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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Autores principales:	Natalia Landázuri, Jennifer Gorwood, Ylva Terelius, Fredrik Öberg, Koon Chu Yaiw, Afsar Rahbar, Cecilia Söderberg-Nauclér
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	cytomegalovirus endothelin receptor repurposing Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/b455b9d8327b4176a0cfab58dc3d66cf
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spelling	oai:doaj.org-article:b455b9d8327b4176a0cfab58dc3d66cf2021-11-25T17:11:17ZThe Endothelin Receptor Antagonist Macitentan Inhibits Human Cytomegalovirus Infection10.3390/cells101130722073-4409https://doaj.org/article/b455b9d8327b4176a0cfab58dc3d66cf2021-11-01T00:00:00Zhttps://www.mdpi.com/2073-4409/10/11/3072https://doaj.org/toc/2073-4409Human 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.Natalia LandázuriJennifer GorwoodYlva TereliusFredrik ÖbergKoon Chu YaiwAfsar RahbarCecilia Söderberg-NauclérMDPI AGarticlecytomegalovirusendothelin receptorrepurposingBiology (General)QH301-705.5ENCells, Vol 10, Iss 3072, p 3072 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	cytomegalovirus endothelin receptor repurposing Biology (General) QH301-705.5
spellingShingle	cytomegalovirus endothelin receptor repurposing Biology (General) QH301-705.5 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
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.
format	article
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
title	The Endothelin Receptor Antagonist Macitentan Inhibits Human Cytomegalovirus Infection
title_short	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_sort	endothelin receptor antagonist macitentan inhibits human cytomegalovirus infection
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/b455b9d8327b4176a0cfab58dc3d66cf
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The Endothelin Receptor Antagonist Macitentan Inhibits Human Cytomegalovirus Infection

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