Melatonin drugs inhibit SARS-CoV-2 entry into the brain and virus-induced damage of cerebral small vessels

Erika Cecon, Daniela Fernandois, Nicolas Renault, Caio Fernando Ferreira Coelho, Jan Wenzel, Corentin Bedart, Charlotte Izabelle, Sarah Gallet, Sophie Le Poder, Bernard Klonjkowski, Markus Schwaninger, Vincent Prevot, Julie Dam, Ralf Jockers


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.

Original languageEnglish
Article number361
JournalCellular and Molecular Life Sciences
Issue number7
Pages (from-to)361
Publication statusPublished - 13.06.2022

Research Areas and Centers

  • Academic Focus: Center for Brain, Behavior and Metabolism (CBBM)

Coronavirus related work

  • Research on SARS-CoV-2 / COVID-19


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