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Inhibition of acid sphingomyelinase by ambroxol prevents SARS-CoV-2 entry into epithelial cells.
Carpinteiro, Alexander; Gripp, Barbara; Hoffmann, Markus; Pöhlmann, Stefan; Hoertel, Nicolas; Edwards, Michael J; Kamler, Markus; Kornhuber, Johannes; Becker, Katrin Anne; Gulbins, Erich.
  • Carpinteiro A; Institute of Molecular Biology, University of Duisburg-Essen, Essen, Germany; Department of Hematology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
  • Gripp B; Zentrum für Seelische Gesundheit des Kindes- und Jugendalters, Sana-Klinikum Remscheid GmbH, Remscheid, Germany.
  • Hoffmann M; Infection Biology Unit, German Primate Center - Leibniz Institute for Primate Research, Göttingen, Germany; Faculty of Biology and Psychology, University of Göttingen, Göttingen, Germany.
  • Pöhlmann S; Infection Biology Unit, German Primate Center - Leibniz Institute for Primate Research, Göttingen, Germany; Faculty of Biology and Psychology, University of Göttingen, Göttingen, Germany.
  • Hoertel N; AP-HP.Centre-Université de Paris, Hôpital Corentin-Celton, Département de Psychiatrie, Issy-les-Moulineaux, and Université de Paris, INSERM, Institut de Psychiatrie et Neurosciences de Paris, UMR_S1266, and Faculté de Santé, UFR de Médecine, Paris, France.
  • Edwards MJ; Department of Surgery, Medical School, University of Cincinnati, Cincinnati, Ohio, USA.
  • Kamler M; Department of Thoracic and Cardiovascular Surgery, Division of Thoracic Transplantation, University Hospital Essen, Essen, Germany.
  • Kornhuber J; Department of Psychiatry and Psychotherapy, University Hospital of Erlangen, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen, Germany.
  • Becker KA; Institute of Molecular Biology, University of Duisburg-Essen, Essen, Germany.
  • Gulbins E; Institute of Molecular Biology, University of Duisburg-Essen, Essen, Germany; Department of Surgery, Medical School, University of Cincinnati, Cincinnati, Ohio, USA. Electronic address: erich.gulbins@uni-due.de.
J Biol Chem ; 296: 100701, 2021.
Article in English | MEDLINE | ID: covidwho-1198856
ABSTRACT
The acid sphingomyelinase/ceramide system has been shown to be important for cellular infection with at least some viruses, for instance, rhinovirus or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Functional inhibition of the acid sphingomyelinase using tricyclic antidepressants prevented infection of epithelial cells, for instance with SARS-CoV-2. The structure of ambroxol, that is, trans-4-[(2,4-dibromanilin-6-yl)-methyamino]-cyclohexanol, a mucolytic drug applied by inhalation, suggests that the drug might inhibit the acid sphingomyelinase and thereby infection with SARS-CoV-2. To test this, we used vesicular stomatitis virus pseudoviral particles presenting SARS-CoV-2 spike protein on their surface (pp-VSV-SARS-CoV-2 spike), a bona fide system for mimicking SARS-CoV-2 entry into cells. Viral uptake and formation of ceramide localization were determined by fluorescence microscopy, activity of the acid sphingomyelinase by consumption of [14C]sphingomyelin and ceramide was quantified by a kinase method. We found that entry of pp-VSV-SARS-CoV-2 spike required activation of acid sphingomyelinase and release of ceramide, events that were all prevented by pretreatment with ambroxol. We also obtained nasal epithelial cells from human volunteers prior to and after inhalation of ambroxol. Inhalation of ambroxol reduced acid sphingomyelinase activity in nasal epithelial cells and prevented pp-VSV-SARS-CoV-2 spike-induced acid sphingomyelinase activation, ceramide release, and entry of pp-VSV-SARS-CoV-2 spike ex vivo. The addition of purified acid sphingomyelinase or C16 ceramide restored entry of pp-VSV-SARS-CoV-2 spike into ambroxol-treated epithelial cells. We propose that ambroxol might be suitable for clinical studies to prevent coronavirus disease 2019.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / Sphingomyelin Phosphodiesterase / Vesiculovirus / Virus Internalization / Ambroxol / SARS-CoV-2 Type of study: Prognostic study Limits: Animals / Humans Language: English Journal: J Biol Chem Year: 2021 Document Type: Article Affiliation country: J.jbc.2021.100701

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / Sphingomyelin Phosphodiesterase / Vesiculovirus / Virus Internalization / Ambroxol / SARS-CoV-2 Type of study: Prognostic study Limits: Animals / Humans Language: English Journal: J Biol Chem Year: 2021 Document Type: Article Affiliation country: J.jbc.2021.100701