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..
{ 'indexed': {'date-parts': [[2021, 12, 8]], 'date-time': '2021-12-08T10:07:44Z', 'timestamp': 1638958064008},
'reference-count': 41,
'publisher': 'Elsevier BV',
'license': [ { 'start': { 'date-parts': [[2021, 1, 1]],
'date-time': '2021-01-01T00:00:00Z',
'timestamp': 1609459200000},
'content-version': 'tdm',
'delay-in-days': 0,
'URL': 'https://www.elsevier.com/tdm/userlicense/1.0/'},
{ 'start': { 'date-parts': [[2021, 4, 22]],
'date-time': '2021-04-22T00:00:00Z',
'timestamp': 1619049600000},
'content-version': 'vor',
'delay-in-days': 111,
'URL': 'http://creativecommons.org/licenses/by/4.0/'}],
'funder': [ { 'DOI': '10.13039/501100001659',
'name': 'Deutsche Forschungsgemeinschaft',
'doi-asserted-by': 'publisher'},
{ 'DOI': '10.13039/501100002347',
'name': 'Bundesministerium für Bildung und Forschung',
'doi-asserted-by': 'publisher',
'award': ['01KI1723D', '01KI2006D', '01KI20328A', '01KI20396']}],
'content-domain': { 'domain': ['jbc.org', 'elsevier.com', 'sciencedirect.com'],
'crossmark-restriction': True},
'short-container-title': ['Journal of Biological Chemistry'],
'published-print': {'date-parts': [[2021, 1]]},
'DOI': '10.1016/j.jbc.2021.100701',
'type': 'journal-article',
'created': {'date-parts': [[2021, 4, 23]], 'date-time': '2021-04-23T06:50:08Z', 'timestamp': 1619160608000},
'page': '100701',
'update-policy': 'http://dx.doi.org/10.1016/elsevier_cm_policy',
'source': 'Crossref',
'is-referenced-by-count': 14,
'title': [ 'Inhibition of acid sphingomyelinase by ambroxol prevents SARS-CoV-2 entry into epithelial '
'cells'],
'prefix': '10.1016',
'volume': '296',
'author': [ {'given': 'Alexander', 'family': 'Carpinteiro', 'sequence': 'first', 'affiliation': []},
{'given': 'Barbara', 'family': 'Gripp', 'sequence': 'additional', 'affiliation': []},
{ 'ORCID': 'http://orcid.org/0000-0003-4603-7696',
'authenticated-orcid': False,
'given': 'Markus',
'family': 'Hoffmann',
'sequence': 'additional',
'affiliation': []},
{ 'ORCID': 'http://orcid.org/0000-0001-6086-9136',
'authenticated-orcid': False,
'given': 'Stefan',
'family': 'Pöhlmann',
'sequence': 'additional',
'affiliation': []},
{'given': 'Nicolas', 'family': 'Hoertel', 'sequence': 'additional', 'affiliation': []},
{'given': 'Michael J.', 'family': 'Edwards', 'sequence': 'additional', 'affiliation': []},
{ 'ORCID': 'http://orcid.org/0000-0001-6608-8496',
'authenticated-orcid': False,
'given': 'Markus',
'family': 'Kamler',
'sequence': 'additional',
'affiliation': []},
{'given': 'Johannes', 'family': 'Kornhuber', 'sequence': 'additional', 'affiliation': []},
{'given': 'Katrin Anne', 'family': 'Becker', 'sequence': 'additional', 'affiliation': []},
{'given': 'Erich', 'family': 'Gulbins', 'sequence': 'additional', 'affiliation': []}],
'member': '78',
'reference': [ { 'key': '10.1016/j.jbc.2021.100701_bib1',
'doi-asserted-by': 'crossref',
'first-page': '270',
'DOI': '10.1038/s41586-020-2012-7',
'article-title': 'A\xa0pneumonia outbreak associated with a new coronavirus of probable '
