The team of Ralf Jockers with E. Cecon and J. Dam (Institut Cochin), in close collaboration with the teams of V. Prevot (Inserm, Université Lille), N. Renault (Inserm, Université Lille), M. Schwaninger (University of Lübeck, Germany), and S. Le Poder/B. Klonjkowski (National Veterinary School of Alfort), show that treatment of K18-hACE2 mice with melatonin and two melatonin-derived marketed drugs, agomelatine and ramelteon, prevents brain infection by SARS-CoV-2 in this COVID-19 model of massive brain infection. Melatoninergic compounds prevent specifically the entry of SARS-CoV-2 in the brain, thereby reducing virus-induced damage of small cerebral vessels, immune cell infiltration and brain inflammation
Using an assay previously developed in the team to probe the interaction of the SARS-CoV-2 spike protein with its cellular receptor human angiotensin-converting enzyme 2 (ACE2) (doi: 10.1016/j.chembiol.2021.06.008.) and molecular dynamics studies, the authors identified the first allosteric binding site at ACE2 that allosterically modifies the spike-ACE2 interface. SARS-CoV-2 entry in brain endothelial cells is prevented by melatonin binding to ACE2, thus interfering with ACE2 function as an entry receptor for SARS-CoV-2.
These 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.
This work was funded by the National Research Agency (ANR-RA-COVID-19: ANR-20-COV4-0001).
Cecon E, Fernandois D, Renault N, Coelho CFF, Wenzel J, Bedart C, Izabelle C, Gallet S, Le Poder S, Klonjkowski B, Schwaninger M, Prevot V, Dam J, Jockers R. Melatonin drugs inhibit SARS-CoV-2 entry into the brain and virus-induced damage of cerebral small vessels. Cell Mol Life Sci. 2022 Jun 13;79(7):361. doi: 10.1007/s00018-022-04390-3. PMID: 35697820; PMCID: PMC9191404.