid (< 5 min) phosphorylation of eukaryotic initiation factor-2 alpha-subunit (eIF2alpha). These events resulted in shutting off viral protein translation and blocking viral replication (IC50 = 2 muM) while protecting host cells from virus-induced damage. Indomethacin did not affect eIF2alpha kinases PKR-like endoplasmic reticulum-resident protein kinase (PERK) and general control non-derepressible-2 (GCN2) kinase, and was unable to trigger eIF2alpha phosphorylation in the presence of PKR inhibitor 2-aminopurine. In addition, small-interfering RNA-mediated PKR gene silencing dampened the antiviral effect in indomethacin-treated cells. The results identify PKR as a critical target for the antiviral activity of indomethacin and indicate that eIF2alpha phosphorylation could be a key element in the broad spectrum antiviral activity of the drug.

DrugBank Data that Cites this Article

Drugs

Indomethacin

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Indomethacin	Interferon-induced, double-stranded RNA-activated protein kinase	Protein	Humans	Unknown	Inducer	Details