'bat origin',
'volume': '579',
'author': 'Zhou',
'year': '2020',
'journal-title': 'Nature'},
{ 'key': '10.1016/j.jbc.2021.100701_bib2',
'doi-asserted-by': 'crossref',
'first-page': '47',
'DOI': '10.1016/j.cmi.2020.10.017',
'article-title': 'Clinical course and outcomes of critically ill patients with COVID-19 '
'infection: A systematic review',
'volume': '27',
'author': 'Serafim',
'year': '2021',
'journal-title': 'Clin. Microbiol. Infect.'},
{ 'key': '10.1016/j.jbc.2021.100701_bib3',
'doi-asserted-by': 'crossref',
'first-page': '1260',
'DOI': '10.1126/science.abb2507',
'article-title': 'Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation',
'volume': '367',
'author': 'Wrapp',
'year': '2020',
'journal-title': 'Science'},
{ 'key': '10.1016/j.jbc.2021.100701_bib4',
'doi-asserted-by': 'crossref',
'first-page': '215',
'DOI': '10.1038/s41586-020-2180-5',
'article-title': 'Structure of the SARS-CoV-2 spike receptor-binding domain bound to the '
'ACE2 receptor',
'volume': '581',
'author': 'Lan',
'year': '2020',
'journal-title': 'Nature'},
{ 'key': '10.1016/j.jbc.2021.100701_bib5',
'doi-asserted-by': 'crossref',
'first-page': '894',
'DOI': '10.1016/j.cell.2020.03.045',
'article-title': 'Structural and functional basis of SARS-CoV-2 entry by using human ACE2',
'volume': '181',
'author': 'Wang',
'year': '2020',
'journal-title': 'Cell'},
{ 'key': '10.1016/j.jbc.2021.100701_bib6',
'doi-asserted-by': 'crossref',
'first-page': '285',
'DOI': '10.1002/1097-4652(200009)184:3<285::AID-JCP2>3.0.CO;2-3',
'article-title': 'Compartmentalization of ceramide signaling: Physical foundations and '
'biological effects',
'volume': '184',
'author': 'Kolesnick',
'year': '2000',
'journal-title': 'J.\xa0Cell. Physiol.'},
{ 'key': '10.1016/j.jbc.2021.100701_bib7',
'doi-asserted-by': 'crossref',
'first-page': '7070',
'DOI': '10.1038/sj.onc.1207146',
'article-title': 'Raft ceramide in molecular medicine',
'volume': '22',
'author': 'Gulbins',
'year': '2003',
'journal-title': 'Oncogene'},
{ 'key': '10.1016/j.jbc.2021.100701_bib8',
'doi-asserted-by': 'crossref',
'first-page': '3419',
'DOI': '10.1096/fj.08-108043',
'article-title': 'The unexpected role of acid sphingomyelinase in cell death and the '
'pathophysiology of common diseases',
'volume': '22',
'author': 'Smith',
'year': '2008',
'journal-title': 'FASEB J.'},
{ 'key': '10.1016/j.jbc.2021.100701_bib9',
'doi-asserted-by': 'crossref',
'first-page': '12129',
'DOI': '10.1021/ja017807r',
'article-title': 'Observation of topical catalysis by sphingomyelinase coupled to '
'microspheres',
'volume': '124',
'author': 'Nurminen',
'year': '2002',
'journal-title': 'J.\xa0Am. Chem. Soc.'},
{ 'key': '10.1016/j.jbc.2021.100701_bib10',
'doi-asserted-by': 'crossref',
'first-page': '20589',
'DOI': '10.1074/jbc.M101207200',
'article-title': 'CD95 signaling via ceramide-rich membrane rafts',
'volume': '276',
'author': 'Grassmé',
'year': '2001',
'journal-title': 'J.\xa0Biol. Chem.'},
{ 'key': '10.1016/j.jbc.2021.100701_bib11',
'doi-asserted-by': 'crossref',
