Fluoxetine and Sertraline Potently Neutralize the Replication of Distinct SARS-CoV-2 Variants
Laura Thümmler, Nadine Beckmann, Carolin Sehl, Matthias Soddemann, Peer Braß, Maren Bormann, Leonie Brochhagen, Carina Elsner, Nicolas Hoertel, Céline Cougoule, Sandra Ciesek, Marek Widera, Ulf Dittmer, Monika Lindemann, Peter A Horn, Oliver Witzke, Stephanie Kadow, Markus Kamler, Erich Gulbins, Katrin Anne Becker, Adalbert Krawczyk
Viruses, doi:10.3390/v16040545
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 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.
spike protein. This is an interesting finding, as fluoxetine and sertraline were described to interfere with SARS-CoV-2 entry, and at least sertraline directly targeted the SARS-CoV-2 spike protein [7] . In addition to targeting the spike protein, fluoxetine and sertraline were described as functional inhibitors of the acid sphingomyelinase (ASM), which plays an important role during SARS-CoV-2 entry into the host cell [38, 39] . ASM is a glycoprotein that catalyzes sphingomyelin degradation to phosphorylcholine and ceramide, which is known to facilitate viral entry into the host cell [40] [41] [42] . SARS-CoV-2 activates the ASM/ceramide system, resulting in the formation of ceramide-enriched membrane domains that cluster ACE2 and thereby facilitate viral entry and infection [39, 40, 43] . Thus, inhibiting ASM represents a SARS-CoV-2 spike mutation-independent mechanism to interfere with viral entry and infection. In the context of other viral infections, our data indicate that FIASMAs are effective not only against, for example, rhinoviruses [44] or ebolaviruses [45] , but also against SARS-CoV-2. In line with prior studies, our findings suggest that fluoxetine and sertraline use in early-stage SARS-CoV-2 infections with recent variants may reduce the risk of a severe course of COVID-19 or death [46] . However, we have demonstrated the antiviral efficacy of fluoxetine and sertraline against the respective SARS-CoV-2 variants in cell culture. Nonetheless, deriving..
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