The thrombopoietin receptor agonist eltrombopag inhibits human cytomegalovirus replication via iron chelation

  • 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 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 interferes with HCMV replication after virus entry. Eltrombopag was effective in thrombopoietin receptor-negative cells, and 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 haematopoietic 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.

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Metadaten
Author:Jens-Uwe VogelORCiDGND, Sophie Marion SchmidtGND, Daniel Schmidt, Florian RothweilerGND, Benjamin Florian KochORCiDGND, Patrick C. BaerORCiDGND, Holger RabenauORCiDGND, Detlef MichelGND, Thomas StammingerORCiD, Martin MichaelisORCiDGND, Jindrich CinatlORCiDGND
URN:urn:nbn:de:hebis:30:3-726569
DOI:https://doi.org/10.1101/828152
Parent Title (English):bioRxiv
Document Type:Preprint
Language:English
Date of Publication (online):2019/11/01
Date of first Publication:2019/11/01
Publishing Institution:Universit├Ątsbibliothek Johann Christian Senckenberg
Release Date:2023/09/14
Issue:828152
Page Number:29
HeBIS-PPN:512669910
Institutes:Medizin
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Sammlungen:Universit├Ątspublikationen
Licence (German):License LogoCreative Commons - CC BY-NC-ND - Namensnennung - Nicht kommerziell - Keine Bearbeitungen 4.0 International