TY - JOUR
T1 - Melatonin drugs inhibit SARS-CoV-2 entry into the brain and virus-induced damage of cerebral small vessels
AU - Cecon, Erika
AU - Fernandois, Daniela
AU - Renault, Nicolas
AU - Coelho, Caio Fernando Ferreira
AU - Wenzel, Jan
AU - Bedart, Corentin
AU - Izabelle, Charlotte
AU - Gallet, Sarah
AU - Le Poder, Sophie
AU - Klonjkowski, Bernard
AU - Schwaninger, Markus
AU - Prevot, Vincent
AU - Dam, Julie
AU - Jockers, Ralf
N1 - Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer Nature Switzerland AG.
PY - 2022/6/13
Y1 - 2022/6/13
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85131805847&partnerID=8YFLogxK
UR - https://www.mendeley.com/catalogue/b3a2e338-ddc0-3284-802c-fc314347c9b0/
U2 - 10.1007/s00018-022-04390-3
DO - 10.1007/s00018-022-04390-3
M3 - Journal articles
C2 - 35697820
SN - 1420-682X
VL - 79
SP - 361
JO - Cellular and Molecular Life Sciences
JF - Cellular and Molecular Life Sciences
IS - 7
M1 - 361
ER -