'first-page': '1411',
'DOI': '10.1089/ars.2007.1736',
'article-title': 'Lipid rafts and redox signaling',
'volume': '9',
'author': 'Li',
'year': '2007',
'journal-title': 'Antioxid. Redox Signal.'},
{ 'key': '10.1016/j.jbc.2021.100701_bib12',
'doi-asserted-by': 'crossref',
'first-page': '322',
'DOI': '10.1038/nm823',
'article-title': 'Host defense against Pseudomonas aeruginosa requires ceramide-rich '
'membrane rafts',
'volume': '9',
'author': 'Grassmé',
'year': '2003',
'journal-title': 'Nat. Med.'},
{ 'key': '10.1016/j.jbc.2021.100701_bib13',
'doi-asserted-by': 'crossref',
'first-page': '707',
'DOI': '10.1016/j.chom.2017.05.001',
'article-title': 'β1-Integrin accumulates in cystic fibrosis luminal airway epithelial '
'membranes and decreases sphingosine, promoting bacterial infections',
'volume': '21',
'author': 'Grassmé',
'year': '2017',
'journal-title': 'Cell Host Microbe'},
{ 'key': '10.1016/j.jbc.2021.100701_bib14',
'doi-asserted-by': 'crossref',
'first-page': '100142',
'DOI': '10.1016/j.xcrm.2020.100142',
'article-title': 'Pharmacological inhibition of acid sphingomyelinase prevents uptake of '
'SARS-CoV-2 by epithelial cells',
'volume': '1',
'author': 'Carpinteiro',
'year': '2020',
'journal-title': 'Cell Rep. Med.'},
{ 'key': '10.1016/j.jbc.2021.100701_bib15',
'doi-asserted-by': 'crossref',
'first-page': '447',
'DOI': '10.1515/bchm3.1994.375.7.447',
'article-title': 'The tricyclic antidepressant desipramine causes proteolytic degradation '
'of lysosomal sphingomyelinase in human fibroblasts',
'volume': '375',
'author': 'Hurwitz',
'year': '1994',
'journal-title': 'Biol. Chem. Hoppe Seyler'},
{ 'key': '10.1016/j.jbc.2021.100701_bib16',
'doi-asserted-by': 'crossref',
'first-page': '96',
'DOI': '10.1016/S0014-5793(04)00033-X',
'article-title': 'Interactions of acid sphingomyelinase and lipid bilayers in the '
'presence of the tricyclic antidepressant desipramine',
'volume': '559',
'author': 'Kölzer',
'year': '2004',
'journal-title': 'FEBS Lett.'},
{ 'key': '10.1016/j.jbc.2021.100701_bib17',
'doi-asserted-by': 'crossref',
'first-page': '219',
'DOI': '10.1021/jm070524a',
'article-title': 'Identification of new functional inhibitors of acid sphingomyelinase '
'using a structure-property-activity relation model',
'volume': '51',
'author': 'Kornhuber',
'year': '2008',
'journal-title': 'J.\xa0Med. Chem.'},
{ 'key': '10.1016/j.jbc.2021.100701_bib18',
'doi-asserted-by': 'crossref',
'first-page': '934',
'DOI': '10.1038/nm.3214',
'article-title': 'Acid sphingomyelinase/ceramide system mediates effects of '
'antidepressant drugs',
'volume': '19',
'author': 'Gulbins',
'year': '2013',
'journal-title': 'Nat. Med.'},
{ 'key': '10.1016/j.jbc.2021.100701_bib19',
'doi-asserted-by': 'crossref',
'first-page': '2324',
'DOI': '10.1038/s41380-018-0090-9',
'article-title': 'Antidepressants act by inducing autophagy controlled by '
'sphingomyelin-ceramide',
'volume': '23',
'author': 'Gulbins',
'year': '2018',
'journal-title': 'Mol. Psychiatry'},
{ 'key': '10.1016/j.jbc.2021.100701_bib20',
