Inhibition of acid sphingomyelinase by ambroxol prevents SARS-CoV-2 entry into epithelial cells
In Vitro study showing that ambroxol (a metabolite of bromhexine) inhibits SARS-CoV-2 infection.
Bromhexine efficacy may vary depending on the degree of TMPRSS-dependent fusion for different variants
Peacock, Willett.
4 preclinical studies support the efficacy of bromhexine for COVID-19:
Carpinteiro et al., 31 Jan 2021, peer-reviewed, 10 authors.
In Vitro studies are an important part of preclinical research, however results may be very different in vivo.
Abstract: RESEARCH ARTICLE
Inhibition of acid sphingomyelinase by ambroxol prevents
SARS-CoV-2 entry into epithelial cells
Received for publication, January 10, 2021, and in revised form, April 15, 2021 Published, Papers in Press, April 23, 2021,
https://doi.org/10.1016/j.jbc.2021.100701
Alexander Carpinteiro1,2, Barbara Gripp3, Markus Hoffmann4,5 , Stefan Pöhlmann4,5 , Nicolas Hoertel6,
Michael J. Edwards7, Markus Kamler8 , Johannes Kornhuber9, Katrin Anne Becker1, and Erich Gulbins1,7, *
From the 1Institute of Molecular Biology and 2Department of Hematology, University Hospital Essen, University of DuisburgEssen, Essen, Germany; 3Zentrum für Seelische Gesundheit des Kindes- und Jugendalters, Sana-Klinikum Remscheid GmbH,
Remscheid, Germany; 4Infection Biology Unit, German Primate Center – Leibniz Institute for Primate Research, Göttingen,
Germany; 5Faculty of Biology and Psychology, University of Göttingen, Göttingen, Germany; 6AP-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; 7Department of Surgery, Medical
School, University of Cincinnati, Cincinnati, Ohio, USA; 8Department of Thoracic and Cardiovascular Surgery, Division of Thoracic
Transplantation, University Hospital Essen, Essen, Germany; and 9Department of Psychiatry and Psychotherapy, University
Hospital of Erlangen, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen, Germany
Edited by Craig Cameron
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 (ppVSV-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 spikeinduced 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.
Infections with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the..
Please send us corrections, updates, or comments. Vaccines and
treatments are complementary. All practical, effective, and safe means should
be used based on risk/benefit analysis. No treatment, vaccine, or intervention
is 100% available and effective for all current and future variants. We do not
provide medical advice. Before taking any medication, consult a qualified
physician who can provide personalized advice and details of risks and
benefits based on your medical history and situation.
FLCCC and
WCH
provide treatment protocols.
Submit