Cellular and Molecular Life Sciences

, Volume 68, Issue 6, pp 1079–1090

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 CinatlJr.
Research Article

DOI: 10.1007/s00018-010-0510-8

Cite this article as:
Michaelis, M., Paulus, C., Löschmann, N. et al. Cell. Mol. Life Sci. (2011) 68: 1079. doi:10.1007/s00018-010-0510-8

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.

Keywords

Human cytomegalovirusSorafenibKinase inhibitorRafImmediate early antigenCancer chemotherapyOncomodulationAntiviral therapy

Supplementary material

18_2010_510_MOESM1_ESM.pdf (285 kb)
Supplementary material 1 (PDF 284 kb)
18_2010_510_MOESM2_ESM.pdf (7 kb)
Supplementary material 2 (PDF 7 kb)
18_2010_510_MOESM3_ESM.pdf (155 kb)
Supplementary material 3 (PDF 155 kb)
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Supplementary material 4 (PDF 46 kb)
18_2010_510_MOESM5_ESM.pdf (5 kb)
Supplementary material 5 (PDF 4 kb)
18_2010_510_MOESM6_ESM.pdf (11 kb)
Supplementary material 6 (PDF 11 kb)

Copyright information

© Springer Basel AG 2010

Authors and Affiliations

  • Martin Michaelis
    • 1
  • Christina Paulus
    • 2
  • Nadine Löschmann
    • 1
  • Stephanie Dauth
    • 1
  • Elisabeth Stange
    • 1
  • Hans Wilhelm Doerr
    • 1
  • Michael Nevels
    • 2
  • Jindrich CinatlJr.
    • 1
  1. 1.Institut Für Medizinische VirologieKlinikum der J.W. Goethe-UniversitätFrankfurt am MainGermany
  2. 2.Institut für Medizinische Mikrobiologie und HygieneUniversität RegensburgRegensburgGermany