'doi-asserted-by': 'crossref',
'first-page': '31',
'DOI': '10.1515/hsz-2019-0270',
'article-title': 'Emerging mechanisms of drug-induced phospholipidosis',
'volume': '401',
'author': 'Breiden',
'year': '2019',
'journal-title': 'Biol. Chem.'},
{ 'key': '10.1016/j.jbc.2021.100701_bib21',
'doi-asserted-by': 'crossref',
'DOI': '10.1371/journal.pone.0023852',
'article-title': 'Identification of novel functional inhibitors of acid sphingomyelinase',
'volume': '6',
'author': 'Kornhuber',
'year': '2011',
'journal-title': 'PLoS One'},
{ 'key': '10.1016/j.jbc.2021.100701_bib22',
'doi-asserted-by': 'crossref',
'first-page': '271',
'DOI': '10.1016/j.cell.2020.02.052',
'article-title': 'SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a '
'clinically proven protease inhibitor',
'volume': '181',
'author': 'Hoffmann',
'year': '2020',
'journal-title': 'Cell'},
{ 'key': '10.1016/j.jbc.2021.100701_bib23',
'doi-asserted-by': 'crossref',
'first-page': '15174',
'DOI': '10.1074/jbc.RA120.015249',
'article-title': 'Sphingosine prevents binding of SARS-CoV-2 spike to its cellular '
'receptor ACE2',
'volume': '295',
'author': 'Edwards',
'year': '2020',
'journal-title': 'J.\xa0Biol. Chem.'},
{ 'key': '10.1016/j.jbc.2021.100701_bib24',
'doi-asserted-by': 'crossref',
'first-page': '1205',
'DOI': '10.15252/emmm.201404075',
'article-title': 'Sphingoid long chain bases prevent lung infection by Pseudomonas '
'aeruginosa',
'volume': '6',
'author': 'Pewzner-Jung',
'year': '2014',
'journal-title': 'EMBO Mol. Med.'},
{ 'key': '10.1016/j.jbc.2021.100701_bib25',
'doi-asserted-by': 'crossref',
'first-page': '26256',
'DOI': '10.1074/jbc.M500835200',
'article-title': 'Rhinoviruses infect human epithelial cells via ceramide-enriched '
'membrane platforms',
'volume': '280',
'author': 'Grassmé',
'year': '2005',
'journal-title': 'J.\xa0Biol. Chem.'},
{ 'key': '10.1016/j.jbc.2021.100701_bib26',
'doi-asserted-by': 'crossref',
'first-page': '675',
'DOI': '10.1007/s00109-014-1246-y',
'article-title': 'Acid sphingomyelinase inhibition protects mice from lung edema and '
'lethal Staphylococcus aureus sepsis',
'volume': '93',
'author': 'Peng',
'year': '2015',
'journal-title': 'J.\xa0Mol. Med. (Berl.)'},
{ 'key': '10.1016/j.jbc.2021.100701_bib27',
'doi-asserted-by': 'crossref',
'first-page': '716',
'DOI': '10.1165/rcmb.2009-0174OC',
'article-title': 'Acid sphingomyelinase inhibitors normalize pulmonary ceramide and '
'inflammation in cystic fibrosis',
'volume': '42',
'author': 'Becker',
'year': '2010',
'journal-title': 'Am. J. Respir. Cell Mol. Biol.'},
{ 'key': '10.1016/j.jbc.2021.100701_bib28',
'doi-asserted-by': 'crossref',
'first-page': '12658',
'DOI': '10.1128/JVI.01542-10',
'article-title': 'Efficient activation of the severe acute respiratory syndrome '
'coronavirus spike protein by the transmembrane protease TMPRSS2',
'volume': '84',
'author': 'Matsuyama',
'year': '2010',
'journal-title': 'J.\xa0Virol.'},
{ 'key': '10.1016/j.jbc.2021.100701_bib29',
'doi-asserted-by': 'crossref',
'first-page': '11876',
