Melatonin drugs inhibit SARS-CoV-2 entry into the brain and virus-induced damage of cerebral small vessels.
Brain infection
COVID-19
Drug repurposing
Melatonin
Neuro-vasculature
SARS-CoV-2
Journal
Cellular and molecular life sciences : CMLS
ISSN: 1420-9071
Titre abrégé: Cell Mol Life Sci
Pays: Switzerland
ID NLM: 9705402
Informations de publication
Date de publication:
13 Jun 2022
13 Jun 2022
Historique:
received:
31
03
2022
accepted:
20
05
2022
revised:
11
05
2022
entrez:
13
6
2022
pubmed:
14
6
2022
medline:
16
6
2022
Statut:
epublish
Résumé
COVID-19 is a complex disease with short- and long-term respiratory, inflammatory and neurological symptoms that are triggered by the infection with SARS-CoV-2. Invasion of the brain by SARS-CoV-2 has been observed in humans and is postulated to be involved in post-COVID state. Brain infection is particularly pronounced in the K18-hACE2 mouse model of COVID-19. Prevention of brain infection in the acute phase of the disease might thus be of therapeutic relevance to prevent long-lasting symptoms of COVID-19. We previously showed that melatonin or two prescribed structural analogs, agomelatine and ramelteon delay the onset of severe clinical symptoms and improve survival of SARS-CoV-2-infected K18-hACE2 mice. Here, we show that treatment of K18-hACE2 mice with melatonin and two melatonin-derived marketed drugs, agomelatine and ramelteon, prevents SARS-CoV-2 entry in the brain, thereby reducing virus-induced damage of small cerebral vessels, immune cell infiltration and brain inflammation. Molecular modeling analyses complemented by experimental studies in cells showed that SARS-CoV-2 entry in endothelial cells is prevented by melatonin binding to an allosteric-binding site on human angiotensin-converting enzyme 2 (ACE2), thus interfering with ACE2 function as an entry receptor for SARS-CoV-2. Our findings open new perspectives for the repurposing of melatonergic drugs and its clinically used analogs in the prevention of brain infection by SARS-CoV-2 and COVID-19-related long-term neurological symptoms.
Identifiants
pubmed: 35697820
doi: 10.1007/s00018-022-04390-3
pii: 10.1007/s00018-022-04390-3
pmc: PMC9191404
doi:
Substances chimiques
Peptidyl-Dipeptidase A
EC 3.4.15.1
Angiotensin-Converting Enzyme 2
EC 3.4.17.23
Melatonin
JL5DK93RCL
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
361Subventions
Organisme : Agence Nationale de la Recherche
ID : ANR-20-COV4-0001
Organisme : Agence Nationale de la Recherche
ID : ANR-19-CE16-0025-01
Organisme : Agence Nationale de la Recherche
ID : ANR-16-CE18-0013
Organisme : Deutsches Krebsforschungszentrum
ID : WE 6456/1-1
Organisme : Fondation pour la Recherche Médicale (FR)
ID : FRM DEQ20130326503
Organisme : Ligue Contre le Cancer
ID : RS19/75-127
Organisme : Association France Alzheimer
ID : grant No. 2042
Organisme : Fondation de France (FR)
ID : Fondadtion de France
Informations de copyright
© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.
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