The Endothelin Receptor Antagonist Macitentan Inhibits Human Cytomegalovirus Infection
Human cytomegalovirus (HCMV) infection is an important cause of morbidity and mortality in immunocompromised patients and a major etiological factor for congenital birth defects in newborns. Ganciclovir and its pro-drug valganciclovir are the preferred drugs in use today for prophylaxis and treatmen...
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MDPI AG
2021-11-01
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| author | Natalia Landázuri Jennifer Gorwood Ylva Terelius Fredrik Öberg Koon Chu Yaiw Afsar Rahbar Cecilia Söderberg-Nauclér |
| author_facet | Natalia Landázuri Jennifer Gorwood Ylva Terelius Fredrik Öberg Koon Chu Yaiw Afsar Rahbar Cecilia Söderberg-Nauclér |
| author_sort | Natalia Landázuri |
| collection | DOAJ |
| description | Human cytomegalovirus (HCMV) infection is an important cause of morbidity and mortality in immunocompromised patients and a major etiological factor for congenital birth defects in newborns. Ganciclovir and its pro-drug valganciclovir are the preferred drugs in use today for prophylaxis and treatment of viremic patients. Due to long treatment times, patients are at risk for developing viral resistance to ganciclovir and to other drugs with a similar mechanism of action. We earlier found that the endothelin receptor B (ETBR) is upregulated during HCMV infection and that it plays an important role in the life cycle of this virus. Here, we tested the hypothesis that ETBR blockade could be used in the treatment of HCMV infection. As HCMV infection is specific to humans, we tested our hypothesis in human cell types that are relevant for HCMV pathogenesis; i.e., endothelial cells, epithelial cells and fibroblasts. We infected these cells with HCMV and treated them with the ETBR specific antagonist BQ788 or ETR antagonists that are approved by the FDA for treatment of pulmonary hypertension; macitentan, its metabolite ACT-132577, bosentan and ambrisentan, and as an anti-viral control, we used ganciclovir or letermovir. At concentrations expected to be relevant in vivo, macitentan, ACT-132577 and BQ788 effectively inhibited productive infection of HCMV. Of importance, macitentan also inhibited productive infection of a ganciclovir-resistant HCMV isolate. Our results suggest that binding or signaling through ETBR is crucial for viral replication, and that selected ETBR blockers inhibit HCMV infection. |
| first_indexed | 2024-03-10T05:36:37Z |
| format | Article |
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| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-10T05:36:37Z |
| publishDate | 2021-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-b455b9d8327b4176a0cfab58dc3d66cf2023-11-22T22:50:58ZengMDPI AGCells2073-44092021-11-011011307210.3390/cells10113072The Endothelin Receptor Antagonist Macitentan Inhibits Human Cytomegalovirus InfectionNatalia Landázuri0Jennifer Gorwood1Ylva Terelius2Fredrik Öberg3Koon Chu Yaiw4Afsar Rahbar5Cecilia Söderberg-Nauclér6Microbial Pathogenesis Unit, Department of Medicine Solna, Karolinska Institutet, SE-171 76 Stockholm, SwedenMicrobial Pathogenesis Unit, Department of Medicine Solna, Karolinska Institutet, SE-171 76 Stockholm, SwedenMedivir AB, SE-141 22 Huddinge, SwedenMedivir AB, SE-141 22 Huddinge, SwedenMicrobial Pathogenesis Unit, Department of Medicine Solna, Karolinska Institutet, SE-171 76 Stockholm, SwedenMicrobial Pathogenesis Unit, Department of Medicine Solna, Karolinska Institutet, SE-171 76 Stockholm, SwedenMicrobial Pathogenesis Unit, Department of Medicine Solna, Karolinska Institutet, SE-171 76 Stockholm, SwedenHuman cytomegalovirus (HCMV) infection is an important cause of morbidity and mortality in immunocompromised patients and a major etiological factor for congenital birth defects in newborns. Ganciclovir and its pro-drug valganciclovir are the preferred drugs in use today for prophylaxis and treatment of viremic patients. Due to long treatment times, patients are at risk for developing viral resistance to ganciclovir and to other drugs with a similar mechanism of action. We earlier found that the endothelin receptor B (ETBR) is upregulated during HCMV infection and that it plays an important role in the life cycle of this virus. Here, we tested the hypothesis that ETBR blockade could be used in the treatment of HCMV infection. As HCMV infection is specific to humans, we tested our hypothesis in human cell types that are relevant for HCMV pathogenesis; i.e., endothelial cells, epithelial cells and fibroblasts. We infected these cells with HCMV and treated them with the ETBR specific antagonist BQ788 or ETR antagonists that are approved by the FDA for treatment of pulmonary hypertension; macitentan, its metabolite ACT-132577, bosentan and ambrisentan, and as an anti-viral control, we used ganciclovir or letermovir. At concentrations expected to be relevant in vivo, macitentan, ACT-132577 and BQ788 effectively inhibited productive infection of HCMV. Of importance, macitentan also inhibited productive infection of a ganciclovir-resistant HCMV isolate. Our results suggest that binding or signaling through ETBR is crucial for viral replication, and that selected ETBR blockers inhibit HCMV infection.https://www.mdpi.com/2073-4409/10/11/3072cytomegalovirusendothelin receptorrepurposing |
| spellingShingle | Natalia Landázuri Jennifer Gorwood Ylva Terelius Fredrik Öberg Koon Chu Yaiw Afsar Rahbar Cecilia Söderberg-Nauclér The Endothelin Receptor Antagonist Macitentan Inhibits Human Cytomegalovirus Infection Cells cytomegalovirus endothelin receptor repurposing |
| title | The Endothelin Receptor Antagonist Macitentan Inhibits Human Cytomegalovirus Infection |
| title_full | The Endothelin Receptor Antagonist Macitentan Inhibits Human Cytomegalovirus Infection |
| title_fullStr | The Endothelin Receptor Antagonist Macitentan Inhibits Human Cytomegalovirus Infection |
| title_full_unstemmed | The Endothelin Receptor Antagonist Macitentan Inhibits Human Cytomegalovirus Infection |
| title_short | The Endothelin Receptor Antagonist Macitentan Inhibits Human Cytomegalovirus Infection |
| title_sort | endothelin receptor antagonist macitentan inhibits human cytomegalovirus infection |
| topic | cytomegalovirus endothelin receptor repurposing |
| url | https://www.mdpi.com/2073-4409/10/11/3072 |
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