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The Thrombopoietin Receptor Agonist Eltrombopag Inhibits Human Cytomegalovirus Replication Via Iron Chelation

Vogel, Jens-Uwe, Schmidt, Sophie, Schmidt, Daniel, Rothweiler, Florian, Koch, Benjamin, Baer, Patrick, Rabenau, Holger, Michel, Detlef, Stamminger, Thomas, Michaelis, Martin, and others. (2019) The Thrombopoietin Receptor Agonist Eltrombopag Inhibits Human Cytomegalovirus Replication Via Iron Chelation. Cells, 9 (1). p. 31. ISSN 2073-4409. (doi:10.3390/cells9010031) (KAR id:79501)

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Abstract

The thrombopoietin receptor agonist eltrombopag was successfully used against human cytomegalovirus (HCMV)-associated thrombocytopenia refractory to immunomodulatory and antiviral drugs. These effects were ascribed to the effects of eltrombopag on megakaryocytes. Here, we tested whether eltrombopag may also exert direct antiviral effects. Therapeutic eltrombopag concentrations inhibited HCMV replication in human fibroblasts and adult mesenchymal stem cells infected with six different virus strains and drug-resistant clinical isolates. Eltrombopag also synergistically increased the anti-HCMV activity of the mainstay drug ganciclovir. Time-of-addition experiments suggested that eltrombopag interfered with HCMV replication after virus entry. Eltrombopag was effective in thrombopoietin receptor-negative cells, and the addition of Fe3+ prevented the anti-HCMV effects, indicating that it inhibits HCMV replication via iron chelation. This may be of particular interest for the treatment of cytopenias after hematopoietic stem cell transplantation, as HCMV reactivation is a major reason for transplantation failure. Since therapeutic eltrombopag concentrations are effective against drug-resistant viruses, and synergistically increase the effects of ganciclovir, eltrombopag is also a drug-repurposing candidate for the treatment of therapy-refractory HCMV disease.

Item Type: Article
DOI/Identification number: 10.3390/cells9010031
Uncontrolled keywords: human cytomegalovirus; antiviral therapy; eltrombopag; thrombopietin receptor agonist; drug resistance; iron chelation
Subjects: R Medicine > RM Therapeutics. Pharmacology
Divisions: Faculties > Sciences > School of Biosciences
Depositing User: Martin Michaelis
Date Deposited: 07 Jan 2020 10:16 UTC
Last Modified: 08 Jan 2020 09:28 UTC
Resource URI: https://kar.kent.ac.uk/id/eprint/79501 (The current URI for this page, for reference purposes)
Michaelis, Martin: https://orcid.org/0000-0002-5710-5888
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