The multi-targeted kinase inhibitor sorafenib inhibits human cytomegalovirus replication

Martin Michaelis, Christina Paulus, Nadine Löschmann, Stephanie Dauth, Elisabeth Stange, Hans Wilhelm Doerr, Michael Nevels, Jindrich Cinatl

Research output: Contribution to journalArticlepeer-review

28 Citations (Scopus)

Abstract

Human cytomegalovirus (HCMV) is a major pathogen in immunocompromised individuals. Here, non-toxic concentrations of the anti-cancer kinase inhibitor sorafenib were shown to inhibit replication of different HCMV strains (including a ganciclovir-resistant strain) in different cell types. In contrast to established anti-HCMV drugs, sorafenib inhibited HCMV major immediate early promoter activity and HCMV immediate early antigen (IEA) expression. Sorafenib is known to inhibit Raf. Comparison of sorafenib with the MEK inhibitor U0126 suggested that sorafenib inhibits HCMV IEA expression through inhibition of Raf but independently of signaling through the Raf downstream kinase MEK 1/2. In concordance, siRNA-mediated depletion of Raf but not of MEK-reduced IEA expression. In conclusion, sorafenib diminished HCMV replication in clinically relevant concentrations and inhibited HCMV IEA expression, a pathophysiologically relevant event that is not affected by established anti-HCMV drugs. Moreover, we demonstrated for the first time that Raf activation is involved in HCMV IEA expression.
Original languageEnglish
Pages (from-to)1079-90
Number of pages12
JournalCellular and Molecular Life Sciences
Volume68
Issue number6
DOIs
Publication statusPublished - Mar 2011

Keywords

  • Benzenesulfonates
  • Cytomegalovirus
  • DNA Primers
  • Genes, Immediate-Early
  • Humans
  • Immunoblotting
  • Luciferases
  • Niacinamide
  • Phenylurea Compounds
  • Promoter Regions, Genetic
  • Protein Kinase Inhibitors
  • Pyridines
  • RNA Interference
  • Reverse Transcriptase Polymerase Chain Reaction
  • Virus Replication
  • raf Kinases

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