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The multi-targeted kinase inhibitor sorafenib inhibits human cytomegalovirus replication

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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.

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Acknowledgments

The authors thank the friendly society “Hilfe für krebskranke Kinder Frankfurt e.V.” and its foundation “Frankfurter Stiftung für krebskranke Kinder” for support. Moreover, the authors thank Mrs. Christina Matreux, Mrs. Gesa Meincke, and Mrs. Ines Tschertner for technical assistance.

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Authors and Affiliations

  1. Institut Für Medizinische Virologie, Klinikum der J.W. Goethe-Universität, Paul Ehrlich-Str. 40, 60596, Frankfurt am Main, Germany

    Martin Michaelis, Nadine Löschmann, Stephanie Dauth, Elisabeth Stange, Hans Wilhelm Doerr & Jindrich Cinatl Jr.

  2. Institut für Medizinische Mikrobiologie und Hygiene, Universität Regensburg, Franz-Josef-Strauss-Allee 11, 93053, Regensburg, Germany

    Christina Paulus & Michael Nevels

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  1. Martin Michaelis
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  2. Christina Paulus
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  3. Nadine Löschmann
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  4. Stephanie Dauth
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Correspondence to Jindrich Cinatl Jr..

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Michaelis, M., Paulus, C., Löschmann, N. et al. The multi-targeted kinase inhibitor sorafenib inhibits human cytomegalovirus replication. Cell. Mol. Life Sci. 68, 1079–1090 (2011). https://doi.org/10.1007/s00018-010-0510-8

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