'DOI': '10.1073/pnas.0505577102',
'article-title': 'Inhibitors of cathepsin L prevent severe acute respiratory syndrome '
'coronavirus entry',
'volume': '102',
'author': 'Simmons',
'year': '2005',
'journal-title': 'Proc. Natl. Acad. Sci. U. S. A.'},
{ 'key': '10.1016/j.jbc.2021.100701_bib30',
'doi-asserted-by': 'crossref',
'first-page': '7473',
'DOI': '10.1128/JVI.00136-12',
'article-title': 'Ebolavirus requires acid sphingomyelinase activity and plasma membrane '
'sphingomyelin for infection',
'volume': '86',
'author': 'Miller',
'year': '2012',
'journal-title': 'J.\xa0Virol.'},
{ 'key': '10.1016/j.jbc.2021.100701_bib31',
'doi-asserted-by': 'crossref',
'DOI': '10.1371/journal.ppat.1001290',
'article-title': 'DC-SIGN mediated sphingomyelinase-activation and ceramide generation is '
'essential for enhancement of viral uptake in dendritic cells',
'volume': '7',
'author': 'Avota',
'year': '2011',
'journal-title': 'PLoS Pathog.'},
{ 'key': '10.1016/j.jbc.2021.100701_bib32',
'doi-asserted-by': 'crossref',
'first-page': '2798',
'DOI': '10.1128/JVI.02499-09',
'article-title': 'Involvement of ceramide in the propagation of Japanese encephalitis '
'virus',
'volume': '84',
'author': 'Tani',
'year': '2010',
'journal-title': 'J.\xa0Virol.'},
{ 'key': '10.1016/j.jbc.2021.100701_bib33',
'doi-asserted-by': 'crossref',
'DOI': '10.1128/JVI.00053-19',
'article-title': 'Ceramide suppresses Influenza A virus replication in\xa0vitro',
'volume': '93',
'author': 'Soudani',
'year': '2019',
'journal-title': 'J.\xa0Virol.'},
{ 'key': '10.1016/j.jbc.2021.100701_bib34',
'doi-asserted-by': 'crossref',
'first-page': '612',
'DOI': '10.3389/fmicb.2020.00612',
'article-title': 'Depletion of host and viral sphingomyelin impairs influenza virus '
'infection',
'volume': '11',
'author': 'Audi',
'year': '2020',
'journal-title': 'Front. Microbiol.'},
{ 'key': '10.1016/j.jbc.2021.100701_bib35',
'doi-asserted-by': 'crossref',
'first-page': '1338',
'DOI': '10.1038/s41467-020-15072-8',
'article-title': 'Acid ceramidase of macrophages traps herpes simplex virus in '
'multivesicular bodies and protects from severe disease',
'volume': '11',
'author': 'Lang',
'year': '2020',
'journal-title': 'Nat. Commun.'},
{ 'key': '10.1016/j.jbc.2021.100701_bib36',
'doi-asserted-by': 'crossref',
'first-page': '1310',
'DOI': '10.1158/2159-8290.CD-13-1010',
'article-title': 'The androgen-regulated protease TMPRSS2 activates a proteolytic cascade '
'involving components of the tumor microenvironment and promotes '
'prostate cancer metastasis',
'volume': '4',
'author': 'Lucas',
'year': '2014',
'journal-title': 'Cancer Discov.'},
{ 'key': '10.1016/j.jbc.2021.100701_bib37',
'doi-asserted-by': 'crossref',
'first-page': '1203',
'DOI': '10.1515/hsz-2018-0161',
'article-title': 'Pulmonary infection of cystic fibrosis mice with Staphylococcus aureus '
'requires expression of α-toxin',
'volume': '399',
'author': 'Keitsch',
'year': '2018',
'journal-title': 'Biol. Chem.'},
{ 'key': '10.1016/j.jbc.2021.100701_bib38',
