PT  - JOURNAL ARTICLE
AU  - Erika Cecon
AU  - Daniela Fernandois
AU  - Nicolas Renault
AU  - Caio Fernando Ferreira Coelho
AU  - Jan Wenzel
AU  - Corentin Bedart
AU  - Charlotte Izabelle
AU  - Sarah Gallet Wimez
AU  - Sophie Le Poder
AU  - Bernard Klonjkowski
AU  - Markus Schwaninger
AU  - Vincent Prevot
AU  - Julie Dam
AU  - Ralf Jockers
TI  - Melatonin drugs inhibit SARS-CoV-2 entry into the brain and virus-induced damage of cerebral small vessels
AID  - 10.1101/2021.12.30.474561
DP  - 2022 Jan 01
TA  - bioRxiv
PG  - 2021.12.30.474561
4099  - http://biorxiv.org/content/early/2022/01/03/2021.12.30.474561.short
4100  - http://biorxiv.org/content/early/2022/01/03/2021.12.30.474561.full
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 condition. Brain infection is particularly pronounced in the K18-hACE2 mouse model of COVID-19. Here, we show that treatment of K18-hACE2 mice with melatonin and two melatonin-derived marketed drugs, agomelatine and ramelteon, prevent SARS-CoV-2 entry in the brain thereby reducing virus-induced damage of small cerebral vessels, immune cell infiltration and brain inflammation. Brain entry of SARS-CoV-2 through endothelial cells is prevented by melatonin through allosteric binding to human angiotensin-converting enzyme 2 (ACE2), which interferes with the cell entry receptor function of ACE2 for SARS-CoV-2. Our findings open new perspectives for the repurposing of melatonergic drugs in the prevention of brain infection by SARS-CoV-2 and COVID-19-related long-term neurological symptoms.Competing Interest StatementThe authors have declared no competing interest.