The multi-targeted kinase inhibitor sorafenib inhibits human cytomegalovirus replication.
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.
Michaelis
Martin
M
Institut Für Medizinische Virologie, Klinikum der J.W. Goethe-Universität, Frankfurt am Main, Germany. michaelis@em.uni-frankfurt.de
Paulus
Christina
C
Löschmann
Nadine
N
Dauth
Stephanie
S
Stange
Elisabeth
E
Doerr
Hans Wilhelm
HW
Nevels
Michael
M
Cinatl
Jindrich
J
D001557:Benzenesulfonates / Q000494:pharmacology*; D003587:Cytomegalovirus / Q000187:drug effects*; D017931:DNA Primers / Q000235:genetics; D017781:Genes, Immediate-Early / Q000235:genetics; D006801:Humans; D015151:Immunoblotting; D008156:Luciferases; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D011401:Promoter Regions, Genetic / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077157:Sorafenib; D014779:Virus Replication / Q000187:drug effects*; D048490:raf Kinases / Q000037:antagonists & inhibitors
D001557:Benzenesulfonates; D017931:DNA Primers; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D009536:Niacinamide; D000077157:Sorafenib; D008156:Luciferases; D048490:raf Kinases
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