ABSTRACT
We have previously shown that the acid sphingomyelinase/ceramide system plays an important role in bacterial and viral infections. Pharmacological inhibition of acid sphingomyelinase with amitriptyline, imipramine, fluoxetine, sertraline, escitalopram or maprotiline or genetic down-regulation of the enzyme prevents infection with authentic SARS-CoV-2 or pseudoviral particles expressing pp-VSV-SARS-CoV-2 spike that served as a bona fide system mimicking SARS-CoV-2 infection. Mechanistically, acid sphingomyelinase mediates the formation of ceramide-enriched membrane platforms that serve the infection with pp-VSV-SARS-CoV-2 spike. Neutralization or consumption of surface ceramide reduces infection with pp-VSV-SARS-CoV-2 spike. Treatment of volunteers with a low dose of amitriptyline prevents infection of freshly isolated nasal epithelial cells with pp-VSV-SARS-CoV-2 spike, indicating that amitriptyline can be repurposed to prevent SARS-CoV-2 infection. Our data suggest the use of amitriptyline, a safe drug clinically used for almost 60 years, other antidepressants blocking the acid sphingomyelinase, anti-ceramide antibodies and neutral ceramidase for prophylaxis and treatment of coronavirus disease-19.Funding: The study was supported by DFG grant Gu-335-35/1 and BMBF, RAPID Consortium,grant 01KI1723D to SP.Conflict of Interest: The authors declare no competing financial interests.Ethical Approval: The experiments were approved by the local ethics committee under the number 20-9348-BO.