The multi-targeted kinase inhibitor sorafenib inhibits human cytomegalovirus replication |
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Authors: | Martin Michaelis Christina Paulus Nadine Löschmann Stephanie Dauth Elisabeth Stange Hans Wilhelm Doerr Michael Nevels Jr" target="_blank">Jindrich CinatlJr |
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Institution: | 1.Institut Für Medizinische Virologie,Klinikum der J.W. Goethe-Universit?t,Frankfurt am Main,Germany;2.Institut für Medizinische Mikrobiologie und Hygiene,Universit?t Regensburg,Regensburg,Germany |
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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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