Fluoxetine and Sertraline Potently Neutralize the Replication of Distinct SARS-CoV-2 Variants (preprint)

The pandemic caused by SARS-CoV-2 is still a major health problem. Newly emerging variants and long-COVID-19 represent a challenge for the global health system. In particular, individuals in developing countries with insufficient health care need easily accessible, affordable and effective treatments of COVID-19. Previous studies have demonstrated the efficacy of functional inhibitors of acid sphingomyelinase (FIASMA) against infections with various viruses, including early variants of SARS-CoV-2. This work investigated whether the acid sphingomyelinase inhibitors fluoxetine and sertraline, usually used as antidepressant molecules in clinical practice, can inhibit the replication of the former and recently emerged SARS-CoV-2 variants in vitro. Fluoxetine and sertraline potently inhibited the infection with pseudotyped virus like particles and SARS-CoV-2 variants D614G, alpha, delta, omicron BA.1 and omicron BA.5. These results highlight fluoxetine and sertraline as priority candidates for large-scale phase 3 clinical trials at different stages of SARS-CoV-2 infections, either alone or in combination with other medications.

Inhibition of Acid Sphingomyelinase Blocks Infection with SARS-CoV-2 (preprint)

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.