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

Abstract

m.michaelis@kent.ac.uk (MM) 18 19 Acknowledgements 20 The work was supported by the Hilfe für krebskranke Kinder Frankfurt e.V. and the 21 Frankfurter Stiftung für krebskranke Kinder. 22 23 2 Abstract 24 The thrombopoietin receptor agonist eltrombopag was successfully used 25 against human cytomegalovirus (HCMV)-associated thrombocytopenia refractory to 26 immunomodulatory and antiviral drugs. These effects were ascribed to effects of 27 eltrombopag on megakaryocytes. Here, we tested whether eltrombopag may also 28 exert direct antiviral effects. Therapeutic eltrombopag concentrations inhibited HCMV 29 replication in human fibroblasts and adult mesenchymal stem cells infected with six 30 different virus strains and drug-resistant clinical isolates. Eltrombopag also 31 synergistically increased the anti-HCMV activity of the mainstay drug ganciclovir. 32 Time-of-addition experiments suggested that eltrombopag interferes with HCMV 33 replication after virus entry. Eltrombopag was effective in thrombopoietin receptor-34 negative cells, and addition of Fe 3+ prevented the anti-HCMV effects, indicating that it 35 inhibits HCMV replication via iron chelation. This may be of particular interest for the 36 treatment of cytopenias after haematopoietic stem cell transplantation, as HCMV 37 reactivation is a major reason for transplantation failure. Since therapeutic 38 eltrombopag concentrations are effective against drug-resistant viruses and 39 synergistically increase the effects of ganciclovir, eltrombopag is also a drug 40 repurposing candidate for the treatment of therapy-refractory HCMV disease. 41 42 Key words: human cytomegalovirus, antiviral therapy, eltrombopag, thrombopietin 43 receptor agonist, drug resistance, iron chelation 44 45 46

Outcomes of Eltrombopag Treatment and Development of Iron Deficiency in Children With Immune Thrombocytopenia in Turkey

“…They confirmed that EPAG is a powerful iron chelator, and when it was used with deferasirox, the iron chelation capacity increased in thalassemia patients [21]. In another study, EPAG therapy was shown to inhibit replication of human cytomegalovirus infection by iron chelation [22]. Following these findings, a clinical study with a limited number of children with Ch-ITP revealed that EPAG treatment reduced the patients' MCV and ferritin levels, ultimately causing IDA [23].…”

Characteristics and outcomes of adults with cytomegalovirus‐associated thrombocytopenia: a case series and literature review

“…It inhibited CMV replication in vitro via iron chelation, and synergistically increased the anti-CMV activity of ganciclovir. 35 Our study has some limitations in addition to its retrospective nature. First, in most of the cases the CMV workup took place after the failure of steroid treatment.…”

Iron status influences the response of cord blood megakaryocyte progenitors to eltrombopag in vitro

“… 4 In more recent studies, however, functionally relevant iron-chelating effects were reported in cardiomyocyte cell lines, 5 osteoclasts, 6 neonatal hippocampal neurons, 7 and human cytomegalovirus. 19 Depending on the specific cell type and clinical situation, the iron-chelating effects of ELT could be either clinically beneficial (as for cardiomyocytes in clinical conditions associated with iron overload) or detrimental (such as for neonatal neurons).…”