'article-title': 'Ambroxol and Ciprofloxacin show activity against SARS-CoV2 in Vero E6 '
'cells at clinically-relevant concentrations',
'author': 'Bradfute',
'year': '2021',
'journal-title': 'bioRxiv'},
{ 'key': '10.1016/j.jbc.2021.100701_bib39',
'article-title': 'Ambroxol Hydrochloride inhibits the interaction between severe acute '
'respiratory syndrome Coronavirus 2 spike protein’s receptor binding '
'domain and recombinant human ACE2',
'author': 'Olaleye',
'year': '2021',
'journal-title': 'bioRxiv'},
{ 'key': '10.1016/j.jbc.2021.100701_bib40',
'doi-asserted-by': 'crossref',
'DOI': '10.1371/journal.pone.0025858',
'article-title': 'A\xa0vesicular stomatitis virus replicon-based bioassay for the rapid '
'and sensitive determination of multi-species type I interferon',
'volume': '6',
'author': 'Berger Rentsch',
'year': '2011',
'journal-title': 'PLoS One'},
{ 'key': '10.1016/j.jbc.2021.100701_bib41',
'doi-asserted-by': 'crossref',
'DOI': '10.1128/JVI.01381-18',
'article-title': 'Mutations in the spike protein of Middle East respiratory syndrome '
'coronavirus transmitted in Korea increase resistance to '
'antibody-mediated neutralization',
'volume': '93',
'author': 'Kleine-Weber',
'year': '2019',
'journal-title': 'J.\xa0Virol.'}],
'container-title': ['Journal of Biological Chemistry'],
'original-title': [],
'language': 'en',
'link': [ { 'URL': 'https://api.elsevier.com/content/article/PII:S0021925821004907?httpAccept=text/xml',
'content-type': 'text/xml',
'content-version': 'vor',
'intended-application': 'text-mining'},
{ 'URL': 'https://api.elsevier.com/content/article/PII:S0021925821004907?httpAccept=text/plain',
'content-type': 'text/plain',
'content-version': 'vor',
'intended-application': 'text-mining'}],
'deposited': { 'date-parts': [[2021, 10, 17]],
'date-time': '2021-10-17T06:55:04Z',
'timestamp': 1634453704000},
'score': 1,
'subtitle': [],
'short-title': [],
'issued': {'date-parts': [[2021, 1]]},
'references-count': 41,
'alternative-id': ['S0021925821004907'],
'URL': 'http://dx.doi.org/10.1016/j.jbc.2021.100701',
'relation': {},
'ISSN': ['0021-9258'],
'issn-type': [{'value': '0021-9258', 'type': 'print'}],
'subject': ['Cell Biology', 'Molecular Biology', 'Biochemistry'],
'published': {'date-parts': [[2021, 1]]},
'assertion': [ {'value': 'Elsevier', 'name': 'publisher', 'label': 'This article is maintained by'},
{ 'value': 'Inhibition of acid sphingomyelinase by ambroxol prevents SARS-CoV-2 entry into '
'epithelial cells',
'name': 'articletitle',
'label': 'Article Title'},
{ 'value': 'Journal of Biological Chemistry',
'name': 'journaltitle',
'label': 'Journal Title'},
{ 'value': 'https://doi.org/10.1016/j.jbc.2021.100701',
'name': 'articlelink',
'label': 'CrossRef DOI link to publisher maintained version'},
{'value': 'article', 'name': 'content_type', 'label': 'Content Type'},
{ 'value': '© 2021 The Authors. Published by Elsevier Inc on behalf of American Society for '
'Biochemistry and Molecular Biology.',
'name': 'copyright',
'label': 'Copyright'}],
'article-number': '100701'}
