The Endothelin Receptor Antagonist Macitentan Inhibits Human Cytomegalovirus Infection

Abstract

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.

Blockade of Endothelin Receptors Mitigates SARS-CoV-2-induced Osteochondral Damage

“…We demonstrated that macitentan could effectively rescue osteochondral damage in a pre-clinical setting, either in acute phase or sub-acute phase of SARS-CoV-2 infection. In addition to the antiinflammatory effect via endothelin receptor blockade 54 , the potential antiviral effect of endothelin receptor antagonists has also been documented to lower influenza and cytomegalovirus viral RNA counts in vitro 55,56 . We observed macitentan could decrease viral spike protein in local joint tissue in infected hamsters in vivo.…”

Inhibition of Human Cytomegalovirus Particle Maturation by Activation of Liver X Receptor

“…Human cytomegalovirus (HCMV) is a large, complex enveloped virus that belongs to the herpesvirus family ( Mettenleiter et al, 2009 ). HCMV infection causes severe diseases in immunocompromised individuals such as AIDS patients and organ transplant recipients and is the most common and harmful pathogen causing congenital infection and birth defects ( Landázuri et al, 2021 ).…”

State of the Art of Innate Immunity—An Overview

“…Drugs such as ganciclovir and its pro-drug valganciclovir are often used to treat viremic patients transfected with, e.g., human cytomegalovirus (HCMV). Results from Landázuri now suggest that binding and signaling through endothelin receptor B (ETBR) is crucial for viral replication and that selected ETBR blockers inhibit HCMV infections [ 10 ].…”