Melatonin drugs inhibit brain infection by SARS-CoV-2

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A study conducted by the team of Ralf Jockers (Institut Cochin, Inserm, CNRS, Université Paris Cité) highlighted the therapeutic potential of melatonin and its derivative drugs to prevent SARS‑CoV‑2 entry into the brain and associated brain inflammation in an animal model of COVID-19 infected with SARS-CoV-2.

The results of this work are published in Cellular and Molecular Life Sciences.

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.

modèle animal de l'effet de la mélatonine sur l'infection du cerveau par 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).

Reference

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.

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Ralf Jockers

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