Small molecule inhibitors of the RNA-dependent protein kinase

Narasimham V. Jammi, Landon R. Whitby, Peter A. Beal

Research output: Contribution to journalArticle

122 Scopus citations

Abstract

The RNA-dependent protein kinase (PKR) is an interferon-induced serine/threonine protein kinase that phosphorylates the α subunit of the eukaryotic initiation factor 2 in response to viral infection. Classical genetic approaches for studying the role of PKR in cell signaling have their limitations due to overlapping but non-redundant pathways. Small molecule inhibitors of PKR will be useful in this regard. We report here, the discovery of a small molecule inhibitor of the kinase reaction of PKR. The inhibitor was discovered by screening a library of 26 different ATP-binding site directed inhibitors of varying structure. We also describe the development of a high-throughput assay for screening a large number of compounds for a PKR inhibitor using a rabbit reticulocyte lysate system and luciferase mRNA. The assay takes advantage of the fact that the reticulocyte lysate is rich in components of the translational machinery, of which PKR is an integral part. This assay can be carried out with added exogenous human PKR to study the effect of various compounds in their ability to rescue the translational block imposed by human PKR.

Original languageEnglish (US)
Pages (from-to)50-57
Number of pages8
JournalBiochemical and Biophysical Research Communications
Volume308
Issue number1
DOIs
StatePublished - Aug 15 2003
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Molecular Biology

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